Anti-CD28x anti-PSMA antibodies
By developing anti-CD28 x anti-PSMA antibodies, using its heterodimer structure to bind CD28 and PSMA, the problem of TIL cells losing their cytotoxic ability is solved, enhancing the anti-tumor activity of the tumor site and reducing peripheral toxicity, providing a kind of use A novel immune response enhancement method for the treatment of PSMA-related cancers.
Patent Information
- Application Number
- CN202380035019.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-02-23
- Filing Date
- 2023-02-22
- Publication Date
- 2024-12-10
AI Technical Summary
The problem that existing antibody therapy methods lose cytotoxicity on TIL cells upregulated by inhibitory immune checkpoints makes it difficult to effectively activate T cells to attack tumor cells when treating prostate cancer, and monospecific full-length antibodies cannot distinguish between tumors and peripherals. Autoantigenic reaction.
Develop an anti-CD28 x anti-PSMA antibody, using a heterodimer structure in the 1+1Fab-scFv-Fc format, enhances anti-tumor activity in the tumor site and minimizes peripheral toxicity by binding to other antibodies such as Anti-CD3 x anti-PSMA antibody is used.
The antibody can selectively activate T cells at the tumor site, enhance anti-tumor activity while reducing toxicity to peripheral tissues, providing a novel immune response enhancement composition for the treatment of PSMA-related cancers.
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Figure CN119110809A_ABST
Abstract
Description
[0001] Priority declaration
[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 313,233, filed on February 23, 2022, the contents of which are hereby incorporated by reference in their entirety.
[0003] Sequence Listing
[0004] This application contains a sequence listing, which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy was created on February 22, 2023, is named 067461-5297-WO_SL.xml and is 1,295,846 bytes in size. Background Art
[0005] Prostate cancer (PC) is one of the most common cancers in men, and there are no curative treatment options for late-stage (castration-resistant prostate cancer). Prostate-specific membrane antigen (PSMA), a type II transmembrane protein with a large extracellular domain, has long generated attention as a therapeutic target. PSMA is highly overexpressed in PC compared to normal tissues, and its expression has been shown to be associated with malignancy. Previous attempts to target PSMA include antibody-based radiotherapy and antibody-drug conjugates, which have shown some success but can be hampered by the inherent toxicity of the modality.
[0006] Antibody-based therapeutics have been successfully used to treat a variety of diseases, including cancer. One increasingly common approach being explored is to engineer a single immunoglobulin molecule to co-bind two different antigens. Such alternative antibody formats that bind two different antigens are often referred to as bispecific antibodies. One particular approach for bispecific antibodies is to engineer a first binding domain that binds CD3 and a second binding domain that binds an antigen associated with or upregulated on cancer cells (e.g., PSMA) so that the bispecific antibody binds CD3. + T cells are redirected to destroy cancer cells.
[0007] However, due to the upregulation of inhibitory immune checkpoints, TILs lose their cytotoxic capacity over time. Although checkpoint blockade has been shown to increase clinical response rates relative to other treatment options, many patients still have difficulty achieving a response to checkpoint blockade. Engagement of co-stimulatory receptors on TILs can provide positive signals that can overcome the negative signals of immune checkpoints. Preclinical and clinical studies of agonistic co-stimulatory receptor antibodies have indeed shown that agonism of co-stimulatory receptors can result in dramatic anti-tumor responses that activate T cells to attack tumor cells.
[0008] It is also important for cancer therapy to enhance anti-tumor activity by specifically destroying tumor cells while minimizing peripheral toxicity. In this case, it is critical to provide co-stimulatory signals to T cells only in the presence of target tumor cells. However, agonism of co-stimulatory receptors by monospecific full-length antibodies may not be able to distinguish TILs vs. peripheral T cells vs. autoantigen-reactive T cells that contribute to autoimmune toxicity. Therefore, there remains a need for novel immune response enhancing compositions for the treatment of cancer, including PSMA-associated cancers. Summary of the invention
[0009] Provided herein are novel anti-CD28 x anti-PSMA antibodies and methods of using such antibodies for treating PSMA-related cancers. The subject anti-CD28 x anti-PSMA antibodies are capable of agonistic binding to CD28 co-stimulatory molecules on T cells and PSMA on tumor cells. Therefore, such antibodies selectively enhance anti-tumor activity at the tumor site while minimizing peripheral toxicity. The subject antibodies provided herein are particularly useful in combination with other anti-cancer therapies (e.g., anti-CD3 x anti-PSMA antibodies) for treating prostate cancer.
[0010] In the first aspect, the present invention provides heterodimeric anti-CD28 x anti-PSMA antibodies in a 1+1 Fab-scFv-Fc format. These antibodies include: a) a first monomer; b) a second monomer; and c) a light chain. The first monomer includes: i) a single-chain variable fragment (scFv); and ii) a first Fc domain, wherein the scFv is covalently linked to the N-terminus of the first Fc domain using a domain linker. The second monomer includes VH1-CH1-hinge-CH2-CH3 from the N-terminus to the C-terminus, wherein VH1 is the first variable heavy domain and CH2-CH3 is the second Fc domain. The light chain includes VL1-CL from the N-terminus to the C-terminus, wherein VL1 is the first variable light domain and CL is a constant light domain. The scFv includes a second VH domain (VH2), an scFv linker, and a second variable light domain (VL2). VH1 and VL1 together form a first antigen binding domain (ABD) and VH2 and VL2 together form a second ABD. Furthermore, one of the first ABD and the second ABD binds CD28 and the other of the first ABD and the second ABD binds prostate specific membrane antigen (PSMA).
[0011] In some embodiments, the first ABD binds human CD28 and the second ABD binds PSMA. In certain embodiments, the first ABD binds PSMA and the second ABD binds human CD28.
[0012] In some embodiments, the scFv comprises VH2-scFv linker-VL2 from N-terminus to C-terminus. In certain embodiments, the scFv comprises VL2-scFv linker-VH2 from N-terminus to C-terminus.
[0013] In some embodiments, the first ABD binds to human PSMA, and VH1 and VL1 are selected from the following:
[0014] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 210; or
[0015] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; or
[0016] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 226; or
[0017] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 234; or
[0018] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 242; or
[0019] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 250; or
[0020] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 258; or
[0021] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 266; or
[0022] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 274; or
[0023] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 282; or
[0024] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 290; or
[0025] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 298; or
[0026] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 306; or
[0027] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 314; or
[0028] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 322; or
[0029] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 330; or
[0030] (i) VH1, which comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1, which comprises vlCDR1, vlCDR2 and vlCDR3, and the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 338.
[0031] In some embodiments, VH1 and VL1 are selected from the following:
[0032] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 207; vhCDR2 having an amino acid sequence of SEQ ID NO: 208; and vhCDR3 having an amino acid sequence of SEQ ID NO: 209; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 211, vlCDR2 having an amino acid sequence of SEQ ID NO: 212, and vlCDR3 having an amino acid sequence of SEQ ID NO: 213; or
[0033] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221;
[0034] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 223; vhCDR2 having an amino acid sequence of SEQ ID NO: 224; and vhCDR3 having an amino acid sequence of SEQ ID NO: 225; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 227, vlCDR2 having an amino acid sequence of SEQ ID NO: 228, and vlCDR3 having an amino acid sequence of SEQ ID NO: 229; or
[0035] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 231; vhCDR2 having an amino acid sequence of SEQ ID NO: 232; and vhCDR3 having an amino acid sequence of SEQ ID NO: 233; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 235, vlCDR2 having an amino acid sequence of SEQ ID NO: 236, and vlCDR3 having an amino acid sequence of SEQ ID NO: 237; or
[0036] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 239; vhCDR2 having an amino acid sequence of SEQ ID NO: 240; and vhCDR3 having an amino acid sequence of SEQ ID NO: 241; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 243, vlCDR2 having an amino acid sequence of SEQ ID NO: 244, and vlCDR3 having an amino acid sequence of SEQ ID NO: 245; or
[0037] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 247; vhCDR2 having an amino acid sequence of SEQ ID NO: 248; and vhCDR3 having an amino acid sequence of SEQ ID NO: 249; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 251, vlCDR2 having an amino acid sequence of SEQ ID NO: 252, and vlCDR3 having an amino acid sequence of SEQ ID NO: 253; or
[0038] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 255; vhCDR2 having an amino acid sequence of SEQ ID NO: 256; and vhCDR3 having an amino acid sequence of SEQ ID NO: 257; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 259, vlCDR2 having an amino acid sequence of SEQ ID NO: 260, and vlCDR3 having an amino acid sequence of SEQ ID NO: 261; or
[0039] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 263; vhCDR2 having an amino acid sequence of SEQ ID NO: 264; and vhCDR3 having an amino acid sequence of SEQ ID NO: 265; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 267, vlCDR2 having an amino acid sequence of SEQ ID NO: 268, and vlCDR3 having an amino acid sequence of SEQ ID NO: 269; or
[0040] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 271; vhCDR2 having an amino acid sequence of SEQ ID NO: 212; and vhCDR3 having an amino acid sequence of SEQ ID NO: 273; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 275, vlCDR2 having an amino acid sequence of SEQ ID NO: 276, and vlCDR3 having an amino acid sequence of SEQ ID NO: 277; or
[0041] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 279; vhCDR2 having an amino acid sequence of SEQ ID NO: 280; and vhCDR3 having an amino acid sequence of SEQ ID NO: 281; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 283, vlCDR2 having an amino acid sequence of SEQ ID NO: 284, and vlCDR3 having an amino acid sequence of SEQ ID NO: 285; or
[0042] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 287; vhCDR2 having an amino acid sequence of SEQ ID NO: 288; and vhCDR3 having an amino acid sequence of SEQ ID NO: 289; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 291, vlCDR2 having an amino acid sequence of SEQ ID NO: 292, and vlCDR3 having an amino acid sequence of SEQ ID NO: 293; or
[0043] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 295; vhCDR2 having an amino acid sequence of SEQ ID NO: 296; and vhCDR3 having an amino acid sequence of SEQ ID NO: 297; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 299, vlCDR2 having an amino acid sequence of SEQ ID NO: 300, and vlCDR3 having an amino acid sequence of SEQ ID NO: 301; or
[0044] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 303; vhCDR2 having an amino acid sequence of SEQ ID NO: 304; and vhCDR3 having an amino acid sequence of SEQ ID NO: 305; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 307, vlCDR2 having an amino acid sequence of SEQ ID NO: 308, and vlCDR3 having an amino acid sequence of SEQ ID NO: 309; or
[0045] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 311; vhCDR2 having an amino acid sequence of SEQ ID NO: 312; and vhCDR3 having an amino acid sequence of SEQ ID NO: 313; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 315, vlCDR2 having an amino acid sequence of SEQ ID NO: 316, and vlCDR3 having an amino acid sequence of SEQ ID NO: 317; or
[0046] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 319; vhCDR2 having an amino acid sequence of SEQ ID NO: 320; and vhCDR3 having an amino acid sequence of SEQ ID NO: 321; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 323, vlCDR2 having an amino acid sequence of SEQ ID NO: 324, and vlCDR3 having an amino acid sequence of SEQ ID NO: 325; or
[0047] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 327; vhCDR2 having an amino acid sequence of SEQ ID NO: 328; and vhCDR3 having an amino acid sequence of SEQ ID NO: 329; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 331, vlCDR2 having an amino acid sequence of SEQ ID NO: 332, and vlCDR3 having an amino acid sequence of SEQ ID NO: 333; or
[0048] (i) VH1, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 335; vhCDR2 having an amino acid sequence of SEQ ID NO: 336; and vhCDR3 having an amino acid sequence of SEQ ID NO: 337; and (ii) VL1, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 339, vlCDR2 having an amino acid sequence of SEQ ID NO: 340, and vlCDR3 having an amino acid sequence of SEQ ID NO: 341.
[0049] In an exemplary embodiment, VH1 and VL1 are selected from the following:
[0050] (i) VH1 having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 210; or
[0051] (i) VH1 having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 218; or
[0052] (i) a VH1 having the amino acid sequence of SEQ ID NO: 222; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 226; or
[0053] (i) VH1 having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 234; or
[0054] (i) VH1 having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 242; or
[0055] (i) a VH1 having the amino acid sequence of SEQ ID NO: 246; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 250; or
[0056] (i) a VH1 having the amino acid sequence of SEQ ID NO: 254; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 258; or
[0057] (i) VH1 having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 266; or
[0058] (i) VH1 having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 274; or
[0059] (i) VH1 having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 282; or
[0060] (i) VH1 having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 290; or
[0061] (i) VH1 having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 298; or
[0062] (i) a VH1 having the amino acid sequence of SEQ ID NO: 302; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 306; or
[0063] (i) VH1 having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 314; or
[0064] (i) VH1 having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 322; or
[0065] (i) VH1 having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 330; or
[0066] (i) VH1 having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 338.
[0067] In some embodiments, the second ABD binds to human CD28, and VH2 and VL2 are selected from the following:
[0068] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 13; or
[0069] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 35; or
[0070] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 43; or
[0071] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 51; or
[0072] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 59; or
[0073] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 67; or
[0074] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 90; or
[0075] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 98; or
[0076] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 106; or
[0077] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 114; or
[0078] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 122; or
[0079] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 130; or
[0080] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 138; or
[0081] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 146; or
[0082] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 154; or
[0083] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 162; or
[0084] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 170; or
[0085] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 178; or
[0086] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 186; or
[0087] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 194; or
[0088] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 202; or
[0089] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 384; or
[0090] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 392; or
[0091] (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 396; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 400; or
[0092] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 408; or
[0093] (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 412; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 416; or
[0094] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 420; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, and the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 424.
[0095] In certain embodiments, VH2 and VL2 are selected from the following:
[0096] (i) VH2, which comprises: vhCDR1 having the amino acid sequence of SEQ ID NO: 10; vhCDR2 having the amino acid sequence of SEQ ID NO: 11; and vhCDR3 having the amino acid sequence of SEQ ID NO: 12; and (ii) VL2, which comprises: vlCDR1 having the amino acid sequence of SEQ ID NO: 14, vlCDR2 having the amino acid sequence of SEQ ID NO: 15, and vlCDR3 having the amino acid sequence of SEQ ID NO: 16; or
[0097] (i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 32; vhCDR2 having an amino acid sequence of SEQ ID NO: 33; and vhCDR3 having an amino acid sequence of SEQ ID NO: 34; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 36, vlCDR2 having an amino acid sequence of SEQ ID NO: 37, and vlCDR3 having an amino acid sequence of SEQ ID NO: 38; or
[0098] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO:40; vhCDR2 having an amino acid sequence of SEQ ID NO:41; and vhCDR3 having an amino acid sequence of SEQ ID NO:42; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO:44, vlCDR2 having an amino acid sequence of SEQ ID NO:45, and vlCDR3 having an amino acid sequence of SEQ ID NO:46; or
[0099] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 48; vhCDR2 having an amino acid sequence of SEQ ID NO: 49; and vhCDR3 having an amino acid sequence of SEQ ID NO: 50; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 52, vlCDR2 having an amino acid sequence of SEQ ID NO: 53, and vlCDR3 having an amino acid sequence of SEQ ID NO: 54; or
[0100] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 56; vhCDR2 having an amino acid sequence of SEQ ID NO: 57; and vhCDR3 having an amino acid sequence of SEQ ID NO: 58; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 60, vlCDR2 having an amino acid sequence of SEQ ID NO: 61, and vlCDR3 having an amino acid sequence of SEQ ID NO: 62; or
[0101] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 64; vhCDR2 having an amino acid sequence of SEQ ID NO: 65; and vhCDR3 having an amino acid sequence of SEQ ID NO: 66; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 68, vlCDR2 having an amino acid sequence of SEQ ID NO: 69, and vlCDR3 having an amino acid sequence of SEQ ID NO: 70; or
[0102] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 87; vhCDR2 having an amino acid sequence of SEQ ID NO: 88; and vhCDR3 having an amino acid sequence of SEQ ID NO: 89; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 91, vlCDR2 having an amino acid sequence of SEQ ID NO: 92, and vlCDR3 having an amino acid sequence of SEQ ID NO: 93; or
[0103] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 95; vhCDR2 having an amino acid sequence of SEQ ID NO: 96; and vhCDR3 having an amino acid sequence of SEQ ID NO: 97; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 99, vlCDR2 having an amino acid sequence of SEQ ID NO: 100, and vlCDR3 having an amino acid sequence of SEQ ID NO: 101; or
[0104] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 103; vhCDR2 having an amino acid sequence of SEQ ID NO: 104; and vhCDR3 having an amino acid sequence of SEQ ID NO: 105; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 107, vlCDR2 having an amino acid sequence of SEQ ID NO: 108, and vlCDR3 having an amino acid sequence of SEQ ID NO: 109; or
[0105] i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 111; vhCDR2 having an amino acid sequence of SEQ ID NO: 112; and vhCDR3 having an amino acid sequence of SEQ ID NO: 113; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 115, vlCDR2 having an amino acid sequence of SEQ ID NO: 116, and vlCDR3 having an amino acid sequence of SEQ ID NO: 117; or
[0106] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 119; vhCDR2 having an amino acid sequence of SEQ ID NO: 120; and vhCDR3 having an amino acid sequence of SEQ ID NO: 121; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 123, vlCDR2 having an amino acid sequence of SEQ ID NO: 124, and vlCDR3 having an amino acid sequence of SEQ ID NO: 125; or
[0107] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 127; vhCDR2 having an amino acid sequence of SEQ ID NO: 128; and vhCDR3 having an amino acid sequence of SEQ ID NO: 129; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 131, vlCDR2 having an amino acid sequence of SEQ ID NO: 132, and vlCDR3 having an amino acid sequence of SEQ ID NO: 133; or
[0108] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 135; vhCDR2 having an amino acid sequence of SEQ ID NO: 136; and vhCDR3 having an amino acid sequence of SEQ ID NO: 137; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 139, vlCDR2 having an amino acid sequence of SEQ ID NO: 140, and vlCDR3 having an amino acid sequence of SEQ ID NO: 141; or
[0109] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 143; vhCDR2 having an amino acid sequence of SEQ ID NO: 144; and vhCDR3 having an amino acid sequence of SEQ ID NO: 115; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 147, vlCDR2 having an amino acid sequence of SEQ ID NO: 149, and vlCDR3 having an amino acid sequence of SEQ ID NO: 149; or
[0110] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 151; vhCDR2 having an amino acid sequence of SEQ ID NO: 152; and vhCDR3 having an amino acid sequence of SEQ ID NO: 153; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 155, vlCDR2 having an amino acid sequence of SEQ ID NO: 156, and vlCDR3 having an amino acid sequence of SEQ ID NO: 157; or
[0111] i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 159; vhCDR2 having an amino acid sequence of SEQ ID NO: 160; and vhCDR3 having an amino acid sequence of SEQ ID NO: 161; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 163, vlCDR2 having an amino acid sequence of SEQ ID NO: 164, and vlCDR3 having an amino acid sequence of SEQ ID NO: 165; or
[0112] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 167; vhCDR2 having an amino acid sequence of SEQ ID NO: 168; and vhCDR3 having an amino acid sequence of SEQ ID NO: 169; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 171, vlCDR2 having an amino acid sequence of SEQ ID NO: 172, and vlCDR3 having an amino acid sequence of SEQ ID NO: 173; or
[0113] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 175; vhCDR2 having an amino acid sequence of SEQ ID NO: 176; and vhCDR3 having an amino acid sequence of SEQ ID NO: 177; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 179, vlCDR2 having an amino acid sequence of SEQ ID NO: 180, and vlCDR3 having an amino acid sequence of SEQ ID NO: 181; or
[0114] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 183; vhCDR2 having an amino acid sequence of SEQ ID NO: 184; and vhCDR3 having an amino acid sequence of SEQ ID NO: 185; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 187, vlCDR2 having an amino acid sequence of SEQ ID NO: 188, and vlCDR3 having an amino acid sequence of SEQ ID NO: 189; or
[0115] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 191; vhCDR2 having an amino acid sequence of SEQ ID NO: 192; and vhCDR3 having an amino acid sequence of SEQ ID NO: 193; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 195, vlCDR2 having an amino acid sequence of SEQ ID NO: 196, and vlCDR3 having an amino acid sequence of SEQ ID NO: 197; or
[0116] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 199; vhCDR2 having an amino acid sequence of SEQ ID NO: 200; and vhCDR3 having an amino acid sequence of SEQ ID NO: 201; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 203, vlCDR2 having an amino acid sequence of SEQ ID NO: 204, and vlCDR3 having an amino acid sequence of SEQ ID NO: 205; or
[0117] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 381; vhCDR2 having an amino acid sequence of SEQ ID NO: 382; and vhCDR3 having an amino acid sequence of SEQ ID NO: 383; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 385, vlCDR2 having an amino acid sequence of SEQ ID NO: 386, and vlCDR3 having an amino acid sequence of SEQ ID NO: 387; or
[0118] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 389; vhCDR2 having an amino acid sequence of SEQ ID NO: 390; and vhCDR3 having an amino acid sequence of SEQ ID NO: 391; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 393, vlCDR2 having an amino acid sequence of SEQ ID NO: 394, and vlCDR3 having an amino acid sequence of SEQ ID NO: 395; or
[0119] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 397; vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 401, vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and vlCDR3 having an amino acid sequence of SEQ ID NO: 403; or
[0120] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 405; vhCDR2 having an amino acid sequence of SEQ ID NO: 406; and vhCDR3 having an amino acid sequence of SEQ ID NO: 407; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 409, vlCDR2 having an amino acid sequence of SEQ ID NO: 410, and vlCDR3 having an amino acid sequence of SEQ ID NO: 411; or
[0121] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 413; vhCDR2 having an amino acid sequence of SEQ ID NO: 414; and vhCDR3 having an amino acid sequence of SEQ ID NO: 415; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 417, vlCDR2 having an amino acid sequence of SEQ ID NO: 418, and vlCDR3 having an amino acid sequence of SEQ ID NO: 419; or
[0122] i) VH2, which comprises: vhCDR1 having the amino acid sequence of SEQ ID NO:421; vhCDR2 having the amino acid sequence of SEQ ID NO:422; and vhCDR3 having the amino acid sequence of SEQ ID NO:423; and (ii) VL2, which comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:425, vlCDR2 having the amino acid sequence of SEQ ID NO:426, and vlCDR3 having the amino acid sequence of SEQ ID NO:427.
[0123] In an exemplary embodiment, VH2 and VL2 are selected from the following:
[0124] (i) VH2 having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 13; or
[0125] (i) VH2 having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 35; or
[0126] (i) VH2 having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 43; or
[0127] (i) VH2 having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 51; or
[0128] (i) a VH2 having the amino acid sequence of SEQ ID NO: 55; and (ii) a VL2 having the amino acid sequence of SEQ ID NO: 59; or
[0129] (i) VH2 having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 67; or
[0130] (i) VH2 having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 90; or
[0131] (i) VH2 having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 98; or
[0132] (i) VH2 having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 106; or
[0133] (i) VH2 having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 114; or
[0134] (i) VH2 having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 122; or
[0135] (i) VH2 having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 130; or
[0136] (i) VH2 having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 138; or
[0137] (i) a VH2 having the amino acid sequence of SEQ ID NO: 142; and (ii) a VL2 having the amino acid sequence of SEQ ID NO: 146; or
[0138] (i) VH2 having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 154; or
[0139] (i) VH2 having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 162; or
[0140] (i) VH2 having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 170; or
[0141] (i) VH2 having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 178; or
[0142] (i) VH2 having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 186; or
[0143] (i) VH2 having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 194; or
[0144] (i) VH2 having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 202; or
[0145] (i) VH2 having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 384; or
[0146] (i) VH2 having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 392; or
[0147] (i) VH2 having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 400; or
[0148] (i) VH2 having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 408; or
[0149] (i) VH2 having the amino acid sequence of SEQ ID NO: 412; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 416; or
[0150] (i) VH2 having the amino acid sequence of SEQ ID NO:420; and (ii) VL2 having the amino acid sequence of SEQ ID NO:424.
[0151] In some embodiments, VH1 comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vlCDR1, vhCDR2 and vhCDR3 of VL having the amino acid sequence of SEQ ID NO: 219. NO:39; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:43.
[0152] In an exemplary embodiment, VH1 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 215; a vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 217; VL1 comprises: a vlCDR1 having an amino acid sequence of SEQ ID NO: 219, a vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 221, VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and VL2 comprises: a vlCDR1 having an amino acid sequence of SEQ ID NO: 44, a vlCDR2 having an amino acid sequence of SEQ ID NO: 45, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 46.
[0153] In some embodiments, the first Fc domain and the second Fc domain are each variant Fc domains. In an exemplary embodiment, one of the first Fc domain and the second Fc domain comprises heterodimerization variant T366W, and the other of the first Fc domain and the second Fc domain comprises heterodimerization variant T366S / L368A / Y407V, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain comprises heterodimerization variant T366W, and the second Fc domain comprises heterodimerization variant T366S / L368A / Y407V.
[0154] In certain embodiments, the first Fc domain and the second Fc domain each comprise one or more ablation variants. In some embodiments, the one or more ablation variants comprise L234A / L235A / D265S, wherein numbering is according to EU numbering.
[0155] In some embodiments, the first Fc domain or the second Fc domain comprises the purification variant H435R / Y436F, wherein numbering is according to EU numbering.
[0156] In an exemplary embodiment, the second Fc domain comprises the purification variant H435R / Y436F.
[0157] In an exemplary embodiment, the first Fc domain comprises amino acid substitutions L234A / L235A / D265S / LT366W, and the second Fc domain comprises amino acid substitutions L234A / L235A / D265S / T366S / L368A / Y407V / H435R / Y436F, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain and the second Fc domain each further comprise amino acid substitutions M252Y / S254T / T256E, wherein numbering is according to EU numbering.
[0158] In some embodiments, the first Fc domain and the second Fc domain comprise a set of heterodimerization skew variants selected from the following heterodimerization variants: S364K / E357Q:L368D / K370S; S364K:L368D / K370S; S364K:L368E / K370S; D401K:T411E / K360E / Q362E; and T366W:T366S / L368A / Y407V, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain and the second Fc domain comprise a heterodimerization skew variant S364K / E357Q:L368D / K370S, wherein numbering is according to EU numbering.
[0159] In certain embodiments, the first Fc domain and the second Fc domain each comprise one or more ablation variants. In an exemplary embodiment, the one or more ablation variants comprise E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.
[0160] In some embodiments, one of the first monomer or the second monomer further comprises a pi variant. In some embodiments, the CH1-hinge-CH2-CH3 of the second monomer comprises a pi variant N208D / Q295E / N384D / Q418E / N421D, wherein numbering is according to EU numbering.
[0161] In some embodiments, the CH1-hinge-CH2-CH3 of the second monomer comprises amino acid variants E233P / L234V / L235A / G236del / S267K / L368D / K370S / N208D / Q295E / N384D / Q418E / N421D, and the first Fc domain comprises amino acid variants E233P / L234V / L235A / G236del / S267K / S364K / E357Q, wherein numbering is according to EU numbering. In an exemplary embodiment, the first variant Fc domain and the second variant Fc domain each further comprise amino acid variants 428L / 434S.
[0162] In some embodiments of the anti-CD28 x anti-PSMA antibody, the scFv linker is selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GGSEGKSSGSGS ESKSTGGS (SEQ ID NO: 456), and GGGSGGSGGCPPCGGSGG (SEQ ID NO: 457).
[0163] In a second aspect, the present invention provides a 2+1 Fab 2 -Heterodimeric anti-CD28 x anti-PSMA antibodies in scFv-Fc format. These antibodies comprise: a) a first monomer; b) a second monomer; and c) a light chain. The first monomer comprises VH1-CH1-first domain linker-scFv-second domain linker-CH2-CH3 from N-terminus to C-terminus, wherein VH1 is the first variable heavy domain, and CH2-CH3 is the first Fc domain. The second monomer comprises VH1-CH1-hinge-CH2-CH3 from N-terminus to C-terminus, wherein CH2-CH3 is the second Fc domain. The light chain comprises VL1-CL from N-terminus to C-terminus, wherein VL1 is the first variable light domain and CL is the constant light domain. The scFv comprises a second VH domain (VH2), an scFv linker, and a second variable light domain (VL2). Each of VH1 and VL1 together form a first antigen binding domain (ABD), and VH2 and VL2 form a second ABD. Furthermore, one of the first ABD and the second ABD binds to human CD28 and the other of the first ABD and the second ABD binds to PSMA.
[0164] In some embodiments, the first ABD binds human CD28 and the second ABD binds PSMA. In certain embodiments, the first ABD binds PSMA and the second ABD binds human CD28.
[0165] In some embodiments, the scFv comprises VH2-scFv linker-VL2 from N-terminus to C-terminus. In certain embodiments, the scFv comprises VL2-scFv linker-VH2 from N-terminus to C-terminus.
[0166] In some embodiments, the first ABD binds to human PSMA, and VH1 and VL1 are selected from the following:
[0167] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 210; or
[0168] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; or
[0169] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 226; or
[0170] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 234; or
[0171] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 242; or
[0172] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 250; or
[0173] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 258; or
[0174] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 266; or
[0175] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 274; or
[0176] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 282; or
[0177] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 290; or
[0178] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 298; or
[0179] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 306; or
[0180] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 314; or
[0181] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 322; or
[0182] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 330; or
[0183] (i) VH1, which comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1, which comprises vlCDR1, vlCDR2 and vlCDR3, and the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 338.
[0184] In some embodiments, VH1 and VL1 are selected from the following:
[0185] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 207; vhCDR2 having an amino acid sequence of SEQ ID NO: 208; and vhCDR3 having an amino acid sequence of SEQ ID NO: 209; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 211, vlCDR2 having an amino acid sequence of SEQ ID NO: 212, and vlCDR3 having an amino acid sequence of SEQ ID NO: 213; or
[0186] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221;
[0187] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 223; vhCDR2 having an amino acid sequence of SEQ ID NO: 224; and vhCDR3 having an amino acid sequence of SEQ ID NO: 225; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 227, vlCDR2 having an amino acid sequence of SEQ ID NO: 228, and vlCDR3 having an amino acid sequence of SEQ ID NO: 229; or
[0188] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 231; vhCDR2 having an amino acid sequence of SEQ ID NO: 232; and vhCDR3 having an amino acid sequence of SEQ ID NO: 233; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 235, vlCDR2 having an amino acid sequence of SEQ ID NO: 236, and vlCDR3 having an amino acid sequence of SEQ ID NO: 237; or
[0189] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 239; vhCDR2 having an amino acid sequence of SEQ ID NO: 240; and vhCDR3 having an amino acid sequence of SEQ ID NO: 241; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 243, vlCDR2 having an amino acid sequence of SEQ ID NO: 244, and vlCDR3 having an amino acid sequence of SEQ ID NO: 245; or
[0190] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 247; vhCDR2 having an amino acid sequence of SEQ ID NO: 248; and vhCDR3 having an amino acid sequence of SEQ ID NO: 249; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 251, vlCDR2 having an amino acid sequence of SEQ ID NO: 252, and vlCDR3 having an amino acid sequence of SEQ ID NO: 253; or
[0191] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 255; vhCDR2 having an amino acid sequence of SEQ ID NO: 256; and vhCDR3 having an amino acid sequence of SEQ ID NO: 257; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 259, vlCDR2 having an amino acid sequence of SEQ ID NO: 260, and vlCDR3 having an amino acid sequence of SEQ ID NO: 261; or
[0192] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 263; vhCDR2 having an amino acid sequence of SEQ ID NO: 264; and vhCDR3 having an amino acid sequence of SEQ ID NO: 265; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 267, vlCDR2 having an amino acid sequence of SEQ ID NO: 268, and vlCDR3 having an amino acid sequence of SEQ ID NO: 269; or
[0193] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 271; vhCDR2 having an amino acid sequence of SEQ ID NO: 212; and vhCDR3 having an amino acid sequence of SEQ ID NO: 273; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 275, vlCDR2 having an amino acid sequence of SEQ ID NO: 276, and vlCDR3 having an amino acid sequence of SEQ ID NO: 277; or
[0194] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 279; vhCDR2 having an amino acid sequence of SEQ ID NO: 280; and vhCDR3 having an amino acid sequence of SEQ ID NO: 281; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 283, vlCDR2 having an amino acid sequence of SEQ ID NO: 284, and vlCDR3 having an amino acid sequence of SEQ ID NO: 285; or
[0195] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 287; vhCDR2 having an amino acid sequence of SEQ ID NO: 288; and vhCDR3 having an amino acid sequence of SEQ ID NO: 289; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 291, vlCDR2 having an amino acid sequence of SEQ ID NO: 292, and vlCDR3 having an amino acid sequence of SEQ ID NO: 293; or
[0196] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 295; vhCDR2 having an amino acid sequence of SEQ ID NO: 296; and vhCDR3 having an amino acid sequence of SEQ ID NO: 297; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 299, vlCDR2 having an amino acid sequence of SEQ ID NO: 300, and vlCDR3 having an amino acid sequence of SEQ ID NO: 301; or
[0197] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 303; vhCDR2 having an amino acid sequence of SEQ ID NO: 304; and vhCDR3 having an amino acid sequence of SEQ ID NO: 305; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 307, vlCDR2 having an amino acid sequence of SEQ ID NO: 308, and vlCDR3 having an amino acid sequence of SEQ ID NO: 309; or
[0198] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 311; vhCDR2 having an amino acid sequence of SEQ ID NO: 312; and vhCDR3 having an amino acid sequence of SEQ ID NO: 313; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 315, vlCDR2 having an amino acid sequence of SEQ ID NO: 316, and vlCDR3 having an amino acid sequence of SEQ ID NO: 317; or
[0199] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 319; vhCDR2 having an amino acid sequence of SEQ ID NO: 320; and vhCDR3 having an amino acid sequence of SEQ ID NO: 321; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 323, vlCDR2 having an amino acid sequence of SEQ ID NO: 324, and vlCDR3 having an amino acid sequence of SEQ ID NO: 325; or
[0200] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 327; vhCDR2 having an amino acid sequence of SEQ ID NO: 328; and vhCDR3 having an amino acid sequence of SEQ ID NO: 329; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 331, vlCDR2 having an amino acid sequence of SEQ ID NO: 332, and vlCDR3 having an amino acid sequence of SEQ ID NO: 333; or
[0201] (i) VH1, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 335; vhCDR2 having an amino acid sequence of SEQ ID NO: 336; and vhCDR3 having an amino acid sequence of SEQ ID NO: 337; and (ii) VL1, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 339, vlCDR2 having an amino acid sequence of SEQ ID NO: 340, and vlCDR3 having an amino acid sequence of SEQ ID NO: 341.
[0202] In an exemplary embodiment, VH1 and VL1 are selected from the following:
[0203] (i) VH1 having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 210; or
[0204] (i) VH1 having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 218; or
[0205] (i) a VH1 having the amino acid sequence of SEQ ID NO: 222; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 226; or
[0206] (i) VH1 having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 234; or
[0207] (i) a VH1 having an amino acid sequence of SEQ ID NO: 238; and (ii) a VL1 having an amino acid sequence of SEQ ID NO: 242; or
[0208] (i) a VH1 having the amino acid sequence of SEQ ID NO: 246; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 250; or
[0209] (i) a VH1 having the amino acid sequence of SEQ ID NO: 254; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 258; or
[0210] (i) VH1 having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 266; or
[0211] (i) VH1 having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 274; or
[0212] (i) VH1 having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 282; or
[0213] (i) VH1 having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 290; or
[0214] (i) VH1 having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 298; or
[0215] (i) a VH1 having the amino acid sequence of SEQ ID NO: 302; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 306; or
[0216] (i) VH1 having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 314; or
[0217] (i) VH1 having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 322; or
[0218] (i) VH1 having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 330; or
[0219] (i) VH1 having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 338.
[0220] In some embodiments, the second ABD binds to human CD28, and VH2 and VL2 are selected from the following:
[0221] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 13; or
[0222] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 35; or
[0223] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 43; or
[0224] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 51; or
[0225] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 59; or
[0226] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 67; or
[0227] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 90; or
[0228] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 98; or
[0229] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 106; or
[0230] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 114; or
[0231] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 122; or
[0232] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 130; or
[0233] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 138; or
[0234] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 146; or
[0235] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 154; or
[0236] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 162; or
[0237] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 170; or
[0238] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 178; or
[0239] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 186; or
[0240] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 194; or
[0241] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 202; or
[0242] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 384; or
[0243] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 392; or
[0244] (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 396; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 400; or
[0245] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 408; or
[0246] (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 412; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 416; or
[0247] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 420; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, and the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 424.
[0248] In certain embodiments, VH2 and VL2 are selected from the following:
[0249] (i) VH2, which comprises: vhCDR1 having the amino acid sequence of SEQ ID NO: 10; vhCDR2 having the amino acid sequence of SEQ ID NO: 11; and vhCDR3 having the amino acid sequence of SEQ ID NO: 12; and (ii) VL2, which comprises: vlCDR1 having the amino acid sequence of SEQ ID NO: 14, vlCDR2 having the amino acid sequence of SEQ ID NO: 15, and vlCDR3 having the amino acid sequence of SEQ ID NO: 16; or
[0250] (i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 32; vhCDR2 having an amino acid sequence of SEQ ID NO: 33; and vhCDR3 having an amino acid sequence of SEQ ID NO: 34; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 36, vlCDR2 having an amino acid sequence of SEQ ID NO: 37, and vlCDR3 having an amino acid sequence of SEQ ID NO: 38; or
[0251] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO:40; vhCDR2 having an amino acid sequence of SEQ ID NO:41; and vhCDR3 having an amino acid sequence of SEQ ID NO:42; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO:44, vlCDR2 having an amino acid sequence of SEQ ID NO:45, and vlCDR3 having an amino acid sequence of SEQ ID NO:46; or
[0252] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 48; vhCDR2 having an amino acid sequence of SEQ ID NO: 49; and vhCDR3 having an amino acid sequence of SEQ ID NO: 50; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 52, vlCDR2 having an amino acid sequence of SEQ ID NO: 53, and vlCDR3 having an amino acid sequence of SEQ ID NO: 54; or
[0253] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 56; vhCDR2 having an amino acid sequence of SEQ ID NO: 57; and vhCDR3 having an amino acid sequence of SEQ ID NO: 58; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 60, vlCDR2 having an amino acid sequence of SEQ ID NO: 61, and vlCDR3 having an amino acid sequence of SEQ ID NO: 62; or
[0254] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 64; vhCDR2 having an amino acid sequence of SEQ ID NO: 65; and vhCDR3 having an amino acid sequence of SEQ ID NO: 66; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 68, vlCDR2 having an amino acid sequence of SEQ ID NO: 69, and vlCDR3 having an amino acid sequence of SEQ ID NO: 70; or
[0255] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 87; vhCDR2 having an amino acid sequence of SEQ ID NO: 88; and vhCDR3 having an amino acid sequence of SEQ ID NO: 89; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 91, vlCDR2 having an amino acid sequence of SEQ ID NO: 92, and vlCDR3 having an amino acid sequence of SEQ ID NO: 93; or
[0256] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 95; vhCDR2 having an amino acid sequence of SEQ ID NO: 96; and vhCDR3 having an amino acid sequence of SEQ ID NO: 97; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 99, vlCDR2 having an amino acid sequence of SEQ ID NO: 100, and vlCDR3 having an amino acid sequence of SEQ ID NO: 101; or
[0257] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 103; vhCDR2 having an amino acid sequence of SEQ ID NO: 104; and vhCDR3 having an amino acid sequence of SEQ ID NO: 105; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 107, vlCDR2 having an amino acid sequence of SEQ ID NO: 108, and vlCDR3 having an amino acid sequence of SEQ ID NO: 109; or
[0258] i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 111; vhCDR2 having an amino acid sequence of SEQ ID NO: 112; and vhCDR3 having an amino acid sequence of SEQ ID NO: 113; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 115, vlCDR2 having an amino acid sequence of SEQ ID NO: 116, and vlCDR3 having an amino acid sequence of SEQ ID NO: 117; or
[0259] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 119; vhCDR2 having an amino acid sequence of SEQ ID NO: 120; and vhCDR3 having an amino acid sequence of SEQ ID NO: 121; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 123, vlCDR2 having an amino acid sequence of SEQ ID NO: 124, and vlCDR3 having an amino acid sequence of SEQ ID NO: 125; or
[0260] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 127; vhCDR2 having an amino acid sequence of SEQ ID NO: 128; and vhCDR3 having an amino acid sequence of SEQ ID NO: 129; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 131, vlCDR2 having an amino acid sequence of SEQ ID NO: 132, and vlCDR3 having an amino acid sequence of SEQ ID NO: 133; or
[0261] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 135; vhCDR2 having an amino acid sequence of SEQ ID NO: 136; and vhCDR3 having an amino acid sequence of SEQ ID NO: 137; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 139, vlCDR2 having an amino acid sequence of SEQ ID NO: 140, and vlCDR3 having an amino acid sequence of SEQ ID NO: 141; or
[0262] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 143; vhCDR2 having an amino acid sequence of SEQ ID NO: 144; and vhCDR3 having an amino acid sequence of SEQ ID NO: 115; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 147, vlCDR2 having an amino acid sequence of SEQ ID NO: 149, and vlCDR3 having an amino acid sequence of SEQ ID NO: 149; or
[0263] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 151; vhCDR2 having an amino acid sequence of SEQ ID NO: 152; and vhCDR3 having an amino acid sequence of SEQ ID NO: 153; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 155, vlCDR2 having an amino acid sequence of SEQ ID NO: 156, and vlCDR3 having an amino acid sequence of SEQ ID NO: 157; or
[0264] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 159; vhCDR2 having an amino acid sequence of SEQ ID NO: 160; and vhCDR3 having an amino acid sequence of SEQ ID NO: 161; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 163, vlCDR2 having an amino acid sequence of SEQ ID NO: 164, and vlCDR3 having an amino acid sequence of SEQ ID NO: 165; or
[0265] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 167; vhCDR2 having an amino acid sequence of SEQ ID NO: 168; and vhCDR3 having an amino acid sequence of SEQ ID NO: 169; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 171, vlCDR2 having an amino acid sequence of SEQ ID NO: 172, and vlCDR3 having an amino acid sequence of SEQ ID NO: 173; or
[0266] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 175; vhCDR2 having an amino acid sequence of SEQ ID NO: 176; and vhCDR3 having an amino acid sequence of SEQ ID NO: 177; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 179, vlCDR2 having an amino acid sequence of SEQ ID NO: 180, and vlCDR3 having an amino acid sequence of SEQ ID NO: 181; or
[0267] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 183; vhCDR2 having an amino acid sequence of SEQ ID NO: 184; and vhCDR3 having an amino acid sequence of SEQ ID NO: 185; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 187, vlCDR2 having an amino acid sequence of SEQ ID NO: 188, and vlCDR3 having an amino acid sequence of SEQ ID NO: 189; or
[0268] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 191; vhCDR2 having an amino acid sequence of SEQ ID NO: 192; and vhCDR3 having an amino acid sequence of SEQ ID NO: 193; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 195, vlCDR2 having an amino acid sequence of SEQ ID NO: 196, and vlCDR3 having an amino acid sequence of SEQ ID NO: 197; or
[0269] i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 199; vhCDR2 having an amino acid sequence of SEQ ID NO: 200; and vhCDR3 having an amino acid sequence of SEQ ID NO: 201; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 203, vlCDR2 having an amino acid sequence of SEQ ID NO: 204, and vlCDR3 having an amino acid sequence of SEQ ID NO: 205; or
[0270] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 381; vhCDR2 having an amino acid sequence of SEQ ID NO: 382; and vhCDR3 having an amino acid sequence of SEQ ID NO: 383; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 385, vlCDR2 having an amino acid sequence of SEQ ID NO: 386, and vlCDR3 having an amino acid sequence of SEQ ID NO: 387; or
[0271] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 389; vhCDR2 having an amino acid sequence of SEQ ID NO: 390; and vhCDR3 having an amino acid sequence of SEQ ID NO: 391; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 393, vlCDR2 having an amino acid sequence of SEQ ID NO: 394, and vlCDR3 having an amino acid sequence of SEQ ID NO: 395; or
[0272] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 397; vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 401, vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and vlCDR3 having an amino acid sequence of SEQ ID NO: 403; or
[0273] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 405; vhCDR2 having an amino acid sequence of SEQ ID NO: 406; and vhCDR3 having an amino acid sequence of SEQ ID NO: 407; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 409, vlCDR2 having an amino acid sequence of SEQ ID NO: 410, and vlCDR3 having an amino acid sequence of SEQ ID NO: 411; or
[0274] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 413; vhCDR2 having an amino acid sequence of SEQ ID NO: 414; and vhCDR3 having an amino acid sequence of SEQ ID NO: 415; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 417, vlCDR2 having an amino acid sequence of SEQ ID NO: 418, and vlCDR3 having an amino acid sequence of SEQ ID NO: 419; or
[0275] i) VH2, which comprises: vhCDR1 having the amino acid sequence of SEQ ID NO:421; vhCDR2 having the amino acid sequence of SEQ ID NO:422; and vhCDR3 having the amino acid sequence of SEQ ID NO:423; and (ii) VL2, which comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:425, vlCDR2 having the amino acid sequence of SEQ ID NO:426, and vlCDR3 having the amino acid sequence of SEQ ID NO:427.
[0276] In an exemplary embodiment, VH2 and VL2 are selected from the following:
[0277] (i) VH2 having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 13; or
[0278] (i) VH2 having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 35; or
[0279] (i) VH2 having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 43; or
[0280] (i) VH2 having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 51; or
[0281] (i) a VH2 having the amino acid sequence of SEQ ID NO: 55; and (ii) a VL2 having the amino acid sequence of SEQ ID NO: 59; or
[0282] (i) VH2 having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 67; or
[0283] (i) VH2 having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 90; or
[0284] (i) VH2 having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 98; or
[0285] (i) VH2 having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 106; or
[0286] (i) VH2 having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 114; or
[0287] (i) VH2 having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 122; or
[0288] (i) VH2 having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 130; or
[0289] (i) VH2 having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 138; or
[0290] (i) a VH2 having the amino acid sequence of SEQ ID NO: 142; and (ii) a VL2 having the amino acid sequence of SEQ ID NO: 146; or
[0291] (i) VH2 having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 154; or
[0292] (i) VH2 having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 162; or
[0293] (i) VH2 having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 170; or
[0294] (i) VH2 having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 178; or
[0295] (i) VH2 having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 186; or
[0296] (i) VH2 having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 194; or
[0297] (i) VH2 having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 202; or
[0298] (i) VH2 having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 384; or
[0299] (i) VH2 having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 392; or
[0300] (i) VH2 having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 400; or
[0301] (i) VH2 having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 408; or
[0302] (i) VH2 having the amino acid sequence of SEQ ID NO: 412; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 416; or
[0303] (i) VH2 having the amino acid sequence of SEQ ID NO:420; and (ii) VL2 having the amino acid sequence of SEQ ID NO:424.
[0304] In some embodiments, VH1 comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vlCDR1, vhCDR2 and vhCDR3 of VL having the amino acid sequence of SEQ ID NO: 219. NO:39; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:43.
[0305] In an exemplary embodiment, VH1 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 215; a vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 217; VL1 comprises: a vlCDR1 having an amino acid sequence of SEQ ID NO: 219, a vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 221, VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and VL2 comprises: a vlCDR1 having an amino acid sequence of SEQ ID NO: 44, a vlCDR2 having an amino acid sequence of SEQ ID NO: 45, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 46.
[0306] In some embodiments, the first Fc domain and the second Fc domain are each variant Fc domains. In an exemplary embodiment, one of the first Fc domain and the second Fc domain comprises heterodimerization variant T366W, and the other of the first Fc domain and the second Fc domain comprises heterodimerization variant T366S / L368A / Y407V, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain comprises heterodimerization variant T366W, and the second Fc domain comprises heterodimerization variant T366S / L368A / Y407V.
[0307] In certain embodiments, the first Fc domain and the second Fc domain each comprise one or more ablation variants. In some embodiments, the one or more ablation variants comprise L234A / L235A / D265S, wherein numbering is according to EU numbering.
[0308] In some embodiments, the first Fc domain or the second Fc domain comprises the purification variant H435R / Y436F, wherein numbering is according to EU numbering.
[0309] In an exemplary embodiment, the second Fc domain comprises the purification variant H435R / Y436F.
[0310] In an exemplary embodiment, the first Fc domain comprises amino acid substitutions L234A / L235A / D265S / LT366W, and the second Fc domain comprises amino acid substitutions L234A / L235A / D265S / T366S / L368A / Y407V / H435R / Y436F, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain and the second Fc domain each further comprise amino acid substitutions M252Y / S254T / T256E, wherein numbering is according to EU numbering.
[0311] In some embodiments, the first Fc domain and the second Fc domain comprise a set of heterodimerization skew variants selected from the following heterodimerization variants: S364K / E357Q:L368D / K370S; S364K:L368D / K370S; S364K:L368E / K370S; D401K:T411E / K360E / Q362E; and T366W:T366S / L368A / Y407V, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain and the second Fc domain comprise a heterodimerization skew variant S364K / E357Q:L368D / K370S, wherein numbering is according to EU numbering.
[0312] In certain embodiments, the first Fc domain and the second Fc domain each comprise one or more ablation variants. In an exemplary embodiment, the one or more ablation variants comprise E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.
[0313] In some embodiments, one of the first monomer or the second monomer further comprises a pi variant. In some embodiments, the CH1-hinge-CH2-CH3 of the second monomer comprises a pi variant N208D / Q295E / N384D / Q418E / N421D, wherein numbering is according to EU numbering.
[0314] In some embodiments, the CH1-hinge-CH2-CH3 of the second monomer comprises amino acid variants E233P / L234V / L235A / G236del / S267K / L368D / K370S / N208D / Q295E / N384D / Q418E / N421D, and the first Fc domain comprises amino acid variants E233P / L234V / L235A / G236del / S267K / S364K / E357Q, wherein numbering is according to EU numbering. In an exemplary embodiment, the first variant Fc domain and the second variant Fc domain each further comprise amino acid variants 428L / 434S.
[0315] In some embodiments of the anti-CD28 x anti-PSMA antibody, the scFv linker is selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GGSEGKSSGSGS ESKSTGGS (SEQ ID NO: 456), and GGGSGGSGGCPPCGGSGG (SEQ ID NO: 457).
[0316] On the other hand, provided herein are heterodimeric anti-CD28x anti-PSMA antibodies in a 2+1 mAb-scFv format. These antibodies comprise: a) a first monomer; b) a second monomer; and c) a light chain. The first monomer comprises VH1-CH1-hinge-CH2-CH3-domain linker-scFv from N-terminus to C-terminus, wherein VH1 is a first variable heavy domain, and CH2-CH3 is a first Fc domain. The second monomer comprises VH1-CH1-hinge-CH2-CH3 from N-terminus to C-terminus, wherein VH1 is a first variable heavy domain and CH2-CH3 is a second Fc domain. The light chain comprises VL1-CL from N-terminus to C-terminus, wherein VL1 is a first variable light domain and CL is a constant light domain. The scFv comprises a second VH domain (VH2), an scFv linker, and a second variable light domain (VL2). Each of VH1 and VL1 together form a first antigen binding domain (ABD), and VH2 and VL2 form a second ABD. Furthermore, one of the first ABD and the second ABD binds to human CD28 and the other of the first ABD and the second ABD binds to PSMA.
[0317] In some embodiments, the first ABD binds human CD28 and the second ABD binds PSMA. In certain embodiments, the first ABD binds PSMA and the second ABD binds human CD28.
[0318] In some embodiments, the scFv comprises VH2-scFv linker-VL2 from N-terminus to C-terminus. In certain embodiments, the scFv comprises VL2-scFv linker-VH2 from N-terminus to C-terminus.
[0319] In some embodiments, the first ABD binds to human PSMA, and VH1 and VL1 are selected from the following:
[0320] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 210; or
[0321] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; or
[0322] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 226; or
[0323] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 234; or
[0324] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 242; or
[0325] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 250; or
[0326] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 258; or
[0327] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 266; or
[0328] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 274; or
[0329] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 282; or
[0330] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 290; or
[0331] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 298; or
[0332] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 306; or
[0333] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 314; or
[0334] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 322; or
[0335] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 330; or
[0336] (i) VH1, which comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1, which comprises vlCDR1, vlCDR2 and vlCDR3, and the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 338.
[0337] In some embodiments, VH1 and VL1 are selected from the following:
[0338] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 207; vhCDR2 having an amino acid sequence of SEQ ID NO: 208; and vhCDR3 having an amino acid sequence of SEQ ID NO: 209; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 211, vlCDR2 having an amino acid sequence of SEQ ID NO: 212, and vlCDR3 having an amino acid sequence of SEQ ID NO: 213; or
[0339] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221;
[0340] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 223; vhCDR2 having an amino acid sequence of SEQ ID NO: 224; and vhCDR3 having an amino acid sequence of SEQ ID NO: 225; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 227, vlCDR2 having an amino acid sequence of SEQ ID NO: 228, and vlCDR3 having an amino acid sequence of SEQ ID NO: 229; or
[0341] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 231; vhCDR2 having an amino acid sequence of SEQ ID NO: 232; and vhCDR3 having an amino acid sequence of SEQ ID NO: 233; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 235, vlCDR2 having an amino acid sequence of SEQ ID NO: 236, and vlCDR3 having an amino acid sequence of SEQ ID NO: 237; or
[0342] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 239; vhCDR2 having an amino acid sequence of SEQ ID NO: 240; and vhCDR3 having an amino acid sequence of SEQ ID NO: 241; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 243, vlCDR2 having an amino acid sequence of SEQ ID NO: 244, and vlCDR3 having an amino acid sequence of SEQ ID NO: 245; or
[0343] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 247; vhCDR2 having an amino acid sequence of SEQ ID NO: 248; and vhCDR3 having an amino acid sequence of SEQ ID NO: 249; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 251, vlCDR2 having an amino acid sequence of SEQ ID NO: 252, and vlCDR3 having an amino acid sequence of SEQ ID NO: 253; or
[0344] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 255; vhCDR2 having an amino acid sequence of SEQ ID NO: 256; and vhCDR3 having an amino acid sequence of SEQ ID NO: 257; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 259, vlCDR2 having an amino acid sequence of SEQ ID NO: 260, and vlCDR3 having an amino acid sequence of SEQ ID NO: 261; or
[0345] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 263; vhCDR2 having an amino acid sequence of SEQ ID NO: 264; and vhCDR3 having an amino acid sequence of SEQ ID NO: 265; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 267, vlCDR2 having an amino acid sequence of SEQ ID NO: 268, and vlCDR3 having an amino acid sequence of SEQ ID NO: 269; or
[0346] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 271; vhCDR2 having an amino acid sequence of SEQ ID NO: 212; and vhCDR3 having an amino acid sequence of SEQ ID NO: 273; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 275, vlCDR2 having an amino acid sequence of SEQ ID NO: 276, and vlCDR3 having an amino acid sequence of SEQ ID NO: 277; or
[0347] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 279; vhCDR2 having an amino acid sequence of SEQ ID NO: 280; and vhCDR3 having an amino acid sequence of SEQ ID NO: 281; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 283, vlCDR2 having an amino acid sequence of SEQ ID NO: 284, and vlCDR3 having an amino acid sequence of SEQ ID NO: 285; or
[0348] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 287; vhCDR2 having an amino acid sequence of SEQ ID NO: 288; and vhCDR3 having an amino acid sequence of SEQ ID NO: 289; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 291, vlCDR2 having an amino acid sequence of SEQ ID NO: 292, and vlCDR3 having an amino acid sequence of SEQ ID NO: 293; or
[0349] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 295; vhCDR2 having an amino acid sequence of SEQ ID NO: 296; and vhCDR3 having an amino acid sequence of SEQ ID NO: 297; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 299, vlCDR2 having an amino acid sequence of SEQ ID NO: 300, and vlCDR3 having an amino acid sequence of SEQ ID NO: 301; or
[0350] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 303; vhCDR2 having an amino acid sequence of SEQ ID NO: 304; and vhCDR3 having an amino acid sequence of SEQ ID NO: 305; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 307, vlCDR2 having an amino acid sequence of SEQ ID NO: 308, and vlCDR3 having an amino acid sequence of SEQ ID NO: 309; or
[0351] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 311; vhCDR2 having an amino acid sequence of SEQ ID NO: 312; and vhCDR3 having an amino acid sequence of SEQ ID NO: 313; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 315, vlCDR2 having an amino acid sequence of SEQ ID NO: 316, and vlCDR3 having an amino acid sequence of SEQ ID NO: 317; or
[0352] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 319; vhCDR2 having an amino acid sequence of SEQ ID NO: 320; and vhCDR3 having an amino acid sequence of SEQ ID NO: 321; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 323, vlCDR2 having an amino acid sequence of SEQ ID NO: 324, and vlCDR3 having an amino acid sequence of SEQ ID NO: 325; or
[0353] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 327; vhCDR2 having an amino acid sequence of SEQ ID NO: 328; and vhCDR3 having an amino acid sequence of SEQ ID NO: 329; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 331, vlCDR2 having an amino acid sequence of SEQ ID NO: 332, and vlCDR3 having an amino acid sequence of SEQ ID NO: 333; or
[0354] (i) VH1, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 335; vhCDR2 having an amino acid sequence of SEQ ID NO: 336; and vhCDR3 having an amino acid sequence of SEQ ID NO: 337; and (ii) VL1, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 339, vlCDR2 having an amino acid sequence of SEQ ID NO: 340, and vlCDR3 having an amino acid sequence of SEQ ID NO: 341.
[0355] In an exemplary embodiment, VH1 and VL1 are selected from the following:
[0356] (i) VH1 having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 210; or
[0357] (i) VH1 having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 218; or
[0358] (i) a VH1 having the amino acid sequence of SEQ ID NO: 222; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 226; or
[0359] (i) VH1 having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 234; or
[0360] (i) VH1 having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 242; or
[0361] (i) a VH1 having the amino acid sequence of SEQ ID NO: 246; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 250; or
[0362] (i) a VH1 having the amino acid sequence of SEQ ID NO: 254; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 258; or
[0363] (i) VH1 having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 266; or
[0364] (i) VH1 having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 274; or
[0365] (i) VH1 having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 282; or
[0366] (i) VH1 having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 290; or
[0367] (i) VH1 having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 298; or
[0368] (i) a VH1 having the amino acid sequence of SEQ ID NO: 302; and (ii) a VL1 having the amino acid sequence of SEQ ID NO: 306; or
[0369] (i) VH1 having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 314; or
[0370] (i) VH1 having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 322; or
[0371] (i) VH1 having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 330; or
[0372] (i) VH1 having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 338.
[0373] In some embodiments, the second ABD binds to human CD28, and VH2 and VL2 are selected from the following:
[0374] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 13; or
[0375] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 35; or
[0376] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 43; or
[0377] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 51; or
[0378] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 59; or
[0379] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 67; or
[0380] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 90; or
[0381] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 98; or
[0382] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 106; or
[0383] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 114; or
[0384] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 122; or
[0385] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 130; or
[0386] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 138; or
[0387] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 146; or
[0388] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 154; or
[0389] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 162; or
[0390] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 170; or
[0391] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 178; or
[0392] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 186; or
[0393] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 194; or
[0394] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 202; or
[0395] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 384; or
[0396] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 392; or
[0397] (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 396; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 400; or
[0398] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 408; or
[0399] (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 412; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 416; or
[0400] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 420; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, and the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 424.
[0401] In certain embodiments, VH2 and VL2 are selected from the following:
[0402] (i) VH2, which comprises: vhCDR1 having the amino acid sequence of SEQ ID NO: 10; vhCDR2 having the amino acid sequence of SEQ ID NO: 11; and vhCDR3 having the amino acid sequence of SEQ ID NO: 12; and (ii) VL2, which comprises: vlCDR1 having the amino acid sequence of SEQ ID NO: 14, vlCDR2 having the amino acid sequence of SEQ ID NO: 15, and vlCDR3 having the amino acid sequence of SEQ ID NO: 16; or
[0403] (i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 32; vhCDR2 having an amino acid sequence of SEQ ID NO: 33; and vhCDR3 having an amino acid sequence of SEQ ID NO: 34; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 36, vlCDR2 having an amino acid sequence of SEQ ID NO: 37, and vlCDR3 having an amino acid sequence of SEQ ID NO: 38; or
[0404] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO:40; vhCDR2 having an amino acid sequence of SEQ ID NO:41; and vhCDR3 having an amino acid sequence of SEQ ID NO:42; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO:44, vlCDR2 having an amino acid sequence of SEQ ID NO:45, and vlCDR3 having an amino acid sequence of SEQ ID NO:46; or
[0405] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 48; vhCDR2 having an amino acid sequence of SEQ ID NO: 49; and vhCDR3 having an amino acid sequence of SEQ ID NO: 50; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 52, vlCDR2 having an amino acid sequence of SEQ ID NO: 53, and vlCDR3 having an amino acid sequence of SEQ ID NO: 54; or
[0406] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 56; vhCDR2 having an amino acid sequence of SEQ ID NO: 57; and vhCDR3 having an amino acid sequence of SEQ ID NO: 58; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 60, vlCDR2 having an amino acid sequence of SEQ ID NO: 61, and vlCDR3 having an amino acid sequence of SEQ ID NO: 62; or
[0407] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 64; vhCDR2 having an amino acid sequence of SEQ ID NO: 65; and vhCDR3 having an amino acid sequence of SEQ ID NO: 66; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 68, vlCDR2 having an amino acid sequence of SEQ ID NO: 69, and vlCDR3 having an amino acid sequence of SEQ ID NO: 70; or
[0408] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 87; vhCDR2 having an amino acid sequence of SEQ ID NO: 88; and vhCDR3 having an amino acid sequence of SEQ ID NO: 89; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 91, vlCDR2 having an amino acid sequence of SEQ ID NO: 92, and vlCDR3 having an amino acid sequence of SEQ ID NO: 93; or
[0409] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 95; vhCDR2 having an amino acid sequence of SEQ ID NO: 96; and vhCDR3 having an amino acid sequence of SEQ ID NO: 97; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 99, vlCDR2 having an amino acid sequence of SEQ ID NO: 100, and vlCDR3 having an amino acid sequence of SEQ ID NO: 101; or
[0410] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 103; vhCDR2 having an amino acid sequence of SEQ ID NO: 104; and vhCDR3 having an amino acid sequence of SEQ ID NO: 105; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 107, vlCDR2 having an amino acid sequence of SEQ ID NO: 108, and vlCDR3 having an amino acid sequence of SEQ ID NO: 109; or
[0411] i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 111; vhCDR2 having an amino acid sequence of SEQ ID NO: 112; and vhCDR3 having an amino acid sequence of SEQ ID NO: 113; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 115, vlCDR2 having an amino acid sequence of SEQ ID NO: 116, and vlCDR3 having an amino acid sequence of SEQ ID NO: 117; or
[0412] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 119; vhCDR2 having an amino acid sequence of SEQ ID NO: 120; and vhCDR3 having an amino acid sequence of SEQ ID NO: 121; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 123, vlCDR2 having an amino acid sequence of SEQ ID NO: 124, and vlCDR3 having an amino acid sequence of SEQ ID NO: 125; or
[0413] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 127; vhCDR2 having an amino acid sequence of SEQ ID NO: 128; and vhCDR3 having an amino acid sequence of SEQ ID NO: 129; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 131, vlCDR2 having an amino acid sequence of SEQ ID NO: 132, and vlCDR3 having an amino acid sequence of SEQ ID NO: 133; or
[0414] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 135; vhCDR2 having an amino acid sequence of SEQ ID NO: 136; and vhCDR3 having an amino acid sequence of SEQ ID NO: 137; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 139, vlCDR2 having an amino acid sequence of SEQ ID NO: 140, and vlCDR3 having an amino acid sequence of SEQ ID NO: 141; or
[0415] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 143; vhCDR2 having an amino acid sequence of SEQ ID NO: 144; and vhCDR3 having an amino acid sequence of SEQ ID NO: 115; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 147, vlCDR2 having an amino acid sequence of SEQ ID NO: 149, and vlCDR3 having an amino acid sequence of SEQ ID NO: 149; or
[0416] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 151; vhCDR2 having an amino acid sequence of SEQ ID NO: 152; and vhCDR3 having an amino acid sequence of SEQ ID NO: 153; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 155, vlCDR2 having an amino acid sequence of SEQ ID NO: 156, and vlCDR3 having an amino acid sequence of SEQ ID NO: 157; or
[0417] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 159; vhCDR2 having an amino acid sequence of SEQ ID NO: 160; and vhCDR3 having an amino acid sequence of SEQ ID NO: 161; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 163, vlCDR2 having an amino acid sequence of SEQ ID NO: 164, and vlCDR3 having an amino acid sequence of SEQ ID NO: 165; or
[0418] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 167; vhCDR2 having an amino acid sequence of SEQ ID NO: 168; and vhCDR3 having an amino acid sequence of SEQ ID NO: 169; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 171, vlCDR2 having an amino acid sequence of SEQ ID NO: 172, and vlCDR3 having an amino acid sequence of SEQ ID NO: 173; or
[0419] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 175; vhCDR2 having an amino acid sequence of SEQ ID NO: 176; and vhCDR3 having an amino acid sequence of SEQ ID NO: 177; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 179, vlCDR2 having an amino acid sequence of SEQ ID NO: 180, and vlCDR3 having an amino acid sequence of SEQ ID NO: 181; or
[0420] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 183; vhCDR2 having an amino acid sequence of SEQ ID NO: 184; and vhCDR3 having an amino acid sequence of SEQ ID NO: 185; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 187, vlCDR2 having an amino acid sequence of SEQ ID NO: 188, and vlCDR3 having an amino acid sequence of SEQ ID NO: 189; or
[0421] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 191; vhCDR2 having an amino acid sequence of SEQ ID NO: 192; and vhCDR3 having an amino acid sequence of SEQ ID NO: 193; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 195, vlCDR2 having an amino acid sequence of SEQ ID NO: 196, and vlCDR3 having an amino acid sequence of SEQ ID NO: 197; or
[0422] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 199; vhCDR2 having an amino acid sequence of SEQ ID NO: 200; and vhCDR3 having an amino acid sequence of SEQ ID NO: 201; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 203, vlCDR2 having an amino acid sequence of SEQ ID NO: 204, and vlCDR3 having an amino acid sequence of SEQ ID NO: 205; or
[0423] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 381; vhCDR2 having an amino acid sequence of SEQ ID NO: 382; and vhCDR3 having an amino acid sequence of SEQ ID NO: 383; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 385, vlCDR2 having an amino acid sequence of SEQ ID NO: 386, and vlCDR3 having an amino acid sequence of SEQ ID NO: 387; or
[0424] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 389; vhCDR2 having an amino acid sequence of SEQ ID NO: 390; and vhCDR3 having an amino acid sequence of SEQ ID NO: 391; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 393, vlCDR2 having an amino acid sequence of SEQ ID NO: 394, and vlCDR3 having an amino acid sequence of SEQ ID NO: 395; or
[0425] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 397; vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 401, vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and vlCDR3 having an amino acid sequence of SEQ ID NO: 403; or
[0426] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 405; vhCDR2 having an amino acid sequence of SEQ ID NO: 406; and vhCDR3 having an amino acid sequence of SEQ ID NO: 407; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 409, vlCDR2 having an amino acid sequence of SEQ ID NO: 410, and vlCDR3 having an amino acid sequence of SEQ ID NO: 411; or
[0427] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 413; vhCDR2 having an amino acid sequence of SEQ ID NO: 414; and vhCDR3 having an amino acid sequence of SEQ ID NO: 415; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 417, vlCDR2 having an amino acid sequence of SEQ ID NO: 418, and vlCDR3 having an amino acid sequence of SEQ ID NO: 419; or
[0428] i) VH2, which comprises: vhCDR1 having the amino acid sequence of SEQ ID NO:421; vhCDR2 having the amino acid sequence of SEQ ID NO:422; and vhCDR3 having the amino acid sequence of SEQ ID NO:423; and (ii) VL2, which comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:425, vlCDR2 having the amino acid sequence of SEQ ID NO:426, and vlCDR3 having the amino acid sequence of SEQ ID NO:427.
[0429] In an exemplary embodiment, VH2 and VL2 are selected from the following:
[0430] (i) VH2 having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 13; or
[0431] (i) VH2 having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 35; or
[0432] (i) VH2 having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 43; or
[0433] (i) VH2 having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 51; or
[0434] (i) a VH2 having the amino acid sequence of SEQ ID NO: 55; and (ii) a VL2 having the amino acid sequence of SEQ ID NO: 59; or
[0435] (i) VH2 having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 67; or
[0436] (i) VH2 having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 90; or
[0437] (i) a VH2 having the amino acid sequence of SEQ ID NO: 94; and (ii) a VL2 having the amino acid sequence of SEQ ID NO: 98; or
[0438] (i) VH2 having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 106; or
[0439] (i) VH2 having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 114; or
[0440] (i) VH2 having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 122; or
[0441] (i) VH2 having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 130; or
[0442] (i) VH2 having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 138; or
[0443] (i) a VH2 having the amino acid sequence of SEQ ID NO: 142; and (ii) a VL2 having the amino acid sequence of SEQ ID NO: 146; or
[0444] (i) VH2 having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 154; or
[0445] (i) VH2 having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 162; or
[0446] (i) VH2 having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 170; or
[0447] (i) VH2 having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 178; or
[0448] (i) VH2 having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 186; or
[0449] (i) VH2 having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 194; or
[0450] (i) VH2 having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 202; or
[0451] (i) VH2 having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 384; or
[0452] (i) VH2 having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 392; or
[0453] (i) VH2 having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 400; or
[0454] (i) VH2 having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 408; or
[0455] (i) VH2 having the amino acid sequence of SEQ ID NO: 412; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 416; or
[0456] (i) VH2 having the amino acid sequence of SEQ ID NO:420; and (ii) VL2 having the amino acid sequence of SEQ ID NO:424.
[0457] In some embodiments, VH1 comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vlCDR1, vhCDR2 and vhCDR3 of VL having the amino acid sequence of SEQ ID NO: 219. NO:39; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:43.
[0458] In an exemplary embodiment, VH1 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 215; a vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 217; VL1 comprises: a vlCDR1 having an amino acid sequence of SEQ ID NO: 219, a vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 221, VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and VL2 comprises: a vlCDR1 having an amino acid sequence of SEQ ID NO: 44, a vlCDR2 having an amino acid sequence of SEQ ID NO: 45, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 46.
[0459] In some embodiments, the first Fc domain and the second Fc domain are each variant Fc domains. In an exemplary embodiment, one of the first Fc domain and the second Fc domain comprises heterodimerization variant T366W, and the other of the first Fc domain and the second Fc domain comprises heterodimerization variant T366S / L368A / Y407V, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain comprises heterodimerization variant T366W, and the second Fc domain comprises heterodimerization variant T366S / L368A / Y407V.
[0460] In certain embodiments, the first Fc domain and the second Fc domain each comprise one or more ablation variants. In some embodiments, the one or more ablation variants comprise L234A / L235A / D265S, wherein numbering is according to EU numbering.
[0461] In some embodiments, the first Fc domain or the second Fc domain comprises the purification variant H435R / Y436F, wherein numbering is according to EU numbering.
[0462] In an exemplary embodiment, the second Fc domain comprises the purification variant H435R / Y436F.
[0463] In an exemplary embodiment, the first Fc domain comprises amino acid substitutions L234A / L235A / D265S / LT366W, and the second Fc domain comprises amino acid substitutions L234A / L235A / D265S / T366S / L368A / Y407V / H435R / Y436F, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain and the second Fc domain each further comprise amino acid substitutions M252Y / S254T / T256E, wherein numbering is according to EU numbering.
[0464] In some embodiments, the first Fc domain and the second Fc domain comprise a set of heterodimerization skew variants selected from the following heterodimerization variants: S364K / E357Q:L368D / K370S; S364K:L368D / K370S; S364K:L368E / K370S; D401K:T411E / K360E / Q362E; and T366W:T366S / L368A / Y407V, wherein numbering is according to EU numbering. In some embodiments, the first Fc domain and the second Fc domain comprise a heterodimerization skew variant S364K / E357Q:L368D / K370S, wherein numbering is according to EU numbering.
[0465] In certain embodiments, the first Fc domain and the second Fc domain each comprise one or more ablation variants. In an exemplary embodiment, the one or more ablation variants comprise E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.
[0466] In some embodiments, one of the first monomer or the second monomer further comprises a pi variant. In some embodiments, the CH1-hinge-CH2-CH3 of the second monomer comprises a pi variant N208D / Q295E / N384D / Q418E / N421D, wherein numbering is according to EU numbering.
[0467] In some embodiments, the CH1-hinge-CH2-CH3 of the second monomer comprises amino acid variants E233P / L234V / L235A / G236del / S267K / L368D / K370S / N208D / Q295E / N384D / Q418E / N421D, and the first Fc domain comprises amino acid variants E233P / L234V / L235A / G236del / S267K / S364K / E357Q, wherein numbering is according to EU numbering. In an exemplary embodiment, the first variant Fc domain and the second variant Fc domain each further comprise amino acid variants 428L / 434S.
[0468] In some embodiments of the anti-CD28 x anti-PSMA antibody, the scFv linker is selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GGSEGKSSGSGS ESKSTGGS (SEQ ID NO: 456), and GGGSGGSGGCPPCGGSGG (SEQ ID NO: 457).
[0469] In another aspect, provided herein is a bispecific antibody comprising a first antigen binding domain that binds to PSMA, and a second antigen binding domain that binds to CD28.
[0470] The first antigen binding domain (i.e., PSMA binding domain) comprises:
[0471] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 210; or
[0472] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; or
[0473] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 226; or
[0474] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 234; or
[0475] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 242; or
[0476] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 250; or
[0477] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 258; or
[0478] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 266; or
[0479] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 274; or
[0480] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 282; or
[0481] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 290; or
[0482] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 298; or
[0483] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 306; or
[0484] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 314; or
[0485] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 322; or
[0486] (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 330; or
[0487] (i) VH1, which comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1, which comprises vlCDR1, vlCDR2 and vlCDR3, and the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 338.
[0488] The second antigen binding domain (i.e., CD28 binding domain) comprises:
[0489] i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 9, respectively; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 13, respectively; or
[0490] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 35; or
[0491] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 43; or
[0492] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 51; or
[0493] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 59; or
[0494] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 67; or
[0495] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 90; or
[0496] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 98; or
[0497] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 106; or
[0498] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 114; or
[0499] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 122; or
[0500] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 130; or
[0501] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 138; or
[0502] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 146; or
[0503] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 154; or
[0504] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 162; or
[0505] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 170; or
[0506] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 178; or
[0507] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 186; or
[0508] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 194; or
[0509] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 202; or
[0510] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 384; or
[0511] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 392; or
[0512] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 400; or
[0513] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 408; or
[0514] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 412; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 416; or
[0515] (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 420; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, and the vlCDR1, vlCDR2 and vlCDR3 respectively have: the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 424.
[0516] In some embodiments, (i) the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 amino acid sequences are according to the Kabat numbering system; (ii) the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 amino acid sequences are according to the Chothia numbering system; (iii) the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 amino acid sequences are according to the AbM numbering system; (iv) the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 amino acid sequences are according to the AbM numbering system; R2 and vlCDR3 amino acid sequences are according to the Contact numbering system; (v) wherein the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the IMGT numbering system; (vi) wherein the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the Kabat+Chothia numbering system; and / or the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the Xencor numbering system.
[0517] In another aspect, provided herein is a bispecific antibody comprising a first antigen binding domain that binds to PSMA, and a second antigen binding domain that binds to CD28.
[0518] The first antigen binding domain (i.e., PSMA binding domain) comprises:
[0519] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 207; vhCDR2 having an amino acid sequence of SEQ ID NO: 208; and vhCDR3 having an amino acid sequence of SEQ ID NO: 209; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 211, vlCDR2 having an amino acid sequence of SEQ ID NO: 212, and vlCDR3 having an amino acid sequence of SEQ ID NO: 213; or
[0520] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221;
[0521] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 223; vhCDR2 having an amino acid sequence of SEQ ID NO: 224; and vhCDR3 having an amino acid sequence of SEQ ID NO: 225; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 227, vlCDR2 having an amino acid sequence of SEQ ID NO: 228, and vlCDR3 having an amino acid sequence of SEQ ID NO: 229; or
[0522] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 231; vhCDR2 having an amino acid sequence of SEQ ID NO: 232; and vhCDR3 having an amino acid sequence of SEQ ID NO: 233; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 235, vlCDR2 having an amino acid sequence of SEQ ID NO: 236, and vlCDR3 having an amino acid sequence of SEQ ID NO: 237; or
[0523] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 239; vhCDR2 having an amino acid sequence of SEQ ID NO: 240; and vhCDR3 having an amino acid sequence of SEQ ID NO: 241; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 243, vlCDR2 having an amino acid sequence of SEQ ID NO: 244, and vlCDR3 having an amino acid sequence of SEQ ID NO: 245; or
[0524] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 247; vhCDR2 having an amino acid sequence of SEQ ID NO: 248; and vhCDR3 having an amino acid sequence of SEQ ID NO: 249; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 251, vlCDR2 having an amino acid sequence of SEQ ID NO: 252, and vlCDR3 having an amino acid sequence of SEQ ID NO: 253; or
[0525] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 255; vhCDR2 having an amino acid sequence of SEQ ID NO: 256; and vhCDR3 having an amino acid sequence of SEQ ID NO: 257; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 259, vlCDR2 having an amino acid sequence of SEQ ID NO: 260, and vlCDR3 having an amino acid sequence of SEQ ID NO: 261; or
[0526] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 263; vhCDR2 having an amino acid sequence of SEQ ID NO: 264; and vhCDR3 having an amino acid sequence of SEQ ID NO: 265; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 267, vlCDR2 having an amino acid sequence of SEQ ID NO: 268, and vlCDR3 having an amino acid sequence of SEQ ID NO: 269; or
[0527] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 271; vhCDR2 having an amino acid sequence of SEQ ID NO: 212; and vhCDR3 having an amino acid sequence of SEQ ID NO: 273; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 275, vlCDR2 having an amino acid sequence of SEQ ID NO: 276, and vlCDR3 having an amino acid sequence of SEQ ID NO: 277; or
[0528] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 279; vhCDR2 having an amino acid sequence of SEQ ID NO: 280; and vhCDR3 having an amino acid sequence of SEQ ID NO: 281; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 283, vlCDR2 having an amino acid sequence of SEQ ID NO: 284, and vlCDR3 having an amino acid sequence of SEQ ID NO: 285; or
[0529] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 287; vhCDR2 having an amino acid sequence of SEQ ID NO: 288; and vhCDR3 having an amino acid sequence of SEQ ID NO: 289; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 291, vlCDR2 having an amino acid sequence of SEQ ID NO: 292, and vlCDR3 having an amino acid sequence of SEQ ID NO: 293; or
[0530] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 295; vhCDR2 having an amino acid sequence of SEQ ID NO: 296; and vhCDR3 having an amino acid sequence of SEQ ID NO: 297; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 299, vlCDR2 having an amino acid sequence of SEQ ID NO: 300, and vlCDR3 having an amino acid sequence of SEQ ID NO: 301; or
[0531] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 303; vhCDR2 having an amino acid sequence of SEQ ID NO: 304; and vhCDR3 having an amino acid sequence of SEQ ID NO: 305; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 307, vlCDR2 having an amino acid sequence of SEQ ID NO: 308, and vlCDR3 having an amino acid sequence of SEQ ID NO: 309; or
[0532] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 311; vhCDR2 having an amino acid sequence of SEQ ID NO: 312; and vhCDR3 having an amino acid sequence of SEQ ID NO: 313; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 315, vlCDR2 having an amino acid sequence of SEQ ID NO: 316, and vlCDR3 having an amino acid sequence of SEQ ID NO: 317; or
[0533] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 319; vhCDR2 having an amino acid sequence of SEQ ID NO: 320; and vhCDR3 having an amino acid sequence of SEQ ID NO: 321; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 323, vlCDR2 having an amino acid sequence of SEQ ID NO: 324, and vlCDR3 having an amino acid sequence of SEQ ID NO: 325; or
[0534] (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 327; vhCDR2 having an amino acid sequence of SEQ ID NO: 328; and vhCDR3 having an amino acid sequence of SEQ ID NO: 329; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 331, vlCDR2 having an amino acid sequence of SEQ ID NO: 332, and vlCDR3 having an amino acid sequence of SEQ ID NO: 333; or
[0535] (i) VH1, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 335; vhCDR2 having an amino acid sequence of SEQ ID NO: 336; and vhCDR3 having an amino acid sequence of SEQ ID NO: 337; and (ii) VL1, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 339, vlCDR2 having an amino acid sequence of SEQ ID NO: 340, and vlCDR3 having an amino acid sequence of SEQ ID NO: 341.
[0536] The second antigen binding domain (i.e., CD28 binding domain) comprises:
[0537] (i) VH2, which comprises: vhCDR1 having the amino acid sequence of SEQ ID NO: 10; vhCDR2 having the amino acid sequence of SEQ ID NO: 11; and vhCDR3 having the amino acid sequence of SEQ ID NO: 12; and (ii) VL2, which comprises: vlCDR1 having the amino acid sequence of SEQ ID NO: 14, vlCDR2 having the amino acid sequence of SEQ ID NO: 15, and vlCDR3 having the amino acid sequence of SEQ ID NO: 16; or
[0538] (i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 32; vhCDR2 having an amino acid sequence of SEQ ID NO: 33; and vhCDR3 having an amino acid sequence of SEQ ID NO: 34; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 36, vlCDR2 having an amino acid sequence of SEQ ID NO: 37, and vlCDR3 having an amino acid sequence of SEQ ID NO: 38; or
[0539] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO:40; vhCDR2 having an amino acid sequence of SEQ ID NO:41; and vhCDR3 having an amino acid sequence of SEQ ID NO:42; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO:44, vlCDR2 having an amino acid sequence of SEQ ID NO:45, and vlCDR3 having an amino acid sequence of SEQ ID NO:46; or
[0540] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 48; vhCDR2 having an amino acid sequence of SEQ ID NO: 49; and vhCDR3 having an amino acid sequence of SEQ ID NO: 50; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 52, vlCDR2 having an amino acid sequence of SEQ ID NO: 53, and vlCDR3 having an amino acid sequence of SEQ ID NO: 54; or
[0541] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 56; vhCDR2 having an amino acid sequence of SEQ ID NO: 57; and vhCDR3 having an amino acid sequence of SEQ ID NO: 58; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 60, vlCDR2 having an amino acid sequence of SEQ ID NO: 61, and vlCDR3 having an amino acid sequence of SEQ ID NO: 62; or
[0542] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 64; vhCDR2 having an amino acid sequence of SEQ ID NO: 65; and vhCDR3 having an amino acid sequence of SEQ ID NO: 66; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 68, vlCDR2 having an amino acid sequence of SEQ ID NO: 69, and vlCDR3 having an amino acid sequence of SEQ ID NO: 70; or
[0543] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 87; vhCDR2 having an amino acid sequence of SEQ ID NO: 88; and vhCDR3 having an amino acid sequence of SEQ ID NO: 89; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 91, vlCDR2 having an amino acid sequence of SEQ ID NO: 92, and vlCDR3 having an amino acid sequence of SEQ ID NO: 93; or
[0544] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 95; vhCDR2 having an amino acid sequence of SEQ ID NO: 96; and vhCDR3 having an amino acid sequence of SEQ ID NO: 97; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 99, vlCDR2 having an amino acid sequence of SEQ ID NO: 100, and vlCDR3 having an amino acid sequence of SEQ ID NO: 101; or
[0545] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 103; vhCDR2 having an amino acid sequence of SEQ ID NO: 104; and vhCDR3 having an amino acid sequence of SEQ ID NO: 105; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 107, vlCDR2 having an amino acid sequence of SEQ ID NO: 108, and vlCDR3 having an amino acid sequence of SEQ ID NO: 109; or
[0546] i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 111; vhCDR2 having an amino acid sequence of SEQ ID NO: 112; and vhCDR3 having an amino acid sequence of SEQ ID NO: 113; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 115, vlCDR2 having an amino acid sequence of SEQ ID NO: 116, and vlCDR3 having an amino acid sequence of SEQ ID NO: 117; or
[0547] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 119; vhCDR2 having an amino acid sequence of SEQ ID NO: 120; and vhCDR3 having an amino acid sequence of SEQ ID NO: 121; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 123, vlCDR2 having an amino acid sequence of SEQ ID NO: 124, and vlCDR3 having an amino acid sequence of SEQ ID NO: 125; or
[0548] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 127; vhCDR2 having an amino acid sequence of SEQ ID NO: 128; and vhCDR3 having an amino acid sequence of SEQ ID NO: 129; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 131, vlCDR2 having an amino acid sequence of SEQ ID NO: 132, and vlCDR3 having an amino acid sequence of SEQ ID NO: 133; or
[0549] i) VH2, which comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 135; vhCDR2 having an amino acid sequence of SEQ ID NO: 136; and vhCDR3 having an amino acid sequence of SEQ ID NO: 137; and (ii) VL2, which comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 139, vlCDR2 having an amino acid sequence of SEQ ID NO: 140, and vlCDR3 having an amino acid sequence of SEQ ID NO: 141; or
[0550] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 143; vhCDR2 having an amino acid sequence of SEQ ID NO: 144; and vhCDR3 having an amino acid sequence of SEQ ID NO: 115; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 147, vlCDR2 having an amino acid sequence of SEQ ID NO: 149, and vlCDR3 having an amino acid sequence of SEQ ID NO: 149; or
[0551] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 151; vhCDR2 having an amino acid sequence of SEQ ID NO: 152; and vhCDR3 having an amino acid sequence of SEQ ID NO: 153; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 155, vlCDR2 having an amino acid sequence of SEQ ID NO: 156, and vlCDR3 having an amino acid sequence of SEQ ID NO: 157; or
[0552] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 159; vhCDR2 having an amino acid sequence of SEQ ID NO: 160; and vhCDR3 having an amino acid sequence of SEQ ID NO: 161; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 163, vlCDR2 having an amino acid sequence of SEQ ID NO: 164, and vlCDR3 having an amino acid sequence of SEQ ID NO: 165; or
[0553] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 167; vhCDR2 having an amino acid sequence of SEQ ID NO: 168; and vhCDR3 having an amino acid sequence of SEQ ID NO: 169; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 171, vlCDR2 having an amino acid sequence of SEQ ID NO: 172, and vlCDR3 having an amino acid sequence of SEQ ID NO: 173; or
[0554] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 175; vhCDR2 having an amino acid sequence of SEQ ID NO: 176; and vhCDR3 having an amino acid sequence of SEQ ID NO: 177; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 179, vlCDR2 having an amino acid sequence of SEQ ID NO: 180, and vlCDR3 having an amino acid sequence of SEQ ID NO: 181; or
[0555] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 183; vhCDR2 having an amino acid sequence of SEQ ID NO: 184; and vhCDR3 having an amino acid sequence of SEQ ID NO: 185; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 187, vlCDR2 having an amino acid sequence of SEQ ID NO: 188, and vlCDR3 having an amino acid sequence of SEQ ID NO: 189; or
[0556] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 191; vhCDR2 having an amino acid sequence of SEQ ID NO: 192; and vhCDR3 having an amino acid sequence of SEQ ID NO: 193; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 195, vlCDR2 having an amino acid sequence of SEQ ID NO: 196, and vlCDR3 having an amino acid sequence of SEQ ID NO: 197; or
[0557] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 199; vhCDR2 having an amino acid sequence of SEQ ID NO: 200; and vhCDR3 having an amino acid sequence of SEQ ID NO: 201; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 203, vlCDR2 having an amino acid sequence of SEQ ID NO: 204, and vlCDR3 having an amino acid sequence of SEQ ID NO: 205; or
[0558] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 381; vhCDR2 having an amino acid sequence of SEQ ID NO: 382; and vhCDR3 having an amino acid sequence of SEQ ID NO: 383; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 385, vlCDR2 having an amino acid sequence of SEQ ID NO: 386, and vlCDR3 having an amino acid sequence of SEQ ID NO: 387; or
[0559] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 389; vhCDR2 having an amino acid sequence of SEQ ID NO: 390; and vhCDR3 having an amino acid sequence of SEQ ID NO: 391; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 393, vlCDR2 having an amino acid sequence of SEQ ID NO: 394, and vlCDR3 having an amino acid sequence of SEQ ID NO: 395; or
[0560] i) a VH comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 397; a vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) a VL comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 401, a vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 403; or
[0561] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 405; vhCDR2 having an amino acid sequence of SEQ ID NO: 406; and vhCDR3 having an amino acid sequence of SEQ ID NO: 407; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 409, vlCDR2 having an amino acid sequence of SEQ ID NO: 410, and vlCDR3 having an amino acid sequence of SEQ ID NO: 411; or
[0562] i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 413; vhCDR2 having an amino acid sequence of SEQ ID NO: 414; and vhCDR3 having an amino acid sequence of SEQ ID NO: 415; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 417, vlCDR2 having an amino acid sequence of SEQ ID NO: 418, and vlCDR3 having an amino acid sequence of SEQ ID NO: 419; or
[0563] i) VH2, which comprises: vhCDR1 having the amino acid sequence of SEQ ID NO:421; vhCDR2 having the amino acid sequence of SEQ ID NO:422; and vhCDR3 having the amino acid sequence of SEQ ID NO:423; and (ii) VL2, which comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:425, vlCDR2 having the amino acid sequence of SEQ ID NO:426, and vlCDR3 having the amino acid sequence of SEQ ID NO:427.
[0564] In another aspect, provided herein is a bispecific antibody comprising a first antigen binding domain that binds to PSMA, and a second antigen binding domain that binds to CD28.
[0565] The first antigen binding domain (i.e., PSMA binding domain) comprises:
[0566] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 206; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 210; or
[0567] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 214; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 218; or
[0568] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 222; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 226; or
[0569] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 230; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 234; or
[0570] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 238; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 242; or
[0571] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 246; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 250; or
[0572] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 254; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 258; or
[0573] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 262; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 266; or
[0574] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 270; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 274; or
[0575] (i) a VH1 having an amino acid sequence that is at least about 95% identical to SEQ ID NO: 278; and (ii) a VL1 having an amino acid sequence that is at least about 95% identical to SEQ ID NO: 282; or
[0576] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 286; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 290; or
[0577] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 294; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 298; or
[0578] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 302; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 306; or
[0579] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 310; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 314; or
[0580] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 318; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 322; or
[0581] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 326; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 330; or
[0582] (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO:334; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO:338.
[0583] The second antigen binding domain (i.e., CD28 binding domain) comprises:
[0584] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 9; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 13; or
[0585] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 31; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 35; or
[0586] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 39; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 43; or
[0587] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 47; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 51; or
[0588] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 55; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 59; or
[0589] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 63; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 67; or
[0590] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 86; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 90; or
[0591] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 94; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 98; or
[0592] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 102; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 106; or
[0593] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 110; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 114; or
[0594] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 118; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 122; or
[0595] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 126; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 130; or
[0596] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 134; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 138; or
[0597] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 142; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 146; or
[0598] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 150; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 154; or
[0599] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 158; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 162; or
[0600] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 166; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 170; or
[0601] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 174; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 178; or
[0602] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 182; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 186; or
[0603] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 190; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 194; or
[0604] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 198; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 202; or
[0605] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 380; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 384; or
[0606] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 388; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 392; or
[0607] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 396; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 400; or
[0608] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 404; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 408; or
[0609] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 412; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 416; or
[0610] (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO:420; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO:424.
[0611] In some embodiments of the bispecific antibody, the antibody is a humanized antibody. In certain embodiments, the antibody is a human antibody.
[0612] In some embodiments of the bispecific antibody, the antibody is an IgG antibody. In some embodiments, the IgG antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In an exemplary embodiment, the IgG antibody is an IgG1 antibody.
[0613] In some embodiments of the bispecific antibody, the first antigen binding domain binds to a PSMA antigen. In exemplary embodiments, the first antigen binding domain binds to a PSMA epitope. In some embodiments, the first antigen binding domain specifically binds to PSMA.
[0614] In some embodiments of the bispecific antibody, the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 of the first antigen binding domain form a binding site for an antigen of PSMA. In certain embodiments, the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 of the first antigen binding domain form a binding site for an epitope of PSMA.
[0615] In some embodiments of the bispecific antibody, the second antigen binding domain binds to the CD28 antigen. In an exemplary embodiment, the second antigen binding domain binds to a CD28 epitope. In some embodiments, the second antigen binding domain specifically binds to CD28.
[0616] In some embodiments of the bispecific antibody, the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 of the second antigen binding domain form a binding site for an antigen of CD28. In an exemplary embodiment, the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 of the second antigen binding domain form a binding site for an epitope of CD28.
[0617] In some embodiments of the bispecific antibody, PSMA is present on the surface of a cell. In certain embodiments, the cell is a prostate cell. In an exemplary embodiment, the cell is a prostate cancer cell.
[0618] In some embodiments of the bispecific antibody, the antibody comprises a first Fc domain and a second Fc domain. In an exemplary embodiment, the first Fc domain and the second Fc domain are each variant Fc domains.
[0619] In some embodiments, one of the first Fc domain and the second Fc domain comprises the heterodimerization variant T366W, and the other of the first Fc domain and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V, wherein numbering is according to EU numbering. In an exemplary embodiment, the first Fc domain comprises the heterodimerization variant T366W, and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V.
[0620] In some embodiments, the first Fc domain and the second Fc domain each comprise one or more ablation variants. In an exemplary embodiment, one or more ablation variants comprise L234A / L235A / D265S, wherein the numbering is according to EU numbering. In some embodiments, the first Fc domain or the second Fc domain comprises the purification variant H435R / Y436F, wherein the numbering is according to EU numbering. In an exemplary embodiment, the second Fc domain comprises the purification variant H435R / Y436F.
[0621] In certain embodiments, the first Fc domain comprises amino acid substitutions L234A / L235A / D265S / LT366W, and the second Fc domain comprises amino acid substitutions L234A / L235A / D265S / T366S / L368A / Y407V / H435R / Y436F, wherein numbering is according to EU numbering. In an exemplary embodiment, the first Fc domain and the second Fc domain each further comprise amino acid substitutions M252Y / S254T / T256E, wherein numbering is according to EU numbering.
[0622] In some embodiments, the first Fc domain and the second Fc domain comprise a set of heterodimerization skew variants selected from the following heterodimerization variants: S364K / E357Q:L368D / K370S; S364K:L368D / K370S; S364K:L368E / K370S; D401K:T411E / K360E / Q362E; and T366W:T366S / L368A / Y407V, wherein numbering is according to EU numbering. In an exemplary embodiment, the first Fc domain and the second Fc domain comprise the heterodimerization skew variant S364K / E357Q:L368D / K370S, wherein numbering is according to EU numbering.
[0623] In some embodiments, the first Fc domain and the second Fc domain each comprise one or more ablation variants. In some embodiments, the one or more ablation variants comprise E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.
[0624] In some embodiments of the bispecific antibody, the bispecific antibody is in a 1+1 Fab-scFv-Fc format. These antibodies comprise: a) a first monomer; b) a second monomer; and c) a light chain. The first monomer comprises: i) a single-chain variable fragment (scFv); and ii) a first Fc domain, wherein the scFv is covalently linked to the N-terminus of the first Fc domain using a domain linker. The second monomer comprises VH1-CH1-hinge-CH2-CH3 from the N-terminus to the C-terminus, wherein VH1 is the first variable heavy domain and CH2-CH3 is the second Fc domain. The light chain comprises VL1-CL from the N-terminus to the C-terminus, wherein VL1 is the first variable light domain and CL is a constant light domain. The scFv comprises a second VH domain (VH2), a scFv linker, and a second variable light domain (VL2). VH1 and VL1 together form a first antigen binding domain (ABD) and VH2 and VL2 together form a second ABD.
[0625] In some embodiments, one of the first monomer or the second monomer further comprises a pi variant. In some embodiments, the CH1-hinge-CH2-CH3 of the second monomer comprises a pi variant N208D / Q295E / N384D / Q418E / N421D, wherein numbering is according to EU numbering.
[0626] In an exemplary embodiment, the CH1-hinge-CH2-CH3 of the second monomer comprises amino acid variants E233P / L234V / L235A / G236del / S267K / L368D / K370S / N208D / Q295E / N384D / Q418E / N421D, and the first Fc domain comprises amino acid variants E233P / L234V / L235A / G236del / S267K / S364K / E357Q, wherein numbering is according to EU numbering. In an exemplary embodiment, the first variant Fc domain and the second variant Fc domain each further comprise amino acid variants 428L / 434S.
[0627] In an exemplary embodiment of a bispecific 1+1 Fab-scFv-Fc format antibody, the sc Fv linker is selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GG SEGKSSGSGSESKSTGGS (SEQ ID NO: 456) and GGGSGGSGGCPP CGGSGG (SEQ ID NO: 457).
[0628] On the other hand, provided herein is a heterodimeric antibody comprising: a) a first monomer having an amino acid sequence of SEQ ID NO:351; b) a second monomer having an amino acid sequence of SEQ ID NO:352; and c) a light chain having an amino acid sequence of SEQ ID NO:353.
[0629] On the other hand, provided herein is a heterodimeric antibody comprising: a) a first monomer having an amino acid sequence of SEQ ID NO: 342; b) a second monomer having an amino acid sequence of SEQ ID NO: 343; and c) a light chain having an amino acid sequence of SEQ ID NO: 344.
[0630] In one aspect, provided herein is a bispecific antibody comprising: a) a first antigen binding domain having: (i) a VH1 having an amino acid sequence of SEQ ID NO: 214; and (ii) a VL1 having an amino acid sequence of SEQ ID NO: 218; and b) a second antigen binding domain having: (i) a VH2 having an amino acid sequence of SEQ ID NO: 39; and (ii) a VL2 having an amino acid sequence of SEQ ID NO: 43.
[0631] In one aspect, provided herein is a bispecific antibody comprising: a) a first antigen binding domain having: (i) VH1 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 215; a vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 219, a vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 221; and b) a second antigen binding domain having: (i) VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and (ii) VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 219, a vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 221. vlCDR1 having the amino acid sequence of SEQ ID NO:44, vlCDR2 having the amino acid sequence of SEQ ID NO:45, and vlCDR3 having the amino acid sequence of SEQ ID NO:46.
[0632] On the other hand, provided herein is a bispecific antibody comprising: a) a first antigen binding domain having: (i) a VH1 having an amino acid sequence of SEQ ID NO: 214; and (ii) a VL1 having an amino acid sequence of SEQ ID NO: 218; and b) a second antigen binding domain having: (i) a VH2 having an amino acid sequence of SEQ ID NO: 396; and (ii) a VL2 having an amino acid sequence of SEQ ID NO: 400.
[0633] In one aspect, provided herein is a bispecific antibody comprising: a) a first antigen binding domain comprising: (i) VH1 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 215; a vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 219, a vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 221; and b) a second antigen binding domain comprising: (i) VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 397; a vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 219, a vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 221. vlCDR1 having the amino acid sequence of SEQ ID NO:401, vlCDR2 having the amino acid sequence of SEQ ID NO:402, and vlCDR3 having the amino acid sequence of SEQ ID NO:403.
[0634] Also provided herein are nucleic acid compositions comprising nucleic acids encoding the antibodies described herein, expression vector compositions comprising such nucleic acids, host cells comprising the expression vector compositions for producing the antibodies, and methods of producing the antibodies.
[0635] In another aspect, provided herein is a method of treating prostate cancer in a patient in need thereof, the method comprising administering to the patient an anti-CD28 x anti-PSMA antibody described herein.
[0636] In yet another aspect, provided herein is a method of treating prostate cancer in a patient in need thereof, the method comprising administering to the patient: a) an anti-CD28 x anti-PSMA as described herein; and b) an anti-CD3 x anti-PSMA, anti-CD3 x anti-B7H3, anti-CD3 x anti-hK2, or anti-CD3 x anti-TMEFF2 antibody.
[0637] In one aspect, provided herein is a method of enhancing T cell proliferation in the presence of a PSMA-expressing cell, the method comprising contacting the cell with an anti-CD28xanti-PSMA as described herein. In some embodiments, the PSMA-expressing cell is a prostate cell.
[0638] In another aspect, provided herein is a method of inhibiting the growth or proliferation of a PSMA-expressing cell, the method comprising contacting the cell with an anti-CD28 x anti-PSMA as described herein. In some embodiments, the PSMA-expressing cell is a prostate cell. BRIEF DESCRIPTION OF THE DRAWINGS
[0639] Figure 1A-1B The sequences of human, mouse, and cynomolgus macaque CD28 are depicted. These CD28s can be used to develop cross-reactive CD28 antigen binding domains for clinical development.
[0640] Figure 2A-2B The sequences of human, mouse, and cynomolgus macaque PSMA are depicted. These PSMAs can be used to develop cross-reactive PSMA antigen-binding domains for clinical development.
[0641] Figures 3A-3F Depict useful sets of paired heterodimerization variants (including skew and pi variants). Figure 3F In , there are variants that do not have a corresponding "monomer 2" variant. Such variants are pI variants that can be used alone on either monomer of a bispecific antibody (e.g., PSMA x CD28 bsAb), or included on the non-scFv side of a format that employs, for example, an scFv as a component, and an appropriately charged scFv linker can be used on the second monomer that employs an scFv as the CD28 binding domain. Suitable charged linkers are shown in Figure 6A-6B middle.
[0642] Figure 4 Describes a list of isosteric variant antibody constant regions and their corresponding substitutions. pI_(-) indicates a lower pI variant, while pI_(+) indicates a higher pI variant. These variants can be optionally and independently combined with other variants, including the heterodimerization variants outlined herein.
[0643] Figure 5 Useful ablation variants (also referred to as "knockout" or "KO" variants) that ablate FcγR binding are depicted. In some embodiments, such ablation variants are included in the Fc domains of both monomers of the subject antibodies described herein. In other embodiments, the ablation variant is included on only one variant Fc domain.
[0644] Figure 6A-6BDepict some charged scFv linkers that can be used to increase or decrease the pI of a subject heterodimeric bispecific antibody that employs one or more scFvs as described herein as components (e.g., PSMA x CD28 bsAb). (+H) positive linkers have particular use herein, particularly the anti-CD28 VL and VH sequences shown herein. A single prior art scFv linker with a single charge is referred to as "Whitlow," from Whitlow et al., Protein Engineering 6(8):989-995 (1993). It should be noted that this linker is used to reduce aggregation of scFvs and enhance the proteolytic stability of scFvs. Such charged scFv linkers can be used in any of the subject antibody formats disclosed herein, including scFvs (e.g., 1+1 Fab-scFv-Fc and 2+1 Fab2-scFv-Fc formats).
[0645] Figure 7 Describe some exemplary domain linkers. In some embodiments, these linkers are used to connect single-chain Fv to Fc chain. In some embodiments, these linkers can be combined in any orientation. For example, GGGGS (SEQ ID NO: 458) linker can be combined with the "lower half hinge" linker at the N-terminus or C-terminus.
[0646] Figure 8 Particularly useful bispecific antibody platforms are shown for the PSMA x CD28 bsAbs of the invention. Although the platforms are described herein in the context of a 1+1 Fab-scFv-Fc format, they are adaptable to other bispecific antibody formats.
[0647] Fig. 9 Various heterodimerization skew variant amino acid substitutions useful for the heterodimeric antibodies described herein are depicted.
[0648] Figures 10A-10EThe sequences of several useful heterodimeric PSMA x CD 28 bsAb backbones based on human IgG1 without cytokine sequences are shown. Heterodimeric Fc backbone 1 is based on human IgG1 (356E / 358M allotype) and includes L368D / K370S skew variant and Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, S364K / E357Q skew variant on the second heterodimeric Fc chain, and E233P / L234V / L235A / G236del / S267K ablation variant on both chains. Heterodimeric Fc backbone 2 is based on human IgG1 (356E / 358M allotype) and includes a L368D / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant on both chains. Heterodimeric Fc backbone 3 is based on human IgG1 (356E / 358M allotype) and includes a L368E / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant on both chains. Heterodimeric Fc backbone 4 is based on human IgG1 (356E / 358M allotype) and includes a K360E / Q362E / T411E skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a D401K skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant on both chains. Heterodimeric Fc backbone 5 is based on human IgG1 (356D / 358L allotype) and includes a L368D / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K / E357Q skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant on both chains.Heterodimeric Fc backbone 6 is based on human IgG1 (356E / 358M allotype) and includes a L368D / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K / E357Q skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant and a glycosylated N297A variant on both chains. The heterodimeric Fc backbone 7 is based on human IgG1 (356E / 358M allotype) and includes a L368D / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K / E357Q skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant and a glycosylated N297S variant on both chains. Heterodimeric Fc backbone 8 is based on human IgG4 and includes L368D / K370S skew variants and Q295E / N384D / Q418E / N421D pI variants on the first heterodimeric Fc chain, S364K / E357Q skew variants on the second heterodimeric Fc chain, and S228P (S241P in Kabat according to EU numbering) variants that ablate Fab arm exchange (as known in the art) on both chains. Heterodimeric Fc backbone 9 is based on human IgG2 and includes L368D / K370S skew variants and Q295E / N384D / Q418E / N421D pI variants on the first heterodimeric Fc chain, S364K / E357Q skew variants on the second heterodimeric Fc chain. The heterodimeric Fc backbone 10 is based on human IgG2 and includes a L368D / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K / E357Q skew variant on the second heterodimeric Fc chain, and a S267K ablation variant on both chains. Heterodimeric Fc backbone 11 is based on human IgG1 (356E / 358M allotype) and includes L368D / K370S skew variant and Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, S364K / E357Q skew variant on the second heterodimeric Fc chain, and E233P / L234V / L235A / G236del / S267K ablation variant and M428L / N434S Xtend variant on both chains.The heterodimeric Fc backbone 12 is based on human IgG1 (356E / 358M allotype) and includes a L368D / K370S skew variant on the first heterodimeric Fc chain, a S364K / E357Q skew variant and a P217R / P229R / N276K pI variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant on both chains. The heterodimeric Fc backbone 13 is based on human IgG1 (356E / 358M allotype) and includes a T366W skew variant on the first heterodimeric Fc chain, a T366S / L368A / Y407V skew variant and a H435R / Y436F purification variant on the second heterodimeric Fc chain, and a L234A / L235A / D265S ablation variant on both chains. The heterodimeric Fc backbone 14 is based on human IgG1 (356E / 358M allotype) and includes a T366W skew variant on the first heterodimeric Fc chain, a T366S / L368A / Y407V skew variant and an H435R / Y436F purification variant on the second heterodimeric Fc chain, and an L234A / L235A / D265S ablation variant and an M252Y / S254T / T256E half-life extension variant on both chains. The heterodimeric Fc backbone 15 is based on human IgG1 (356D / 358L allotype) and includes a L368D / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K / E357Q skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant and an M428L / N434SXtend variant on both chains. The heterodimeric Fc backbone 16 is based on human IgG1 (356E / 358M allotype) and includes a L368D / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K / E357Q skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant and an M428L / N434A Xtend variant on both chains.The heterodimeric Fc backbone 17 is based on human IgG1 (356D / 358L allotype) and includes a L368D / K370S skew variant and a Q295E / N384D / Q418E / N421D pI variant on the first heterodimeric Fc chain, a S364K / E357Q skew variant on the second heterodimeric Fc chain, and an E233P / L234V / L235A / G236del / S267K ablation variant and an M428L / N434A Xtend variant on both chains.
[0649] Included within each of these frameworks are sequences that are 90%, 95%, 98% and 99% identical (as defined herein) to the sequence, and / or sequences containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 additional amino acid substitutions (compared to the "parent" of the accompanying drawings), which, as understood by those skilled in the art, have contained some amino acid modifications compared to the parent human IgG1 (or IgG2 or IgG4, depending on the framework). That is, in addition to or as an alternative to the skew, pI and ablation variants contained within the framework of this figure, the framework may contain additional amino acid modifications (usually amino acid substitutions). In addition, the frameworks depicted herein may include C-terminal glycine (K446_) and / or lysine (K447_) deletions. C-terminal glycine and / or lysine deletions may be deliberately engineered to reduce heterogeneity or in the case of certain bispecific formats such as mAb-scFv formats. In addition, C-terminal glycine and / or lysine deletions may occur naturally during, for example, production and storage.
[0650] Fig.11 Depicts an illustrative sequence for a heterodimeric PSMA x CD28 bsAb backbone in a 2+1 mAb-scFv format. The format depicted herein is based on Figures 10A-10E The heterodimeric Fc backbone 1 depicted differs in that it also includes G446_ on monomer 1 (-) and G446_ / K447_ on monomer 2 (+). It should be noted that Figures 10A-10E Any of the additional scaffolds depicted are adaptable for use in the 2+1 mAb-scFv format, whether or not K447_ is included on one or both chains. Note that these sequences may also include the M428L / N434S variant or the M252Y / S254T / T256E half-life extension variant.
[0651] Fig.12 Depicted is the sequence of "CH1" that may be used in embodiments of PSMA x CD28 bsAbs.
[0652] Fig.13 Depicted are sequences of the "hinge" that may be used in embodiments of the PSMA x CD28 bsAb.
[0653] Fig.14 Depicted are the constant domains of the cognate light chains useful for the subject PSMA x CD28 bsAbs employing a Fab binding domain.
[0654] Fig.15 Depicted are the variable heavy and variable light chain sequences of 1A7 (an exemplary phage-derived CD28 binding domain), and the sequence of XENP28428 (an anti-CD28 mAb based on 1A7 and an IgG1 backbone with E233P / L234V / L235A / G236del / S267K ablation variant). The CDRs are underlined, and the slashes indicate the boundaries between the variable and constant domains. As mentioned herein and for each sequence containing CDRs herein, the exact identification of the CDR positions may be slightly different depending on the numbering used (as shown in Table 2), and therefore not only the underlined CDRs are included herein, but also CDRs included within the VH and VL domains using other numbering systems. In addition, with respect to all sequences in the accompanying drawings, these VH and VL sequences can be used in either scFv format or Fab format.
[0655] Fig.16 Depicted is the sequence of the affinity optimized variable heavy domain from anti-CD28 clone 1A7. It should be noted that the variable heavy domain can be paired with any of the other variable light domains depicted herein, including those depicted in Fig.17 , Figures 18A-18C and Figures 21A-21H Those in (such as 1A7_H1.1_L1.71 used in XENP37559).
[0656] Fig.17 Depicted is the sequence of the affinity optimized variable light domain from anti-CD28 clone 1A7. It should be noted that the variable light domain can be paired with any of the other variable light domains depicted herein, including those depicted in Fig.16 , those in Figures 18 and 21 (e.g., 1A7_H1.1_L1.71 used in XENP37559).
[0657] Figures 18A-18C Depict the sequence of illustrative affinity optimized 1A7 VH / VH pairs. It should be noted that these pairs can be formatted as Fab or scFv. Additionally, in the scFv format, these pairs can be formatted as VHVL orientation or VLVH orientation.
[0658] Figures 19A-19B The consensus framework regions (FRs) and complementarity determining regions (CDRs) (as in Kabat) of the anti-CD28 clone 1A7 variable heavy and variable light domain variants are depicted.
[0659] Fig. 20Depicted are illustrative affinity engineered 1A7 VH / VL pairs and their binding affinities in the context of scFv (in the context of a 1+1 Fab-scFv-Fc bsAb format).
[0660] Figures 21A-21H Depicts variable heavy and variable light chain sequences of additional CD28 binding domains that can be used for the PSMA x CD28 bsAbs of the present invention. As mentioned herein and for each sequence containing CDRs herein, the exact identifying CDR positions may differ slightly depending on the numbering used (as shown in Table 2), and therefore not only the underlined CDRs are included herein, but also CDRs included within the VH and VL domains using other numbering systems. In addition, as for all sequences in the figures, these VH and VL sequences can be used in either scFv format or Fab format.
[0661] Fig. 22 Depicted are the sequences of XENP27181, a bivalent anti-CD28 mAb based on the HuTN228 binding domain and an IgG1 backbone with E233P / L234V / L235A / G236del / S267K ablation variants; and XENP29154, an in-house generated version of TGN1412.
[0662] Fig.23 Binding of illustrative bivalent anti-CD28 mAbs based on phage-derived clones on human PBMCs is depicted. The data show that phage activity produces a CD28 binding domain with weaker maximal binding than prior art HuTN228 (which is related to the humanized CD28 binding domain described in Example 1A).
[0663] Figures 24A-24M The bispecific formats of the invention are depicted. Fig.24A A "1+1 Fab-scFv-Fc" format is depicted, having a first Fab arm that binds a first antigen and a second scFv arm that binds a second antigen. The 1+1 Fab-scFv-Fc format comprises a first monomer comprising a first heavy chain variable region (VH1) covalently linked (optionally via a linker) to the N-terminus of a first heterodimeric Fc backbone, a second monomer comprising a single chain Fv covalently linked (optionally via a linker) to the N-terminus of a second corresponding heterodimeric Fc backbone, and a third monomer comprising a light chain variable region covalently linked to a light chain constant domain, wherein the light chain variable region is complementary to VH1. Fig. 24BA "2+1 Fab2-scFv-Fc" format is depicted, having a first Fab arm and a second Fab-scFv arm, wherein the Fab binds a first antigen and the scFv binds a second antigen. The 2+1 Fab2-scFv-Fc format comprises a first monomer comprising a first heavy chain variable region (VH1) covalently linked (optionally via a linker) to the N-terminus of a first heterodimeric Fc backbone, a second monomer comprising VH1 covalently linked (optionally via a linker) to a single chain Fv, wherein the single chain Fv is covalently linked (optionally via a linker) to the N-terminus of a second corresponding heterodimeric Fc backbone, and the third monomer comprising a light chain variable region covalently linked to a light chain constant domain, wherein the light chain variable region is complementary to VH1. Fig.24C A "1+1 common light chain" or "1+1 CLC" format is depicted, having a first Fc comprising a first Fab arm that binds a first antigen and a second Fc comprising a second Fab arm that binds a second antigen. The 1+1 CLC format comprises a first monomer comprising VH1-CH1-hinge-CH2-CH3, a second monomer comprising VH2-CH1-hinge-CH2-CH3, and a third monomer comprising VL-CL. VL pairs with VH1 to form a binding domain with a first antigen binding specificity; and VL pairs with VH2 to form a binding domain with a second antigen binding specificity. Fig.24D A "2+1 common light chain" or "2+1 CLC" format is depicted, having a first Fc comprising 2 Fab arms that each bind a first antigen and a second Fc comprising 1 Fab arm that binds a second antigen. The 2+1 CLC format comprises a first monomer comprising VH1-CH1-hinge-VH1-CH1-hinge-CH2-CH3, a second monomer comprising VH2-CH1-hinge-CH2-CH3, and a third monomer comprising VL-CL. VL pairs with the first VH1 and the second VH1 to form a binding domain with a first antigen binding specificity; and VL pairs with VH2 to form a binding domain with a second antigen binding specificity. Fig.24EA "2+1 mAb-scFv" format is depicted, having a first Fc comprising an N-terminal Fab arm that binds a first antigen, and a second Fc comprising an N-terminal Fab arm that binds a first antigen and a C-terminal scFv that binds a second antigen. The 2+1 mAb-scFv format comprises a first monomer, a second monomer, and a third monomer, wherein the first monomer comprises VH1-CH1-hinge-CH2-CH3, the second monomer comprises VH1-CH1-hinge-CH2-CH3-scFv, and the third monomer comprises VL-CL. VL pairs with the first VH1 and the second VH1 to form a binding domain with binding specificity for the first antigen. Additional bispecific formats include F) dual scFv, G) single-arm scFv-mAb, H) scFv-mAb, I) bispecific mAb, J) single-arm central scFv, K) mAb-Fv, L) central Fv, and M) trident.
[0664] Figures 25A-25E Depicts the variable heavy and variable light chain sequences of exemplary PSMA binding domains that can be used for the PSMA x CD28 bsAbs of the present invention. As mentioned herein and for each sequence containing CDRs herein, the exact identifying CDR positions may differ slightly depending on the numbering used (as shown in Table 2), and therefore not only the underlined CDRs are included herein, but also CDRs included within the VH and VL domains using other numbering systems. In addition, with respect to all sequences in the figures, these VH and VL sequences can be used in either scFv format or Fab format.
[0665] Figures 26A-26B Depicts variable heavy and variable light chain sequences of additional PSMA binding domains that can be used for the PSMA x CD28 bsAbs of the present invention. As mentioned herein and for each sequence containing CDRs herein, the exact identifying CDR positions may be slightly different depending on the numbering used (as shown in Table 2), and therefore not only the underlined CDRs are included herein, but also CDRs included within the VH and VL domains using other numbering systems. In addition, as for all sequences in the figures, these VH and VL sequences can be used in either scFv format or Fab format.
[0666] Figures 27A-27BDepict A) Classical T cell / APC interactions and B) Replication of classical T cell / APC interactions by combining CD3 bispecific antibodies with CD28 bispecific antibodies. In classical T cell / APC interactions, the first signal is provided by the reaction of TCR with peptide-MHC (signal 1), and the second signal is provided by CD80 / CD86 cross-linked CD28 expressed on APC (signal 2), which together fully activate T cells. In contrast, treatment with CD3 bispecific only provides the first signal. The CD28 signal can be provided by CD28 bispecific, in order to promote activation and proliferation through CD28 co-stimulation. In some embodiments, TAA1 and TAA2 may be different antigens. In some embodiments, TAA1 and TAA2 may be the same antigen, but different epitopes. In some embodiments, TAA1 and TAA2 may be the same antigen and the same epitope.
[0667] Figures 28A-28C Depicted are the sequences of illustrative PSMA x CD3 bsAbs that can be combined with the PSMA x CD28 bsAbs of the invention.
[0668] Figure 29A-29RR Depicted are sequences of illustrative PSMA x CD28 bsAbs in a 1+1 Fab-scFv-Fc format using platform X. While these sequences employ platform X, they may use platform J or any other suitable backbone, including those depicted in Figures 10A-10E The CDRs are underlined and slashes indicate the boundaries between the variable region, Fc region, and constant domain. It should be noted that PSMA x CD28 bsAbs may employ variable region, Fc region, and constant domain sequences that are 90%, 95%, 98%, and 99% identical (as defined herein) and / or contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In addition, each of the sequences outlined herein may include or exclude the M428L / N434S variant in one or preferably both Fc domains, with the inclusion of M428L / N434S resulting in a longer serum half-life.
[0669] Figures 30A-30L Depicted are sequences of illustrative PSMA x CD28 bsAbs in a 1+1 Fab-scFv-Fc format using Platform J. While these sequences employ Platform J, they may use Platform X or any other suitable backbone, including those depicted in Figures 10A-10EThe CDRs are underlined and slashes indicate the boundaries between the variable region, Fc region, and constant domain. It should be noted that PSMA x CD28 bsAbs may employ variable region, Fc region, and constant domain sequences that are 90%, 95%, 98%, and 99% identical (as defined herein) and / or contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In addition, each of the sequences outlined herein may include or exclude the M252Y / S254T / T256E variant in one or preferably both Fc domains, with the inclusion of M252Y / S254T / T256E resulting in a longer serum half-life.
[0670] Fig.31 IFNγ release from human PBMCs treated with air-dried XENP28428 (anti-CD28 clone 1A7), TGN1412 (XENP29154), or negative control PBS is depicted.
[0671] Figures 32A-32B Depicted incubation of C42B-NLR (PSMA 高 ) cells with T cells (E:T1:1) and 1 μg / mL B7H3 x CD3 bsAb alone or in combination with 1 μg / mL prototype PSMA xCD28 bsAb XENP37902 or XENP37903, A) redirected T cell cytotoxicity (RTCC) (as shown by decreased target cell counts over time) and B) T cell proliferation (as shown by increased T cell area over time). Data are shown in PSMA 高 In the presence of WT cells, combination with PSMA x CD28 bsAb enhanced both RTCC and T cell proliferation. Notably, the low affinity CD28 binding domain in XENP37902 was sufficient to enhance activity.
[0672] Figures 33A-33B Depicted incubation of DU145 (PSMA 空 ) cells with T cells (E:T 1:1) and 1 μg / mL B7H3 x CD3 bsAb alone or in combination with the prototype 1 μg / mL PSMA x CD28 bsAb XENP37902 or XENP37903, A) RTCC (as shown by decreased target cell counts over time) and B) T cell proliferation (as shown by increased T cell area over time). Data are shown in PSMA 空 Combination with PSMA x CD28 bsAb did not enhance RTCC or T cell proliferation in the presence of WT cells.
[0673] Figures 34A-34B Depicted incubation of C42B-NLR (PSMA 高Figure 2. A) RTCC (as shown by decreased target cell counts over time) and B) T cell proliferation (as shown by increased T cell area over time) after incubation of ) cells with T cells (E:T1:1) and 1 μg / mL PSMA x CD3 bsAb alone or in combination with 1 μg / mL prototype PSMA x CD28 bsAb XENP37902 or XENP37903. It should be noted that the PSMA x CD3 and PSMA x CD28 bsAbs bind to non-competing PSMA epitopes. Data are shown in PSMA 高 In the presence of WT cells, combination with PSMA x CD28 bsAb enhanced both RTCC and T cell proliferation. Notably, the low affinity CD28 binding domain in XENP37902 was sufficient to enhance activity.
[0674] Figures 35A-35B Depicted incubation of DU145-NLR (PSMA 空 Figure 2. A) RTCC (as shown by decreased target cell counts over time) and B) T cell proliferation (as shown by increased T cell area over time) after incubation of ) cells with T cells (E:T1:1) and 1 μg / mL PSMA x CD3 bsAb alone or in combination with 1 μg / mL prototype PSMA x CD28 bsAb XENP37902 or XENP37903. It should be noted that the PSMA x CD3 and PSMA x CD28 bsAbs bind to non-competing PSMA epitopes. Data are shown in PSMA 空 Combination with PSMA x CD28 bsAb did not enhance RTCC or T cell proliferation in the presence of WT cells.
[0675] Figures 36A-36B Figure 2 depicts IL-2 secretion induced by incubation of A) XENP37902 PSMA x CD28 with 230 nM CD28 binding affinity and B) XENP37903 PSMA x CD28 with 37 nM CD28 binding affinity in combination with illustrative non-competing PSMA x CD3 bsAbs with T cells and PC3 cells transfected with various surface PSMA densities. 高 and PSMA 中 Cell lines enhanced cytokine secretion in the presence of TNFα. Notably, the low affinity CD28 binding domain in XENP37902 was sufficient to enhance activity.
[0676] Figures 37A-37BDepicted are IL-2 secretion induced by incubation of A) XENP37902 PSMA x CD28 with 230 nM CD28 binding affinity and B) XENP37903 PSMA x CD28 with 37 nM CD28 binding affinity in combination with illustrative competing PSMA x CD3 bsAbs (i.e., binding to the same PSMA epitope) with T cells and PC3 cells transfected with various surface PSMA densities. Data show that PSMA x CD28 bsAbs bind to PSMA 高 and PSMA 中 Cell lines enhanced cytokine secretion in the presence of α-glucose. Notably, a hook effect was observed at higher concentrations.
[0677] Fig.38 Depicts the interaction of PSMAxCD28 bsAbs incorporating the 1A7_H1_L1.71 180 nM CD28 binding domain and various PSMA binding domains with A) C42B-NLR (PSMA 高 ) and B) 22Rv1-NLR (PSMA 中 ) cell binding.
[0678] Fig.39 Figure 2 shows the interaction of PSMA x CD28 bsAbs incorporating the 1A7_H1_L1.71 180 nM CD28 binding domain and various PSMA binding domains with illustrative B7H3 x CD3 bsAbs in combination with T cells and 22Rv1-NLR (PSMA 中 ) induced IL-2 secretion upon incubation with WT cells. The data showed a range of potency consistent with cell binding.
[0679] Fig.40 Figure 3 shows the interaction of PSMA x CD28 bsAbs incorporating the 1A7_H1_L1.71 180 nM CD28 binding domain and various PSMA binding domains with 1391 PSMA x CD3 in combination with T cells and 22Rv1-NLR (PSMA 中 ) induced IL-2 secretion by cell incubation.
[0680] Fig.41 Figure 3 shows the interaction of PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities in combination with 1391 PSMA x CD3 (constant 1 μg / mL PSMA x CD28 and dose titration of PSMA x CD3) with T cells and A) C42B-NLR (PSMA 高 )、B) PC3-PSMA (about 100K), C) 22Rv1-NLR (PSMA 中) and D) IL-2 secretion induced by incubation of PC3-PSMA (about 50K) cells.
[0681] Fig.42 Figure 3 shows the interaction of PSMA x CD28 bsAbs incorporating the D01v2 PSMA binding domain and CD28 binding domains of various affinities in combination with 1391 PSMA x CD3 (constant 1 μg / mL PSMA x CD28 and dose titration of PSMA x CD3) with T cells and A) C42B-NLR (PSMA 高 )、B) PC3-PSMA (about 100K), C) 22Rv1-NLR (PSMA 中 ) and D) IL-2 secretion induced by incubation of PC3-PSMA (about 50K) cells.
[0682] Fig.43 Figure 3. Depicted is the combination of a PSMA x CD28 bsAb incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities with 1391 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) with T cells and A) C42B-NLR (PSMA 高 )、B) PC3-PSMA (about 100K), C) 22Rv1-NLR (PSMA 中 ) and D) IL-2 secretion induced by incubation of PC3-PSMA (about 50K) cells.
[0683] Fig.44 Figure 3. Depicted is the combination of a PSMA x CD28 bsAb incorporating the D01v2 PSMA binding domain and CD28 binding domains of various affinities with 1391 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) with T cells and A) C42B-NLR (PSMA 高 )、B) PC3-PSMA (about 100K), C) 22Rv1-NLR (PSMA 中 ) and D) IL-2 secretion induced by incubation of PC3-PSMA (about 50K) cells.
[0684] Fig.45 Figure 3 shows the immunofluorescence staining of PSMA x CD28 bsAbs incorporating various PSMA binding domains and CD28 binding domains of various affinities in combination with 1391PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) with T cells and 22Rv1-NLR (PSMA) at A) 1:1 and B) 0.1:1 effector:target ratios. 中) induced IL-2 secretion by incubation.
[0685] Fig.46 Depicted are IL-2 secretion induced by PSMA x CD28 bsAbs incorporating various PSMA binding domains and CD28 binding domains of various affinities in combination with 1391 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) incubated with T cells and PSMA-PC3 (approximately 50K) at A) 1:1 and B) 0.1:1 effector:target ratios.
[0686] Fig.47 Figure 3 shows the immunofluorescence staining of PSMA x CD28 bsAbs incorporating various PSMA binding domains and CD28 binding domains of various affinities in combination with 1391PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) with T cells and 22Rv1-NLR (PSMA 中 ) T cell proliferation induced by incubation.
[0687] Fig.48 Depicted incubation with 22Rv1-NLR (PSMA 中 ) cells with T cells (E:T 1:1) and induced RTCC (as shown by reduction in target cell counts over time) after A) 0.3 mg / mL, B) 1 ng / mL, C) 10 ng / mL, or D) 2.5 μg / mL 1391PSMA x CD3 alone or in combination with 1 μg / mL PSMA x CD28 bsAbs incorporating various PSMA binding domains and CD28 binding domains of various affinities. The data show that combination with PSMA x CD28 bsAbs enhances RTCC. Notably, at the higher 2.5 μg / mL concentration, the high affinity CD28 binding domains in XENP39234 and XENP39233 did not perform as well as the low affinity CD28 binding domains in XENP38936 and XENP39232.
[0688] Fig.49 Figure 3. PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and an additional lower affinity CD28 binding domain in combination with 1391 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) in combination with T cells and A) PSMA-PC3 (approximately 100K) or B) 22Rv1-NLR (PSMA 中 ) induced IL-2 secretion by incubation.
[0689] Fig.50Depicted are IL-2 secretion induced by PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities in combination with 1391 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) incubated with T cells and PSMA-PC3-NLR (approximately 50K PSMA), PSMA-PC3-NLR (approximately 3K PSMA), or DU145-NLR (0K PSMA).
[0690] Fig.51 Depicted are IL-2 secretion induced by PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities established on either Platform X or Platform J in combination with 1391 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) incubated with T cells and PSMA-PC3 (~50K).
[0691] Fig.52 Depicted are IL-2 secretion, IFNγ secretion, and RTCC induced by XENP39234 and XENP38936 in combination with A) B7H3 x CD3 bsAb and B) XENP33063 PSMA x CD3 bsAb. The combination of PSMA x CD28 with tumor antigen matched CD3 bispecific was more potent.
[0692] Fig.53 Depicted are changes in tumor volume (as determined by caliper measurement) over time in PSMA-transfected PC3 (-100K) and huPBMC-implanted NSG-DKO mice dosed with XENP33063 PSMA x CD3 or B7H3 x CD3 bsAb alone or in combination with XENP38936 (PSMA x CD28 180 nM) or XENP39231 (PSMA x CD28 1 μM).
[0693] Fig.54 Depicted are tumor volumes (as determined by caliper measurements) at A) day 16 and B) day 19 in PSMA-transfected PC3 (approximately 100K) and huPBMC-implanted NSG-DKO mice dosed with PSMA x CD3 or B7H3 x CD3 bsAbs alone or in combination with XENP38936 (PSMA x CD28 1 80 nM) or XENP39231 (PSMA x CD28 1 μM).
[0694] Fig.55Depicted are A) human CD4+ and B) human CD8+ cell counts at day 14 in PSMA-transfected PC3 (-100K) and huPBMC-implanted NSG-DKO mice dosed with PSMA x CD3 or B7H3 x CD3 bsAbs alone or in combination with XENP38936 (PSMA x CD28 180 nM) or XENP39231 (PSMA x CD28 1 μM).
[0695] Fig.56 Figure 3 shows the interaction of PSMA x CD28 bsAbs incorporating the 1A7_H1_L1.71 180 nM CD28 binding domain and various PSMA binding domains with 1508PSMA x CD3 in combination with T cells and 22Rv1-NLR (PSMA 中 ) induced IL-2 secretion by cell incubation.
[0696] Fig.57 Figure 3 shows the interaction of PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities in combination with 1508 PSMA x CD3 (constant 1 μg / mL PSMA x CD28 and dose titration of PSMA x CD3) with T cells and A) C42B-NLR (PSMA 高 )、B) PC3-PSMA (about 100K), C) 22Rv1-NLR (PSMA 中 ) and D) IL-2 secretion induced by incubation of PC3-PSMA (about 50K) cells.
[0697] Fig.58 Figure 3 shows the interaction of PSMA x CD28 bsAbs incorporating the D01v2 PSMA binding domain and CD28 binding domains of various affinities in combination with 1508 PSMA x CD3 (constant 1 μg / mL PSMA x CD28 and dose titration of PSMA x CD3) with T cells and A) C42B-NLR (PSMA 高 )、B) PC3-PSMA (about 100K), C) 22Rv1-NLR (PSMA 中 ) and D) IL-2 secretion induced by incubation of PC3-PSMA (about 50K) cells.
[0698] Fig.59 Figure 3 shows the interaction of PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities in combination with 1508 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) with T cells and A) C42B-NLR (PSMA高 )、B) PC3-PSMA (about 100K), C) 22Rv1-NLR (PSMA 中 ) and D) IL-2 secretion induced by incubation of PC3-PSMA (about 50K) cells.
[0699] Fig.60 Figure 3 shows the interaction of PSMA x CD28 bsAbs incorporating the D01v2 PSMA binding domain and CD28 binding domains of various affinities in combination with 1508 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) with T cells and A) C42B-NLR (PSMA 高 )、B) PC3-PSMA (about 100K), C) 22Rv1-NLR (PSMA 中 ) and D) IL-2 secretion induced by incubation of PC3-PSMA (about 50K) cells.
[0700] Fig.61 Figure 3 shows the immunofluorescence staining of PSMA x CD28 bsAbs incorporating various PSMA binding domains and CD28 binding domains of various affinities in combination with 1508PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) with T cells and 22Rv1-NLR (PSMA) at A) 1:1 and B) 0.1:1 effector:target ratios. 中 ) induced IL-2 secretion by incubation.
[0701] Fig.62 Depicted are IL-2 secretion induced by PSMA x CD28 bsAbs incorporating various PSMA binding domains and CD28 binding domains of various affinities in combination with 1508 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) incubated with T cells and PSMA-PC3 (approximately 50K) at A) 1:1 and B) 0.1:1 effector:target ratios.
[0702] Fig.63 Figure 3. PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and an additional lower affinity CD28 binding domain in combination with 1508 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) in combination with T cells and A) PSMA-PC3 (approximately 100K) or B) 22Rv1-NLR (PSMA 中 ) induced IL-2 secretion by incubation.
[0703] Fig.64Depicted is IL-2 secretion induced by PSMA x CD28 bsAb incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities in combination with 1508 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) incubated with T cells and PSMA-PC3-NLR (approximately 50K PSMA), PSMA-PC3-NLR (approximately 3K PSMA), or DU145-NLR (0K PSMA).
[0704] Fig.65 Depicted is IL-2 secretion induced by PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities established on either Platform X or Platform J in combination with 1508 PSMA x CD3 (constant 1 μg / mL PSMA x CD3 and dose titration of PSMA x CD28) incubated with T cells and PSMA-PC3 (approximately 50K).
[0705] Fig.66 Figure 3 PSMA x CD28 bsAbs incorporating the A10v2 PSMA binding domain and CD28 binding domains of various affinities built on Platform X or Platform J versus C42B (PSMA 高 ) combination.
[0706] Fig.67 Depicted is the sequence of an illustrative variable heavy domain from anti-CD28 clone 1A7, which has an introduced cysteine to allow for "stapled" scFv. It should be noted that the variable heavy domain can be paired with any of the other CD28 binding domain variable light domains depicted herein, including those depicted in Fig.68 Those employed in (e.g., those employed in C28PB405, C28PB404, C28PB403, C28PB402, C28PB401, C28PB400, and C28PB397).
[0707] Fig.68 Depicted is the sequence of an illustrative variable light domain from anti-CD28 clone 1A7, which has an introduced cysteine to allow for "stapled" scFv. It should be noted that the variable heavy domain can be paired with any of the other CD28 binding domain variable heavy domains depicted herein, including those depicted in Fig.67 Those employed in (e.g., those employed in C28PB405, C28PB404, C28PB403, C28PB402, C28PB401, C28PB400, and C28PB397).
[0708] Figures 69A-69CDepicted are sequences of illustrative stapled 1A7 VH / VL pairs. These pairs can be formatted as either a VHVL orientation or a VLVH orientation.
[0709] Figures 70A-70F Additional sequences of affinity-optimized variable heavy domains from anti-CD28 clone 1A7 are depicted. It should be noted that the variable heavy domains can be paired with any of the other CD28 binding domain variable light domains depicted herein, including those depicted in Figures 71A-71I Those in .
[0710] Figures 71A-71I Additional sequences of affinity-optimized variable light domains from anti-CD28 clone 1A7 are depicted. Note that the variable light domains can be paired with any of the other CD28 binding domain variable heavy domains depicted herein, including those depicted in Figures 70-70F.
[0711] Fig.72 The addition of PSMAxCD28 was shown to increase IL2 production by PSMAxCD3 in a dose-dependent manner in C42B cells using human PBMCs. DETAILED DESCRIPTION
[0712] I. Overview
[0713] Prostate cancer (PC) is one of the most common cancers in men, and there are no curative treatment options for late-stage (castration-resistant prostate cancer). Prostate-specific membrane antigen (PSMA), a type II transmembrane protein with a large extracellular domain, has long generated attention as a therapeutic target. PSMA is highly overexpressed in PC compared to normal tissues, and its expression has been shown to be associated with malignancy. Previous attempts to target PSMA include antibody-based radiotherapy and antibody-drug conjugates, which have shown some success but can be hampered by the inherent toxicity of the modality.
[0714] T cell activation in cancer therapy has been widely explored. Full activation and differentiation of T cells requires multiple signals. Fig.27AAs shown, signal 1 promoted by T cell receptor (TCR) recognition of peptide-MHC (pMHC) complex is absolutely required for T cell activation. Signal 2, which cooperates with signal 1 and amplifies signal 1, is usually provided by the interaction of CD28 ligands CD80 and CD86 with CD28 itself. Although CD28 engagement alone is usually inert, when combined with signal 1 activation, it promotes additional activation, survival and proliferation signals, including IL-2 secretion. Since CD80 and CD86 are only naturally expressed by professional antigen presenting cells (APCs), the extent of CD28 co-stimulation in the tumor environment can be highly variable. Therefore, the present invention relates to a novel class of tumor-targeted anti-CD28 x anti-PSMA bispecific antibodies that mimic CD80 / CD86 engagement with CD28, thereby providing artificially derived signal 2. It is worth noting that signal 1 can be provided by natural TCR: pMHC recognition of tumor cells, or it can be provided by combining CD28 bispecific with CD3 bispecific (e.g., anti-CD3 x anti-PSMA) that can mimic signal 1.
[0715] Thus, provided herein are novel anti-CD28 x anti-PSMA (also referred to as "αCD28 xαPSMA" and sometimes referred to as "CD28 x PSMA") bispecific antibodies and methods of using such antibodies for treating PSMA-associated cancers. In many cases, these bispecific antibodies are heterodimers. The subject αCD28 xαPSMA antibodies are capable of agonistic binding to CD28 co-stimulatory molecules on T cells and targeting PSMA on PSMA-expressing tumor cells. Thus, such antibodies selectively enhance anti-tumor activity at PSMA-expressing tumor sites while minimizing peripheral toxicity. The subject antibodies provided herein are particularly useful for enhancing anti-tumor activity alone as a monotherapy, or when used in combination with other anti-cancer therapies as more fully described herein.
[0716] Thus, in one aspect, provided herein are heterodimeric antibodies that bind to two different antigens, e.g., the antibodies are "bispecific" because they bind to two different target antigens, typically CD28 and PSMA as described below. These heterodimeric antibodies can bind to each of the target antigens monovalently (e.g., there is a single antigen binding domain such as a variable heavy domain and a variable light domain pair) or bivalently (there are two antigen binding domains that each independently bind to the antigen). In some embodiments, the heterodimeric antibodies provided herein include one CD28 binding domain and one PSMA binding domain (e.g., a heterodimeric antibody in the "1+1 Fab-scFv-Fc" format described herein, which is therefore bispecific and bivalent). In other embodiments, the heterodimeric antibodies provided herein include one CD28 binding domain and two PSMA binding domains (e.g., in the "2+1 Fab-scFv-Fc" format described herein). 2The heterodimeric antibodies provided herein are based on the use of different monomers containing amino acid substitutions (i.e., skew variants) that are "skewed" to form heterodimers rather than homodimers, as more fully outlined below. In some embodiments, the heterodimeric antibodies are also coupled to purification variants (e.g., "pI variants"), thereby allowing for simple purification of heterodimers from homodimers, as similarly outlined below. The heterodimeric bispecific antibodies provided generally rely on the use of engineered or variant Fc domains that can self-assemble in production cells to produce heterodimeric proteins, as well as methods for producing and purifying such heterodimeric proteins.
[0717] II. Nomenclature
[0718] The nomenclature for specific antigen binding domains (e.g., PSMA and CD28 binding domains) uses a format of the type "Hx.xx_Ly.yy", where the number is a unique identifier for the specific variable chain sequence. Thus, for example, the CD28 binding domain is "1A7[CD28]_H1_L1" ( Fig.15 ) includes a variable heavy domain H1 and a variable light domain L1. In the case where these sequences are used as scFv, the nomenclature "H1_L1" indicates that the binding domain includes a variable heavy domain "H1" combined with a variable light domain "L1" and is oriented VH-linker-VL from N-terminus to C-terminus. This molecule with the same heavy and light variable domain sequences but in reverse order (oriented VL-linker-VH from N-terminus to C-terminus) will be named "L1_H1". Similarly, different constructs can "mix and match" heavy and light chains, as is apparent from the sequence listing and accompanying drawings.
[0719] III. Definitions
[0720] In order that this application may be more fully understood, several definitions are set forth below. Such definitions are intended to encompass grammatical equivalents.
[0721] "CD28", "cluster of differentiation 28" and "Tp44" herein (e.g., Genebank accession numbers NP_001230006 (human), NP_001230007 (human), NP_006130 (human) and NP_031668 (mouse)) refer to the B7 receptor expressed on T cells, which provides the co-stimulatory signals required for T cell activation and survival. T cell stimulation by CD28 provides a potent signal for the production of various interleukins in addition to the T cell receptor (TCR). CD28 is a receptor for CD80 (B7.1) and CD86 (B7.2) proteins. CD28 includes an extracellular domain with a YMNM motif (SEQ ID NO: 1044), which is key to recruiting proteins containing SH2 domains, particularly PI3K. CD28 also includes two proline-rich motifs that are capable of binding to SH3-containing proteins. An exemplary CD28 sequence is depicted in Figure 1A-1B Unless otherwise indicated, references to CD28 are to the human CD28 sequence.
[0722] "PSMA" or "prostate specific membrane antigen" (e.g., Genebank Accession No. NP 005012.2) herein refers to a type II transmembrane protein that is expressed in prostate tissue, including primary prostate adenocarcinoma, metastatic prostate cancer, and in tumor neovascularization of many solid tumors. In prostate cancer (PCa), PSMA is highly expressed in poorly differentiated, highly metastatic prostate cells and castration-resistant models. Exemplary PSMA sequences are disclosed in Figure 2A-2B Unless otherwise indicated, references to PSMA are to the human PSMA sequence.
[0723] "B7H3", "B7-H3", "B7RP-2", "CD276", "differentiation cluster 276" (e.g., Genebank accession numbers NP_001019907 (human), NP_001316557 (human), NP_001316558 (human), NP_079516 (human), and NP_598744 (mouse)) herein means a type 1 transmembrane protein that is a member of the B7 family with an extracellular domain consisting of a single IgV-IgC domain pair. B7H3 is an immune checkpoint molecule and is abnormally overexpressed in many types of cancer. Unless otherwise indicated, reference to B7H3 refers to the human B7H3 sequence.
[0724] As used herein, "ablation" means to reduce or remove an activity. Thus, for example, "ablation of FcγR binding" means that the Fc region amino acid variant has less than 50% of the initial binding compared to an Fc region not containing the specific variant, wherein loss of more than 70-80-90-95-98% activity is preferred, and generally the activity is below the level of detectable binding in a Biacore, SPR or BLI assay. Of particular use in ablating FcγR binding are those shown in Figure 5 Those in which are usually added to two monomers.
[0725] As used herein, "ADCC" or "antibody-dependent cell-mediated cytotoxicity" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγRs recognize bound antibodies on target cells and subsequently cause lysis of the target cells. ADCC is associated with binding to FcγRIIIa; increased binding to FcγRIIIa results in increased ADCC activity.
[0726] As used herein, "ADCP" or antibody-dependent cell-mediated phagocytosis refers to a cell-mediated reaction in which nonspecific phagocytes expressing FcγRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.
[0727] As used herein, the term "antibody" is used generically. The antibodies provided herein can be in a number of formats as described herein, including traditional antibodies as well as antibody derivatives, fragments and mimetics described herein.
[0728] Traditional immunoglobulin (Ig) antibodies are "Y"-shaped tetramers. Each tetramer is usually composed of two pairs of identical polypeptide chains, each pair having a "light chain" monomer (usually with a molecular weight of about 25 kDa) and a "heavy chain" monomer (usually with a molecular weight of about 50-70 kDa).
[0729] Other useful antibody formats include, but are not limited to, the "1+1 Fab-scFv-Fc" and "2+1 Fab" provided herein. 2 -scFv-Fc" format (see e.g. Figures 24A-24M Additional useful antibody formats include, but are not limited to, "1+1 common light chain" and "2+1 common light chain", "mAb-Fv", "mAb-scFv", "central Fv", "single-armed scFv-mAb", "scFv-mAb", "dual scFv" and "trident" format antibodies ( Figures 24A-24M ). See also US20180127501A1, which is incorporated herein by reference, particularly the relevant parts related to antibody formats (see, e.g., FIG. 2 of US20180127501A1).
[0730] The antibody heavy chain generally includes a variable heavy (VH) domain (which includes vhCDR1-3) and an Fc domain (which includes a CH2-CH3 monomer). In some embodiments, the antibody heavy chain includes a hinge and a CH1 domain. Traditional antibody heavy chains are monomers, which are organized from N-terminus to C-terminus as: VH-CH1-hinge-CH2-CH3. CH1-hinge-CH2-CH3 are collectively referred to as the heavy chain "constant domain" or "constant region" of antibodies, of which there are five different classes or "isotypes": IgA, IgD, IgG, IgE, and IgM.
[0731] In some embodiments, antibodies provided herein include IgG isotype constant domains, which have several subtypes, including but not limited to IgG1, IgG2, IgG3 and IgG4. In the IgG subtype of immunoglobulin, there are several immunoglobulin domains in the heavy chain. "Immunoglobulin (Ig) domain" herein means the region of the immunoglobulin with a unique tertiary structure. What is concerned in the present invention is the heavy chain domain, which includes a constant heavy (CH) domain and a hinge domain. In the case of IgG antibodies, IgG isotypes each have three CH regions. Therefore, in the case of IgG, "CH" domains are as follows: "CH1" refers to positions 118-215 according to the EU index in Kabat. "Hinge" refers to positions 216-230 according to the EU index in Kabat. "CH2" refers to positions 231-340 according to the EU index in Kabat, and "CH3" refers to positions 341-447 according to the EU index in Kabat. As shown in Table 1, the exact numbering and placement of the heavy chain domains may be different between different numbering systems. As shown herein and described below, the pi variants may be in one or more of the CH regions as well as the hinge region discussed below.
[0732] It should be noted that IgG1 has different allotypes, which have polymorphisms at 356 (D or E) and 358 (L or M). The sequences depicted herein use the 356E / 358M allotype, however other allotypes are included herein. That is, any sequence comprising an IgG1 Fc domain included herein may replace the 356E / 358M allotype with 356D / 358L. It should be understood that therapeutic antibodies may also include hybrids of isotypes and / or subtypes. For example, as shown in U.S. Publication 2009 / 0163699, incorporated by reference, the antibodies of the present invention include human IgG1 / G2 hybrids in some embodiments.
[0733] As used herein, "Fc" or "Fc region" or "Fc domain" means a polypeptide comprising the constant region of an antibody, which in some cases excludes all first constant region immunoglobulin domains (e.g., CH1) or portions thereof, and in some cases optionally includes all or part of a hinge. For IgG, the Fc domain includes immunoglobulin domains CH2 and CH3 (Cγ2 and Cγ3), and optionally all or part of a hinge region between CH1 (Cγ1) and CH2 (Cγ2). Therefore, in some cases, the Fc domain includes CH2-CH3 and hinge-CH2-CH3 from N-terminus to C-terminus. In some embodiments, the Fc domain is from IgG1, IgG2, IgG3, or IgG4, wherein IgG1 hinge-CH2-CH3 and IgG4 hinge-CH2-CH3 have specific uses in many embodiments. In addition, in the case of human IgG1 Fc domains, the hinge may include a C220S amino acid substitution. In addition, in the case of human IgG4 Fc domains, the hinge may include a S228P amino acid substitution. Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is generally defined to include residues E216, C226, or A231 to its carboxyl terminus, wherein numbering is according to the EU index as in Kabat. In some embodiments, as described more fully below, amino acid modifications are made in the Fc region, e.g., to alter binding to one or more FcγRs or FcRn.
[0734] By "heavy chain constant region" herein is meant the CH1-hinge-CH2-CH3 portion of an antibody (or a fragment thereof), excluding the variable heavy domain; in EU numbering of human IgG1, this is amino acids 118-447. By "heavy chain constant region fragment" herein is meant a heavy chain constant region that contains fewer amino acids at either or both of the N-terminus and the C-terminus, but still retains the ability to form a dimer with another heavy chain constant region.
[0735] The domain of another type of heavy chain is the hinge region. "Hinge" or "hinge region" or "antibody hinge region" or "hinge domain" herein means a flexible polypeptide, which is included in the amino acid between the first constant domain and the second constant domain of the antibody. Structurally, the IgG CH1 domain ends at EU position 215, and the IgG CH2 domain begins at residue EU position 231. Therefore, for IgG, the antibody hinge is defined herein as including positions 216 (E216 in IgG1) to 230 (P230 in IgG1), wherein numbering is according to the EU index in Kabat. In some cases, a "hinge fragment" is used, which contains less amino acids at either or both of the N-terminal and C-terminal ends of the hinge domain. As mentioned herein, pI variants can also be made in the hinge region. Many antibodies herein have at least one cysteine replaced by serine at position 220 (hinge region) according to EU numbering. Typically, this modification is on the "scFv monomer" side of most of the sequences depicted herein (when using a 1+1 or 2+1 format), although it may also be on the "Fab monomer" side or both sides to reduce disulfide bond formation. Specifically included within the sequences herein is the replacement of one or both of these cysteines (C220S).
[0736] As will be appreciated by those skilled in the art, the exact numbering and placement of the heavy chain constant regions (i.e., CH1, hinge, CH2, and CH3 domains) may differ between different numbering systems. A useful comparison of the heavy constant region numbering according to EU and Kabat is as follows, see Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85 and Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Edition, United States Public Health Service, National Institutes of Health, Bethesda, which are incorporated herein by reference in their entirety.
[0737] Table 1
[0738] EU Number Kabat Number CH1 118-215 114-223 Hinge 216-230 226-243 CH2 231-340 244-360 CH3 341-447 361-478
[0739] The antibody light chain usually comprises two domains: a variable light domain (VL), which includes light chain CDR v1CDR1-3; and a constant light chain region (usually referred to as CL or Cκ). The antibody light chain is usually organized from N-terminus to C-terminus as: VL-CL.
[0740] The term "antigen binding domain" or "ABD" herein means a set of six complementary determining regions (CDRs) that, when present as part of a polypeptide sequence, specifically bind to a target antigen as discussed herein (e.g., PSMA or CD28). As known in the art, these CDRs are generally present in the form of a first set of variable heavy CDRs (vhCDRs or VHCDRs) and a second set of variable light CDRs (vlCDRs or VLCDRs), each comprising three CDRs: vhCDR1, vhCDR2, vhCDR3 variable heavy CDRs and vlCDR1, vlCDR2 and vlCDR3 variable light CDRs. The CDRs are present in variable heavy domains (vhCDR1-3) and variable light domains (vlCDR1-3). The variable heavy domains and variable light domains are from the Fv region.
[0741] The present invention provides a large number of different CDR groups. In this case, a "complete CDR group" comprises three variable light CDRs and three variable heavy CDRs, such as vlCDR1, vlCDR2, vlCDR3, vhCDR1, vhCDR2 and vhCDR3. These can be part of a larger variable light domain or a variable heavy domain, respectively. In addition, as more fully outlined herein, when heavy and light chains are used (e.g., when Fab is used), the variable heavy domain and the variable light domain can be on separate polypeptide chains, or on a single polypeptide chain in the case of scFv sequences.
[0742] As will be appreciated by those skilled in the art, the exact numbering and placement of CDRs may be different between different numbering systems. However, it will be appreciated that the disclosure of a variable heavy sequence and / or variable light sequence includes the disclosure of the associated (intrinsic) CDRs. Thus, the disclosure of each variable heavy chain region is the disclosure of vhCDRs (e.g., vhCDR1, vhCDR2, and vhCDR3), and the disclosure of each variable light chain region is the disclosure of vlCDRs (e.g., vlCDR1, vlCDR2, and vlCDR3). A useful comparison of CDR numbering is as follows, see Lafranc et al., Dev. Comp. Immunol. 27(1): 55-77 (2003):
[0743] Table 2
[0744]
[0745]
[0746] Throughout this specification, the Kabat numbering system is generally used when referring to residues in the variable domain (approximately residues 1-107 in the light chain variable region and residues 1-113 in the heavy chain variable region) and the EU numbering system is used for the Fc region (e.g., Kabat et al., supra (1991)).
[0747] CDRs contribute to the formation of antigen binding domains and the antigen binding site of an antibody, or more specifically, an epitope binding site. An "epitope" refers to a determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule called a paratope. An epitope is a molecular grouping of, for example, amino acids or sugar side chains and generally has specific structural characteristics as well as specific charge characteristics. A single antigen may have more than one epitope.
[0748] An epitope may include amino acid residues that are directly involved in binding (also called the immunodominant component of the epitope) and other amino acid residues that are not directly involved in binding, such as amino acid residues that are effectively blocked by the specific antigen binding peptide; in other words, the amino acid residues are within the footprint of the specific antigen binding peptide.
[0749] Epitopes can be conformational or linear. Conformational epitopes are produced by spatial juxtaposition of amino acids from different segments of a linear polypeptide chain. Linear epitopes are epitopes produced by adjacent amino acid residues in a polypeptide chain. Conformational and non-conformational epitopes may be distinguished in that binding to the former but not the latter is abolished in the presence of denaturing solvents.
[0750] An epitope typically includes at least 3 and more typically at least 5 or 8-10 amino acids in a unique spatial conformation. Antibodies that recognize the same epitope can be validated in a simple immunoassay showing the ability of one antibody to block the binding of another antibody to the target antigen, such as "binning". As outlined below, the present invention includes not only the antigen binding domains and antibodies listed herein, but also those that compete for binding to the epitopes bound by the listed antigen binding domains.
[0751] In some embodiments, the six CDRs of the antigen binding domain are provided by a variable heavy domain and a variable light domain. In the "Fab" format, the set of 6 CDRs is provided by two different polypeptide sequences, namely a variable heavy domain (vh or VH; containing vhCDR1, vhCDR2 and vhCDR3) and a variable light domain (vl or VL; containing vlCDR1, vlCDR2 and vlCDR3), wherein the C-terminus of the vh domain is connected to the N-terminus of the CH1 domain of the heavy chain, and the C-terminus of the vl domain is connected to the N-terminus of the constant light domain (and thus forms a light chain). In the scFv format, the vh and vl domains are usually covalently linked to a single polypeptide sequence via the use of a linker as outlined herein ("scFv linker"), which may be (starting from the N-terminus) vh-linker-vl or vl-linker-vh, wherein the former is usually preferred (depending on the form used, including an optional domain linker on each side). Generally, the C-terminus of the scFv domain is linked to the N-terminus of all or part of the hinge in the second monomer.
[0752] As used herein, "variable region" or "variable domain" means an immunoglobulin region comprising one or more Ig domains substantially encoded by any one of the Vκ, Vλ and / or VH genes constituting κ, λ and heavy chain immunoglobulin genetic loci, respectively, and containing CDRs that confer antigen specificity. Thus, a "variable heavy domain" is paired with a "variable light domain" to form an antigen binding domain ("ABD"). In addition, each variable domain comprises three hypervariable regions ("complementarity determining regions", "CDRs") (vhCDR1, vhCDR2 and vhCDR3 of the variable heavy domain, and vlCDR1, vlCDR2 and vlCDR3 of the variable light domain) and four framework (FR) regions, which are configured in the following order from the amino terminus to the carboxyl terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
[0753] As used herein, "Fab" or "Fab region" means the region of an antibody comprising the VH, CH1, VL, and CL immunoglobulin domains, which are typically on two different polypeptide chains (e.g., VH-CH1 on one chain and VL-CL on another chain). Fab may refer to this region in isolation, or in the case of the bispecific antibodies of the invention. In the case of Fab, Fab comprises an Fv region in addition to the CH1 and CL domains.
[0754] As used herein, "Fv" or "Fv fragment" or "Fv region" means the region of an antibody comprising the VL and VH domains. The Fv region can be formatted as both a Fab (as discussed above, typically two different polypeptides that also include constant regions as outlined above) and a single-chain Fv (scFv), in which the VL and VH domains are included in a single peptide, typically connected with a linker as discussed herein.
[0755] "Single-chain Fv" or "scFv" herein means that the variable heavy domain is covalently linked to the variable light domain, usually using an scFv linker as discussed herein, to form an scFv or scFv domain. The scFv domain can be in either orientation (vh-linker-vl or vl-linker-vh) from the N-terminus to the C-terminus. In the sequences depicted in the sequence table and the accompanying drawings, the order of the vh and vl domains is as indicated by the name, for example, H.X_L.Y means vh-linker-vl from the N-terminus to the C-terminus, and L.Y_H.X is vl-linker-vh.
[0756] Some embodiments of the subject antibodies provided herein comprise at least one scFv domain, which, although non-naturally occurring, typically includes a variable heavy domain and a variable light domain connected together by a scFv linker. As outlined herein, although the scFv domain is typically oriented as VH-scFv linker-VL from N-terminus to C-terminus, the orientation of any of the scFv domains (or those constructed using vh and vl sequences from Fab) can be reversed to VL-scFv linker-VH, with an optional linker at one or both ends depending on the format.
[0757] By "modification" or "variant" herein is meant an amino acid substitution, insertion and / or deletion in a polypeptide sequence or a change in a portion chemically linked to a protein. For example, a modification may be a variant carbohydrate or PEG structure linked to a protein. By "amino acid modification" herein is meant an amino acid substitution, insertion and / or deletion in a polypeptide sequence. For clarity, unless otherwise indicated, an amino acid modification is always an amino acid encoded by DNA, such as the 20 amino acids with codons in DNA and RNA.
[0758] "Amino acid substitution" or "substitution" herein means replacing an amino acid at a specific position in a parent polypeptide sequence with a different amino acid. In particular, in some embodiments, the substitution is an amino acid that does not naturally occur at a specific position, i.e., does not naturally occur in an organism or in any organism. For example, the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which the glutamic acid at position 272 is replaced by tyrosine. For clarity, a protein that is engineered to change the nucleic acid coding sequence but does not change the starting amino acid (e.g., changing CGG (encoding arginine) to CGA (still encoding arginine) to increase the expression level of the host organism) is not an "amino acid substitution"; that is, although a new gene encoding the same protein is generated, if the protein has the same amino acid at the specific position where it starts, it is not an amino acid substitution.
[0759] As used herein, "amino acid insertion" or "insertion" means adding an amino acid sequence at a specific position in a parent polypeptide sequence. For example, -233E or 233E indicates that glutamic acid is inserted after position 233 and before position 234. In addition, -233ADE or A233ADE indicates that AlaAspGlu is inserted after position 233 and before position 234.
[0760] As used herein, "amino acid deletion" or "deletion" means the removal of an amino acid sequence at a specific position in a parent polypeptide sequence. For example, E233- or E233#, E233() or E233del indicates that the glutamic acid at position 233 is deleted. In addition, EDA233- or EDA233# indicates that the sequence GluAspAla starting at position 233 is deleted.
[0761] As used herein, "variant protein" or "protein variant" or "variant" means a protein that differs from a parent protein by virtue of at least one amino acid modification. A protein variant has at least one amino acid modification compared to a parent protein, but not so many that the variant protein does not align with the parent protein when using, for example, an alignment program described below. In general, variant proteins (e.g., variant Fc domains as outlined herein, etc.) are typically at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a parent protein when using an alignment program such as BLAST described below.
[0762] As used herein, "variant" also refers to specific amino acid modifications that confer a specific function (eg, "heterodimerization variant," "pi variant," "ablation variant," etc.).
[0763] As described below, in some embodiments, the parent polypeptide (e.g., Fc parent polypeptide) is a human wild-type sequence, such as a heavy constant domain or Fc region from IgG1, IgG2, IgG3, or IgG4, although human sequences with variants may also serve as "parent polypeptides", such as the IgG1 / 2 hybrids of U.S. Publication 2006 / 0134105. The protein variant sequences herein will preferably have at least about 80% identity with the parent protein sequence, and most preferably at least about 90% identity, more preferably at least about 95-98-99% identity. Thus, as used herein, "antibody variant" or "variant antibody" means an antibody that differs from a parent antibody by means of at least one amino acid modification, as used herein, "IgG variant" or "variant IgG" means an antibody that differs from a parent IgG (again, in many cases, from a human IgG sequence) by means of at least one amino acid modification, and as used herein, "immunoglobulin variant" or "variant immunoglobulin" means an immunoglobulin sequence that differs from a parent immunoglobulin sequence by means of at least one amino acid modification. As used herein, "Fc variant" or "variant Fc" means a protein comprising amino acid modifications in the Fc domain compared to the Fc domain of human IgG1, IgG2 or IgG4.
[0764] As used herein, "Fc variant" or "variant Fc" means a protein comprising an amino acid modification in an Fc domain. The modification may be an addition, a deletion or a substitution. An Fc variant is defined according to the amino acid modification that constitutes it. Thus, for example, N434S or 434S is an Fc variant having a serine substitution at position 434 relative to a parent Fc polypeptide, wherein the numbering is according to the EU index. Similarly, M428L / N434S defines an Fc variant having substitutions M428L and N434S (relative to a parent Fc polypeptide). The identity of the WT amino acid may be non-specific, in which case the aforementioned variant is referred to as 428L / 434S. It should be noted that the order in which the substitution is provided is arbitrary, that is, for example, 428L / 434S is an Fc variant identical to 434S / 428L, and so on. For all positions discussed herein regarding antibodies or derivatives thereof and fragments (e.g., Fc domains), unless otherwise indicated, the amino acid position numbering is according to the EU index. The "EU index" or "EU index as in Kabat" or "EU numbering" scheme refers to the EU numbering for antibodies (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, which is incorporated herein by reference in its entirety). A modification may be an addition, deletion or substitution.
[0765] Generally, the variant Fc domain has at least about 80%, 85%, 90%, 95%, 97%, 98% or 99% identity to the corresponding parent human IgG Fc domain (using the identity algorithm discussed below, one embodiment of which employs the BLAST algorithm as known in the art, using default parameters). Alternatively, the variant Fc domain may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acid modifications compared to the parent Fc domain. Alternatively, the variant Fc domain may have up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid modifications compared to the parent Fc domain. In addition, as discussed herein, the variant Fc domains described herein still retain the ability to form a dimer with another Fc domain as measured using known techniques such as non-denaturing gel electrophoresis as described herein.
[0766] As used herein, "protein" means at least two covalently linked amino acids, including proteins, polypeptides, oligopeptides and peptides. In addition, the polypeptides constituting the antibodies of the present invention may include synthetic derivatization of one or more side chains or termini, glycosylation, pegylation, cyclic arrangement, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.
[0767] As used herein, "residue" means a position in a protein and its associated amino acid identity. For example, asparagine 297 (also known as Asn297 or N297) is the residue at position 297 in the human antibody IgG1.
[0768] As used herein, "IgG subtype modification" or "isotype modification" means an amino acid modification that converts one amino acid of one IgG isotype to the corresponding amino acid in a different, aligned IgG isotype. For example, since IgG1 contains a tyrosine at EU position 296 and IgG2 contains a phenylalanine, a F296Y substitution in IgG2 is considered an IgG subtype modification.
[0769] As used herein, "non-naturally occurring modification" means a non-isotypic amino acid modification. For example, since human IgG does not contain serine at position 434, the substitution 434S of IgG1, IgG2, IgG3 or IgG4 (or a hybrid thereof) is considered a non-naturally occurring modification.
[0770] As used herein, "amino acid" and "amino acid identity" mean one of the 20 naturally occurring amino acids encoded by DNA and RNA.
[0771] As used herein, "effector function" refers to the biochemical events resulting from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include, but are not limited to, ADCC, ADCP, and CDC.
[0772] As used herein, "IgG Fc ligand" means a molecule, preferably a polypeptide, that binds to the Fc region of an IgG antibody from any organism to form an Fc / Fc ligand complex. Fc ligands include, but are not limited to, FcγRI, FcγRII, FcγRIII, FcRn, C1q, C3, mannan binding lectin, mannose receptor, staphylococcal protein A, streptococcal protein G, and viral FcγR. Fc ligands also include Fc receptor homologs (FcRH), which are Fc receptor families homologous to FcγR (Davis et al., 2002, Immunological Reviews 190: 123-136, which are incorporated herein by reference in their entirety). Fc ligands may include undiscovered molecules that bind to Fc. Specific IgG Fc ligands are FcRn and Fcγ receptors. As used herein, "Fc ligand" means a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an antibody to form an Fc / Fc ligand complex.
[0773] "Fcγ receptor," "FcγR," or "FcgammaR" as used herein means any member of the family of proteins that binds the Fc region of an IgG antibody and is encoded by an FcγR gene. In humans, this family includes, but is not limited to, FcγRI (CD64), including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIb-NA1 and FcγRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, which is incorporated herein by reference in its entirety), as well as any undiscovered human FcγR or FcγR isoform or allotype. FcγRs can be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcγRs include but are not limited to FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), and FcγRIII-2 (CD16-2), as well as any undiscovered mouse FcγR or FcγR isoform or allotype.
[0774] As used herein, "FcRn" or "neonatal Fc receptor" means a protein that binds to the Fc region of an IgG antibody and is at least partially encoded by an FcRn gene. FcRn can be from any organism, including but not limited to humans, mice, rats, rabbits and monkeys. As is known in the art, a functional FcRn protein comprises two polypeptides, which are generally referred to as a heavy chain and a light chain. The light chain is beta-2-microglobulin and the heavy chain is encoded by the FcRn gene. Unless otherwise specified in this article, FcRn or FcRn protein refers to a complex of the FcRn heavy chain and beta-2-microglobulin. A variety of FcRn variants are used to increase binding to the FcRn receptor, and in some cases increase serum half-life. "FcRn variants" are amino acid modifications that contribute to increased binding to the FcRn receptor, and suitable FcRn variants are shown below.
[0775] As used herein, "parent polypeptide" means a starting polypeptide that is subsequently modified to produce a variant. A parent polypeptide may be a naturally occurring polypeptide, or a variant or engineered version of a naturally occurring polypeptide. Thus, as used herein, "parent immunoglobulin" means an unmodified immunoglobulin polypeptide that is modified to produce a variant, and as used herein, "parent antibody" means an unmodified antibody that is modified to produce a variant antibody. It should be noted that "parent antibody" includes known commercial, recombinantly produced antibodies, as outlined below. In this case, the "parent Fc domain" will be relative to the variant; thus, a "variant human IgG1 Fc domain" is the parent Fc domain compared to human IgG1, a "variant human IgG4 Fc domain" is the parent Fc domain compared to human IgG4, and so on.
[0776] As used herein, "position" means a position in the sequence of a protein. Positions may be numbered sequentially or according to an established format, such as the EU index for numbering antibody domains (eg, CH1, CH2, CH3 or hinge domains).
[0777] As used herein, "target antigen" means a molecule that is specifically bound by an antigen binding domain comprising the variable region of a given antibody.
[0778] In the case of monomers of heterodimeric antibodies of the present invention, "strandedness" herein means two chains of DNA similar to "matching", and heterodimerization variants are incorporated into each monomer to retain the ability to "match" to form heterodimers. For example, if some pI variants are engineered into monomer A (e.g., to make pI higher), it is also possible to use steric variants that do not interfere with pI variants as "charge pairs", for example, charge variants that make pI higher are placed on the same "chain" or "monomer" to retain two functionalities. Similarly, for "skewed" variants of paired groups as more fully outlined below, those skilled in the art will consider pI when deciding which chain or monomer a group in the pair will be incorporated into, so as to also maximize the pI separation using skewed pI.
[0779] As used herein, "target cell" means a cell expressing a target antigen.
[0780] In the case of producing a bispecific antibody according to the present invention, "host cell" herein means a cell that contains exogenous nucleic acid encoding components of the bispecific antibody and is capable of expressing the bispecific antibody under appropriate conditions. Suitable host cells are discussed below.
[0781] "Wild type" or "WT" herein means an amino acid sequence or nucleotide sequence found in nature, including allelic variants. A WT protein has an amino acid sequence or nucleotide sequence that has not been intentionally modified.
[0782] Provided herein are certain antibody domains (eg, Fc domains) that have sequence identity to human antibody domains. Sequence identity between two similar sequences (e.g., antibody variable domains) can be measured by algorithms, such as those of Smith, TF and Waterman, MS (1981) "Comparison Of Biosequences," Adv. Appl. Math. 2:482 [local homology algorithm]; Needleman, SB and Wunsch, CD. (1970) "A General Method Applicable To The Search For Similarities In The Amino Acid Sequence Of Two Proteins," J. Mol. Biol. 48:443 [homology alignment algorithm]; Pearson, WR and Lipman, DJ (1988) "Improved Tools For Biological Sequence Comparison," Proc. Natl. Acad. Sci. (USA) 85:2444 [method for searching similarities]; or Altschul, SF et al., (1990) "Basic Local Alignment Search Tool," J. Mol. Biol. 215:403-10, "BLAST" algorithm, see http: / / blast.ncbi.nlm.nih.gov / Blast.cgi. When using any of the foregoing algorithms, the default parameters (window length, gap penalty, etc.) are used. In one embodiment, sequence identity is performed using the BLAST algorithm, which uses default parameters.
[0783] The antibodies of the present invention are generally isolated or recombinant. When used to describe the various polypeptides disclosed herein, "isolated" means identifying and separating and / or recovering the polypeptide from a cell or cell culture expressing the polypeptide. Typically, an isolated polypeptide will be prepared by at least one purification step. An "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic specificities. "Recombinant" means that the antibodies are produced in exogenous host cells using recombinant nucleic acid technology, and they may also be isolated.
[0784] "Specific binding" or "specifically binds to" or "is specific for" a particular antigen or epitope means binding that is measurably distinct from non-specific interactions. Specific binding can be measured, for example, by measuring the binding of a molecule compared to the binding of a control molecule, which is typically a molecule of similar structure that has no binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.
[0785] Specific binding for a particular antigen or epitope can be exhibited, for example, by an antibody with a KD for the antigen or epitope of at least about 10 -4 M, at least about 10 -5 M, at least about 10 -6 M, at least about 10 -7 M, at least about 10 -8 M, at least about 10 -9 M, or at least about 10 -10 M, at least about 10 -11 M, at least about 10 -12 M or higher, where KD refers to the dissociation rate of a specific antibody-antigen interaction. Typically, an antibody that specifically binds to an antigen should have a KD relative to the antigen or epitope that is 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5,000-fold, 10,000-fold, or more greater than a control molecule.
[0786] In addition, specific binding for a particular antigen or epitope can be exhibited, for example, by an antibody having a KA or Ka for the antigen or epitope that is at least 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5,000-fold, 10,000-fold or more greater relative to a control, where KA or Ka refers to the association rate of a specific antibody-antigen interaction. Binding affinity is typically measured using Biacore, SPR or BLI assays.
[0787] IV. Anti-CD28 x Anti-PSMA Antibodies
[0788] In one aspect, novel anti-CD28 x anti-PSMA antibodies are provided herein. In some embodiments, the anti-CD28 x anti-PSMA antibodies described herein are capable of agonistic binding to CD28 co-stimulatory molecules on T cells and PSMA on tumor cells. Such antibodies selectively enhance anti-tumor activity at PSMA-associated tumor sites while minimizing peripheral toxicity. The subject antibodies provided herein are particularly useful in combination with other anti-cancer therapies, including, for example, multivalent antibodies for the treatment of prostate cancer.
[0789] The anti-CD28 x anti-PSMA antibodies are multivalent and include at least two antigen binding domains (ABDs), wherein at least one antigen binding domain is a CD28 binding domain and at least one antigen binding domain is a PSMA binding domain. Any suitable CD28 binding domain and PSMA binding domain can be included in the subject anti-CD28 x anti-PSMA antibodies, including, for example, the CD28 binding domains and PSMA binding domains provided herein.
[0790] The antigen binding domains provided herein generally include a variable heavy domain (VH) having VH-CDR1, VH-CDR-2, and VH-CDR-3; and a variable light domain (VL) having VL-CDR1, VL-CDR-2, and VL-CDR-3.
[0791] Furthermore, as discussed above, the numbering used in the sequence listing and figures to identify the CDRs is that of Kabat, however, different numbering may be used which would alter the amino acid sequences of the CDRs as shown in Table 2.
[0792] For all variable heavy and light domains listed herein, further variants may be made. As outlined herein, in some embodiments, 6 CDR groups may have 0, 1, 2, 3, 4 or 5 amino acid modifications (wherein amino acid substitutions have specific uses), as well as changes in the framework regions of the variable heavy and light domains, as long as the framework (excluding CDRs) retains at least about 80%, 85% or 90% identity to those human germline sequences listed in Figure 1 selected from U.S. Patent No. 7,657,380, and the accompanying drawings and legends are incorporated herein by reference in their entirety. Thus, for example, the same CDRs as described herein may be combined with different framework sequences from human germline sequences, as long as the framework regions retain at least 80%, 85%, 90%, 95% or 99% identity to those human germline sequences listed in Figure 1 selected from U.S. Patent No. 7,657,380. Alternatively, the CDRs may have amino acid modifications (e.g., 1, 2, 3, 4, or 5 amino acid modifications in a CDR set (i.e., a CDR may be modified as long as the total number of changes in a set of 6 CDRs is less than 6 amino acid modifications, with any combination of CDRs being changed; e.g., vlCDR1 may have one change, vhCDR2 two changes, vhCDR3 no change, etc.)), as well as framework region changes, as long as the framework regions retain at least 80%, 85%, 90%, 95%, or 99% identity to a human germline sequence selected from those listed in Figure 1 of U.S. Patent No. 7,657,380.
[0793] As will be appreciated by those skilled in the art, any set of six CDRs or VH and VL domains can be in scFv format or in Fab format and then added to the heavy and light constant domains, wherein the heavy constant domain comprises variants (including within the CH1 domain as well as the Fc domain).
[0794] Furthermore, in embodiments where the subject antibody comprises an scFv, the scFv may be oriented from the N-terminus to the C-terminus VH-scFv linker-VL or VL-scFv linker-VH. In some formats, one or more of the ABDs is typically a Fab, which includes a VH domain on one protein chain (usually as a component of the heavy chain) and a VL on another protein chain (usually as a component of the light chain). Exemplary scFv linkers for use in subject antibodies are depicted in Figure 6A-6B middle.
[0795] Useful CD28-binding domains and PSMA-binding domains that may be included in the subject anti-CD28 x anti-PSMA antibodies are described in further detail herein.
[0796] In some embodiments, the anti-CD28 x anti-PSMA antibody is a bispecific antibody. In some embodiments, the anti-CD28 x anti-PSMA antibody is a bivalent antibody. In some embodiments, the anti-CD28 x anti-PSMA antibody is a trivalent antibody. In some embodiments, the anti-CD28 x ant...
Claims
1. A bispecific antibody, comprising: (a) a first antigen binding domain that binds to CD28, wherein the first antigen binding domain comprises: (1) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 400; or (2) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 35; or (3) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 43; or (4) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 51; or (5) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 59; or (6) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 67; or (7) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 90; or (8) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 98; or (9) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 106; or (10) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 114; or (11) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 122; or (12) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 130; or (13) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 138; or (14) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 146; or (15) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 154; or (16) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 162; or (17) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 170; or (18) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 178; or (19) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 186; or (20) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 194; or (21) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 202; or (22) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 384; or (23) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 392; or (24) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 13; or (25) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 408; or (26) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 412; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 416; or (27) (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 420; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 424; and (b) a second antigen binding domain that binds to PSMA, wherein the second antigen binding domain comprises: (1) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; or (2) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 210; or (3) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 226; or (4) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 234; or (5) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 242; or (6) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 250; or (7) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 258; or (8) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 266; or (9) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 274; or (10) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 282; or (11) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 290; or (12) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 298; or (13) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 306; or (14) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 314; or (15) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 322; or (16) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 330; or (17) (i) VH1, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
338.
2. The bispecific antibody of claim 1, (i) wherein the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the Kabat numbering system; (ii) wherein the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the Chothia numbering system; (iii) wherein the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the AbM numbering system; (iv) wherein the vhCDR1, vhCDR2, vhCDR3, The vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the Contact numbering system; (v) wherein the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the IMGT numbering system; (vi) wherein the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the Kabat+Chothia numbering system; and / or wherein the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2 and vlCDR3 amino acid sequences are according to the Xencor numbering system.
3. A bispecific antibody, comprising: (a) a first antigen binding domain that binds to CD28, wherein the first antigen binding domain comprises: (1) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 397; vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 401, vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and vlCDR3 having an amino acid sequence of SEQ ID NO: 403; or (2) (i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 32; a vhCDR2 having an amino acid sequence of SEQ ID NO: 33; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 34; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 36, a vlCDR2 having an amino acid sequence of SEQ ID NO: 37, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 38; or (3) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 44, a vlCDR2 having an amino acid sequence of SEQ ID NO: 45, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 46; or (4) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 48; a vhCDR2 having an amino acid sequence of SEQ ID NO: 49; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 50; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 52, a vlCDR2 having an amino acid sequence of SEQ ID NO: 53, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 54; or (5) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 56; a vhCDR2 having an amino acid sequence of SEQ ID NO: 57; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 58; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 60, a vlCDR2 having an amino acid sequence of SEQ ID NO: 61, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 62; or (6) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 64; vhCDR2 having an amino acid sequence of SEQ ID NO: 65; and vhCDR3 having an amino acid sequence of SEQ ID NO: 66; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 68, vlCDR2 having an amino acid sequence of SEQ ID NO: 69, and vlCDR3 having an amino acid sequence of SEQ ID NO: 70; or (7) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 87; a vhCDR2 having an amino acid sequence of SEQ ID NO: 88; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 89; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 91, a vlCDR2 having an amino acid sequence of SEQ ID NO: 92, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 93; or (8) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 95; vhCDR2 having an amino acid sequence of SEQ ID NO: 96; and vhCDR3 having an amino acid sequence of SEQ ID NO: 97; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 99, vlCDR2 having an amino acid sequence of SEQ ID NO: 100, and vlCDR3 having an amino acid sequence of SEQ ID NO: 101; or (9) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 103; a vhCDR2 having an amino acid sequence of SEQ ID NO: 104; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 105; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 107, a vlCDR2 having an amino acid sequence of SEQ ID NO: 108, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 109; or (10) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 111; a vhCDR2 having an amino acid sequence of SEQ ID NO: 112; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 113; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 115, a vlCDR2 having an amino acid sequence of SEQ ID NO: 116, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 117; or (11) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 119; vhCDR2 having an amino acid sequence of SEQ ID NO: 120; and vhCDR3 having an amino acid sequence of SEQ ID NO: 121; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 123, vlCDR2 having an amino acid sequence of SEQ ID NO: 124, and vlCDR3 having an amino acid sequence of SEQ ID NO: 125; or (12) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 127; a vhCDR2 having an amino acid sequence of SEQ ID NO: 128; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 129; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 131, a vlCDR2 having an amino acid sequence of SEQ ID NO: 132, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 133; or (13) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 135; a vhCDR2 having an amino acid sequence of SEQ ID NO: 136; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 137; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 139, a vlCDR2 having an amino acid sequence of SEQ ID NO: 140, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 141; or (14) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 143; a vhCDR2 having an amino acid sequence of SEQ ID NO: 144; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 115; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 147, a vlCDR2 having an amino acid sequence of SEQ ID NO: 149, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 149; or (15) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 151; a vhCDR2 having an amino acid sequence of SEQ ID NO: 152; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 153; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 155, a vlCDR2 having an amino acid sequence of SEQ ID NO: 156, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 157; or (16) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 159; vhCDR2 having an amino acid sequence of SEQ ID NO: 160; and vhCDR3 having an amino acid sequence of SEQ ID NO: 161; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 163, vlCDR2 having an amino acid sequence of SEQ ID NO: 164, and vlCDR3 having an amino acid sequence of SEQ ID NO: 165; or (17) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 167; a vhCDR2 having an amino acid sequence of SEQ ID NO: 168; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 169; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 171, a vlCDR2 having an amino acid sequence of SEQ ID NO: 172, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 173; or (18) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 175; a vhCDR2 having an amino acid sequence of SEQ ID NO: 176; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 177; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 179, a vlCDR2 having an amino acid sequence of SEQ ID NO: 180, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 181; or (19) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 183; vhCDR2 having an amino acid sequence of SEQ ID NO: 184; and vhCDR3 having an amino acid sequence of SEQ ID NO: 185; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 187, vlCDR2 having an amino acid sequence of SEQ ID NO: 188, and vlCDR3 having an amino acid sequence of SEQ ID NO: 189; or (20) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 191; vhCDR2 having an amino acid sequence of SEQ ID NO: 192; and vhCDR3 having an amino acid sequence of SEQ ID NO: 193; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 195, vlCDR2 having an amino acid sequence of SEQ ID NO: 196, and vlCDR3 having an amino acid sequence of SEQ ID NO: 197; or (21) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 199; vhCDR2 having an amino acid sequence of SEQ ID NO: 200; and vhCDR3 having an amino acid sequence of SEQ ID NO: 201; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 203, vlCDR2 having an amino acid sequence of SEQ ID NO: 204, and vlCDR3 having an amino acid sequence of SEQ ID NO: 205; or (22) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 381; vhCDR2 having an amino acid sequence of SEQ ID NO: 382; and vhCDR3 having an amino acid sequence of SEQ ID NO: 383; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 385, vlCDR2 having an amino acid sequence of SEQ ID NO: 386, and vlCDR3 having an amino acid sequence of SEQ ID NO: 387; or (23) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 389; vhCDR2 having an amino acid sequence of SEQ ID NO: 390; and vhCDR3 having an amino acid sequence of SEQ ID NO: 391; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 393, vlCDR2 having an amino acid sequence of SEQ ID NO: 394, and vlCDR3 having an amino acid sequence of SEQ ID NO: 395; or (24) (i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 10; a vhCDR2 having an amino acid sequence of SEQ ID NO: 11; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 12; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 14, a vlCDR2 having an amino acid sequence of SEQ ID NO: 15, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 16; or (25) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 405; a vhCDR2 having an amino acid sequence of SEQ ID NO: 406; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 407; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 409, a vlCDR2 having an amino acid sequence of SEQ ID NO: 410, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 411; or (26) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 413; vhCDR2 having an amino acid sequence of SEQ ID NO: 414; and vhCDR3 having an amino acid sequence of SEQ ID NO: 415; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 417, vlCDR2 having an amino acid sequence of SEQ ID NO: 418, and vlCDR3 having an amino acid sequence of SEQ ID NO: 419; or (27) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 421; vhCDR2 having an amino acid sequence of SEQ ID NO: 422; and vhCDR3 having an amino acid sequence of SEQ ID NO: 423; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 425, vlCDR2 having an amino acid sequence of SEQ ID NO: 426, and vlCDR3 having an amino acid sequence of SEQ ID NO: 427; and (b) a second antigen binding domain that binds to PSMA, wherein the second antigen binding domain comprises: (1) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; or (2) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 207; vhCDR2 having an amino acid sequence of SEQ ID NO: 208; and vhCDR3 having an amino acid sequence of SEQ ID NO: 209; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 211, vlCDR2 having an amino acid sequence of SEQ ID NO: 212, and vlCDR3 having an amino acid sequence of SEQ ID NO: 213; or (3) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 223; vhCDR2 having an amino acid sequence of SEQ ID NO: 224; and vhCDR3 having an amino acid sequence of SEQ ID NO: 225; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 227, vlCDR2 having an amino acid sequence of SEQ ID NO: 228, and vlCDR3 having an amino acid sequence of SEQ ID NO: 229; or (4) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 231; vhCDR2 having an amino acid sequence of SEQ ID NO: 232; and vhCDR3 having an amino acid sequence of SEQ ID NO: 233; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 235, vlCDR2 having an amino acid sequence of SEQ ID NO: 236, and vlCDR3 having an amino acid sequence of SEQ ID NO: 237; or (5) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 239; vhCDR2 having an amino acid sequence of SEQ ID NO: 240; and vhCDR3 having an amino acid sequence of SEQ ID NO: 241; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 243, vlCDR2 having an amino acid sequence of SEQ ID NO: 244, and vlCDR3 having an amino acid sequence of SEQ ID NO: 245; or (6) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 247; vhCDR2 having an amino acid sequence of SEQ ID NO: 248; and vhCDR3 having an amino acid sequence of SEQ ID NO: 249; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 251, vlCDR2 having an amino acid sequence of SEQ ID NO: 252, and vlCDR3 having an amino acid sequence of SEQ ID NO: 253; or (7) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 255; vhCDR2 having an amino acid sequence of SEQ ID NO: 256; and vhCDR3 having an amino acid sequence of SEQ ID NO: 257; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 259, vlCDR2 having an amino acid sequence of SEQ ID NO: 260, and vlCDR3 having an amino acid sequence of SEQ ID NO: 261; or (8) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 263; vhCDR2 having an amino acid sequence of SEQ ID NO: 264; and vhCDR3 having an amino acid sequence of SEQ ID NO: 265; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 267, vlCDR2 having an amino acid sequence of SEQ ID NO: 268, and vlCDR3 having an amino acid sequence of SEQ ID NO: 269; or (9) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 271; vhCDR2 having an amino acid sequence of SEQ ID NO: 212; and vhCDR3 having an amino acid sequence of SEQ ID NO: 273; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 275, vlCDR2 having an amino acid sequence of SEQ ID NO: 276, and vlCDR3 having an amino acid sequence of SEQ ID NO: 277; or (10) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 279; vhCDR2 having an amino acid sequence of SEQ ID NO: 280; and vhCDR3 having an amino acid sequence of SEQ ID NO: 281; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 283, vlCDR2 having an amino acid sequence of SEQ ID NO: 284, and vlCDR3 having an amino acid sequence of SEQ ID NO: 285; or (11) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 287; vhCDR2 having an amino acid sequence of SEQ ID NO: 288; and vhCDR3 having an amino acid sequence of SEQ ID NO: 289; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 291, vlCDR2 having an amino acid sequence of SEQ ID NO: 292, and vlCDR3 having an amino acid sequence of SEQ ID NO: 293; or (12) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 295; vhCDR2 having an amino acid sequence of SEQ ID NO: 296; and vhCDR3 having an amino acid sequence of SEQ ID NO: 297; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 299, vlCDR2 having an amino acid sequence of SEQ ID NO: 300, and vlCDR3 having an amino acid sequence of SEQ ID NO: 301; or (13) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 303; vhCDR2 having an amino acid sequence of SEQ ID NO: 304; and vhCDR3 having an amino acid sequence of SEQ ID NO: 305; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 307, vlCDR2 having an amino acid sequence of SEQ ID NO: 308, and vlCDR3 having an amino acid sequence of SEQ ID NO: 309; or (14) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 311; vhCDR2 having an amino acid sequence of SEQ ID NO: 312; and vhCDR3 having an amino acid sequence of SEQ ID NO: 313; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 315, vlCDR2 having an amino acid sequence of SEQ ID NO: 316, and vlCDR3 having an amino acid sequence of SEQ ID NO: 317; or (15) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 319; vhCDR2 having an amino acid sequence of SEQ ID NO: 320; and vhCDR3 having an amino acid sequence of SEQ ID NO: 321; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 323, vlCDR2 having an amino acid sequence of SEQ ID NO: 324, and vlCDR3 having an amino acid sequence of SEQ ID NO: 325; or (16) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 327; vhCDR2 having an amino acid sequence of SEQ ID NO: 328; and vhCDR3 having an amino acid sequence of SEQ ID NO: 329; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 331, vlCDR2 having an amino acid sequence of SEQ ID NO: 332, and vlCDR3 having an amino acid sequence of SEQ ID NO: 333; or (17) (i) VH1, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 335; vhCDR2 having an amino acid sequence of SEQ ID NO: 336; and vhCDR3 having an amino acid sequence of SEQ ID NO: 337; and (ii) VL1, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 339, vlCDR2 having an amino acid sequence of SEQ ID NO: 340, and vlCDR3 having an amino acid sequence of SEQ ID NO:
341.
4. A bispecific antibody, comprising: (a) a first antigen binding domain that binds to CD28, wherein the first antigen binding domain comprises: (1) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 396; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 400; or (2) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 31; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 35; or (3) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 39; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 43; or (4) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 47; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 51; or (5) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 55; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 59; or (6) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 63; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 67; or (7) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 86; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 90; or (8) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 94; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 98; or (9) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 102; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 106; or (10) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 110; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 114; or (11) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 118; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 122; or (12) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 126; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 130; or (13) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 134; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 138; or (14) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 142; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 146; or (15) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 150; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 154; or (16) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 158; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 162; or (17) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 166; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 170; or (18) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 174; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 178; or (19) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 182; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 186; or (20) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 190; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 194; or (21) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 198; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 202; or (22) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 380; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 384; or (23) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 388; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 392; or (24) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 9; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 13; or (25) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 404; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 408; or (26) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 412; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 416; or (27) (i) a VH2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 420; and (ii) a VL2 having an amino acid sequence at least about 95% identical to SEQ ID NO: 424; and (b) a second antigen binding domain that binds to CD28, wherein the second antigen binding domain comprises: (1) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 214; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 218; or (2) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 206; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 210; or (3) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 222; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 226; or (4) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 230; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 234; or (5) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 238; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 242; or (6) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 246; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 250; or (7) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 254; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 258; or (8) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 262; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 266; or (9) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 270; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 274; or (10) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 278; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 282; or (11) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 286; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 290; or (12) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 294; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 298; or (13) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 302; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 306; or (14) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 310; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 314; or (15) (i) a VH1 having an amino acid sequence that is at least about 95% identical to SEQ ID NO: 318; and (ii) a VL1 having an amino acid sequence that is at least about 95% identical to SEQ ID NO: 322; or (16) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 326; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO: 330; or (17) (i) a VH1 having an amino acid sequence at least about 95% identical to SEQ ID NO:334; and (ii) a VL1 having an amino acid sequence at least about 95% identical to SEQ ID NO:
338.
5. The bispecific antibody of any one of claims 1 to 4, wherein the antibody is a humanized antibody.
6. The antibody of any one of claims 1-4, wherein the antibody is a human antibody.
7. The bispecific antibody of any one of claims 1-6, wherein the antibody is an IgG antibody. The bispecific antibody of claim 7 , wherein the IgG antibody is an IgG1, IgG2, IgG3 or IgG4 antibody.
9. The bispecific antibody of claim 8, wherein the IgG antibody is an IgG1 antibody.
10. The bispecific antibody of any one of claims 1-9, wherein the PSMA is present on the surface of a cell. The bispecific antibody of claim 10 , wherein the cell is a prostate cell.
12. The bispecific antibody of claim 11, wherein the cell is a prostate cancer cell.
13. The bispecific antibody of any one of claims 1-12, wherein the antibody comprises a first Fc domain and a second Fc domain.
14. The bispecific antibody of any one of claims 1-12, wherein the antibody comprises a first Fc domain and a second Fc domain, and the first Fc domain and the second Fc domain are each variant Fc domains.
15. The bispecific antibody of claim 14, wherein one of the first and second Fc domains comprises the heterodimerization variant T366W and the other of the first and second Fc domains comprises the heterodimerization variant T366S / L368A / Y407V, wherein numbering is according to EU numbering.
16. The bispecific antibody of claim 15, wherein the first Fc domain comprises the heterodimerization variant T366W, and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V.
17. The bispecific antibody according to any one of claims 14 to 16, wherein the first Fc domain and the second Fc domain each comprise one or more ablation variants.
18. The bispecific antibody of claim 17, wherein the one or more ablation variants comprise L234A / L235A / D265S, wherein numbering is according to EU numbering.
19. The bispecific antibody according to any one of claims 14 to 18, wherein the first Fc domain or the second Fc domain comprises the purification variant H435R / Y436F, wherein the numbering is according to EU numbering.
20. The bispecific antibody of claim 19, wherein the second Fc domain comprises the purified variant H435R / Y436F.
21. The bispecific antibody according to any one of claims 14 to 20, wherein the first Fc domain comprises the amino acid substitutions L234A / L235A / D265S / LT366W and the second Fc domain comprises the amino acid substitutions L234A / L235A / D265S / T366S / L368A / Y407V / H435R / Y436F, wherein the numbering is according to EU numbering.
22. The bispecific antibody according to any one of claims 15 to 21, wherein the first Fc domain and the second Fc domain each further comprise the amino acid substitutions M252Y / S254T / T256E, wherein the numbering is according to EU numbering.
23. The bispecific antibody of claim 14, wherein the first and second Fc domains comprise a set of heterodimerization skew variants selected from the following heterodimerization variants: S364K / E357Q:L368D / K370S; S364K:L368D / K370S; S364K:L368E / K370S; D401K:T411E / K360E / Q362E; and T366W:T366S / L368A / Y407V, wherein numbering is according to EU numbering.
24. The bispecific antibody of claim 23, wherein the first and second Fc domains comprise the heterodimerization skew variant S364K / E357Q:L368D / K370S, wherein numbering is according to EU numbering.
25. The bispecific antibody of any one of claims 14, 23 or 24, wherein the first Fc domain and the second Fc domain each comprise one or more ablation variants.
26. The bispecific antibody of claim 25, wherein the one or more ablation variants comprise E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.
27. The bispecific antibody according to any one of claims 13 to 26, comprising: a) a first monomer comprising: i) single chain variable fragment (scFv); and ii) said first Fc domain, wherein said scFv is covalently linked to the N-terminus of said first Fc domain using a domain linker; b) a second monomer comprising, from N-terminus to C-terminus, VH1-CH1-hinge-CH2-CH3, wherein said VH1 is the first variable heavy domain and CH2-CH3 is the second Fc domain; and c) a light chain comprising from N-terminus to C-terminus VL1-CL, wherein said VL1 is a first variable light domain and CL is a constant light domain, wherein the scFv comprises a second VH domain (VH2), an scFv linker and a second variable light domain (VL2), wherein said VH2 and said VL2 together form said first antigen binding domain and said VH1 and said VL1 together form said second binding domain.
28. The bispecific antibody according to any one of claims 13 to 26, comprising: a) a first monomer, which comprises, from N-terminus to C-terminus, VH1-CH1-first domain linker-scFv-second domain linker-CH2-CH3, wherein VH1 is the first variable heavy domain, and CH2-CH3 is the first Fc domain; b) a second monomer comprising, from N-terminus to C-terminus, VH1-CH1-hinge-CH2-CH3, wherein CH2-CH3 is a second Fc domain; and c) a light chain comprising from N-terminus to C-terminus VL1-CL, wherein VL1 is the first variable light domain and CL is the constant light domain, wherein the scFv comprises a second VH domain (VH2), a scFv linker and a second variable light domain (VL2) wherein said VH2 and said VL2 form a first ABD, and each of said VH1 and said VL1 together form a second antigen binding domain (ABD), and Wherein the first ABD binds human CD28 and the second ABD binds PSMA.
29. The bispecific antibody according to any one of claims 13 to 26, comprising: a) a first monomer comprising, from N-terminus to C-terminus, VH1-CH1-hinge-CH2-CH3-domain linker-scFv, wherein VH1 is the first variable heavy domain, and CH2-CH3 is the first Fc domain; b) a second monomer comprising, from N-terminus to C-terminus, VH1-CH1-hinge-CH2-CH3, wherein VH1 is a first variable heavy domain and CH2-CH3 is a second Fc domain; and c) a light chain comprising from N-terminus to C-terminus VL1-CL, wherein VL1 is the first variable light domain and CL is the constant light domain, wherein the scFv comprises a second VH domain (VH2), a scFv linker and a second variable light domain (VL2) wherein said VH2 and said VL2 form a first ABD, and each of said VH1 and said VL1 together form a second antigen binding domain (ABD), and Wherein the first ABD binds human CD28 and the second ABD binds PSMA.
30. The bispecific antibody of any one of claims 27-29, wherein one of the first monomer or the second monomer further comprises a pi variant.
31. The bispecific antibody of claim 30, wherein the CH1-hinge-CH2-CH3 of the second monomer comprises the pi variant N208D / Q295E / N384D / Q418E / N421D, wherein the numbering is according to EU numbering.
32. The bispecific antibody according to any one of claims 27 to 31, wherein the CH1-hinge-CH2-CH3 of the second monomer comprises the amino acid variants E233P / L234V / L235A / G236del / S267K / L368D / K370S / N208D / Q295E / N384D / Q418E / N421D, wherein the first Fc domain comprises the amino acid variants E233P / L234V / L235A / G236del / S267K / S364K / E357Q, And the numbering is based on EU numbering.
33. The bispecific antibody of any one of claims 23-32, wherein the first variant Fc domain and the second variant Fc domain each further comprise the amino acid variants 428L / 434S.
34. The bispecific antibody according to any one of claims 27 to 33, wherein the scFv linker is selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 456) and GGGSGGS GGCPPCGGSGG (SEQ ID NO: 457).
35. A heterodimeric antibody, comprising: a) a first monomer comprising: i) single chain variable fragment (scFv); and ii) a first Fc domain, wherein the scFv is covalently linked to the N-terminus of the first Fc domain using a domain linker; b) a second monomer comprising, from N-terminus to C-terminus, VH1-CH1-hinge-CH2-CH3, wherein VH1 is a first variable heavy domain and CH2-CH3 is a second Fc domain; and c) a light chain comprising from N-terminus to C-terminus VL1-CL, wherein VL1 is the first variable light domain and CL is the constant light domain, wherein the scFv comprises a second VH domain (VH2), an scFv linker and a second variable light domain (VL2), wherein said VH1 and said VL1 together form a first antigen binding domain (ABD) and said VH2 and said VL2 together form a second ABD, and wherein one of the first ABD and the second ABD binds CD28 and the other of the first ABD and the second ABD binds prostate specific membrane antigen (PSMA).
36. The heterodimeric antibody of claim 35, wherein the first ABD binds human CD28 and the second ABD binds PSMA.
37. The heterodimeric antibody of claim 35, wherein the first ABD binds PSMA and the second ABD binds human CD28.
38. The heterodimeric antibody of claim 35, wherein the scFv comprises VH2-scFv linker-VL2 from N-terminus to C-terminus.
39. The heterodimeric antibody of claim 35, wherein the scFv comprises VL2-scFv linker-VH2 from N-terminus to C-terminus.
40. The heterodimeric antibody of any one of claims 35 to 39, wherein the first ABD binds to human PSMA, and wherein VH1 and VL1 are selected from the group consisting of: (1) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; or (2) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 210; or (3) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 226; or (4) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 234; or (5) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 242; or (6) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 250; or (7) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 258; or (8) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 266; or (9) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 274; or (10) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 282; or (11) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 290; or (12) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 298; or (13) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 306; or (14) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 314; or (15) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 322; or (16) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 330; or (17) (i) VH1, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
338.
41. The heterodimeric antibody of claim 40, wherein VH1 and VL1 are selected from the following: (1) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; or (2) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 207; vhCDR2 having an amino acid sequence of SEQ ID NO: 208; and vhCDR3 having an amino acid sequence of SEQ ID NO: 209; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 211, vlCDR2 having an amino acid sequence of SEQ ID NO: 212, and vlCDR3 having an amino acid sequence of SEQ ID NO: 213; (3) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 223; vhCDR2 having an amino acid sequence of SEQ ID NO: 224; and vhCDR3 having an amino acid sequence of SEQ ID NO: 225; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 227, vlCDR2 having an amino acid sequence of SEQ ID NO: 228, and vlCDR3 having an amino acid sequence of SEQ ID NO: 229; or (4) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 231; vhCDR2 having an amino acid sequence of SEQ ID NO: 232; and vhCDR3 having an amino acid sequence of SEQ ID NO: 233; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 235, vlCDR2 having an amino acid sequence of SEQ ID NO: 236, and vlCDR3 having an amino acid sequence of SEQ ID NO: 237; or (5) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 239; vhCDR2 having an amino acid sequence of SEQ ID NO: 240; and vhCDR3 having an amino acid sequence of SEQ ID NO: 241; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 243, vlCDR2 having an amino acid sequence of SEQ ID NO: 244, and vlCDR3 having an amino acid sequence of SEQ ID NO: 245; or (6) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 247; vhCDR2 having an amino acid sequence of SEQ ID NO: 248; and vhCDR3 having an amino acid sequence of SEQ ID NO: 249; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 251, vlCDR2 having an amino acid sequence of SEQ ID NO: 252, and vlCDR3 having an amino acid sequence of SEQ ID NO: 253; or (7) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 255; vhCDR2 having an amino acid sequence of SEQ ID NO: 256; and vhCDR3 having an amino acid sequence of SEQ ID NO: 257; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 259, vlCDR2 having an amino acid sequence of SEQ ID NO: 260, and vlCDR3 having an amino acid sequence of SEQ ID NO: 261; or (8) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 263; vhCDR2 having an amino acid sequence of SEQ ID NO: 264; and vhCDR3 having an amino acid sequence of SEQ ID NO: 265; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 267, vlCDR2 having an amino acid sequence of SEQ ID NO: 268, and vlCDR3 having an amino acid sequence of SEQ ID NO: 269; or (9) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 271; vhCDR2 having an amino acid sequence of SEQ ID NO: 212; and vhCDR3 having an amino acid sequence of SEQ ID NO: 273; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 275, vlCDR2 having an amino acid sequence of SEQ ID NO: 276, and vlCDR3 having an amino acid sequence of SEQ ID NO: 277; or (10) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 279; vhCDR2 having an amino acid sequence of SEQ ID NO: 280; and vhCDR3 having an amino acid sequence of SEQ ID NO: 281; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 283, vlCDR2 having an amino acid sequence of SEQ ID NO: 284, and vlCDR3 having an amino acid sequence of SEQ ID NO: 285; or (11) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 287; vhCDR2 having an amino acid sequence of SEQ ID NO: 288; and vhCDR3 having an amino acid sequence of SEQ ID NO: 289; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 291, vlCDR2 having an amino acid sequence of SEQ ID NO: 292, and vlCDR3 having an amino acid sequence of SEQ ID NO: 293; or (12) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 295; vhCDR2 having an amino acid sequence of SEQ ID NO: 296; and vhCDR3 having an amino acid sequence of SEQ ID NO: 297; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 299, vlCDR2 having an amino acid sequence of SEQ ID NO: 300, and vlCDR3 having an amino acid sequence of SEQ ID NO: 301; or (13) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 303; vhCDR2 having an amino acid sequence of SEQ ID NO: 304; and vhCDR3 having an amino acid sequence of SEQ ID NO: 305; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 307, vlCDR2 having an amino acid sequence of SEQ ID NO: 308, and vlCDR3 having an amino acid sequence of SEQ ID NO: 309; or (14) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 311; vhCDR2 having an amino acid sequence of SEQ ID NO: 312; and vhCDR3 having an amino acid sequence of SEQ ID NO: 313; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 315, vlCDR2 having an amino acid sequence of SEQ ID NO: 316, and vlCDR3 having an amino acid sequence of SEQ ID NO: 317; or (15) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 319; vhCDR2 having an amino acid sequence of SEQ ID NO: 320; and vhCDR3 having an amino acid sequence of SEQ ID NO: 321; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 323, vlCDR2 having an amino acid sequence of SEQ ID NO: 324, and vlCDR3 having an amino acid sequence of SEQ ID NO: 325; or (16) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 327; vhCDR2 having an amino acid sequence of SEQ ID NO: 328; and vhCDR3 having an amino acid sequence of SEQ ID NO: 329; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 331, vlCDR2 having an amino acid sequence of SEQ ID NO: 332, and vlCDR3 having an amino acid sequence of SEQ ID NO: 333; or (17) (i) VH1, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 335; vhCDR2 having an amino acid sequence of SEQ ID NO: 336; and vhCDR3 having an amino acid sequence of SEQ ID NO: 337; and (ii) VL1, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 339, vlCDR2 having an amino acid sequence of SEQ ID NO: 340, and vlCDR3 having an amino acid sequence of SEQ ID NO:
341.
42. The heterodimeric antibody of claim 40, wherein VH1 and VL1 are selected from the following: (1) (i) VH1 having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 218; or (2) (i) VH1 having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 210; or (3) (i) VH1 having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 226; or (4) (i) VH1 having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 234; or (5) (i) VH1 having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 242; or (6) (i) VH1 having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 250; or (7) (i) VH1 having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 258; or (8) (i) VH1 having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 266; or (9) (i) VH1 having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 274; or (10) (i) VH1 having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 282; or (11) (i) VH1 having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 290; or (12) (i) VH1 having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 298; or (13) (i) VH1 having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 306; or (14) (i) VH1 having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 314; or (15) (i) VH1 having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 322; or (16) (i) VH1 having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 330; or (17) (i) VH1 having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1 having the amino acid sequence of SEQ ID NO:
338.
43. The heterodimeric antibody of any one of claims 35 to 43, wherein the second ABD binds to human CD28, and wherein VH2 and VL2 are selected from the following: (1) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 400; or (2) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 35; or (3) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 43; or (4) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 51; or (5) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 59; or (6) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 67; or (7) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 90; or (8) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 98; or (9) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 106; or (10) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 114; or (11) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 122; or (12) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 130; or (13) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 138; or (14) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 146; or (15) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 154; or (16) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 162; or (17) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 170; or (18) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 178; or (19) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 186; or (20) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 194; or (21) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 202; or (22) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 384; or (23) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 392; or (24) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 13; or (25) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 408; or (26) (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 412; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 416; or (27) (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 420; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
424.
44. The heterodimeric antibody of claim 43, wherein VH2 and VL2 are selected from the following: (1) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 397; vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 401, vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and vlCDR3 having an amino acid sequence of SEQ ID NO: 403; or (2) (i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 32; a vhCDR2 having an amino acid sequence of SEQ ID NO: 33; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 34; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 36, a vlCDR2 having an amino acid sequence of SEQ ID NO: 37, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 38; or (3) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 44, a vlCDR2 having an amino acid sequence of SEQ ID NO: 45, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 46; or (4) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 48; a vhCDR2 having an amino acid sequence of SEQ ID NO: 49; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 50; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 52, a vlCDR2 having an amino acid sequence of SEQ ID NO: 53, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 54; or (5) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 56; a vhCDR2 having an amino acid sequence of SEQ ID NO: 57; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 58; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 60, a vlCDR2 having an amino acid sequence of SEQ ID NO: 61, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 62; or (6) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 64; vhCDR2 having an amino acid sequence of SEQ ID NO: 65; and vhCDR3 having an amino acid sequence of SEQ ID NO: 66; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 68, vlCDR2 having an amino acid sequence of SEQ ID NO: 69, and vlCDR3 having an amino acid sequence of SEQ ID NO: 70; or (7) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 87; a vhCDR2 having an amino acid sequence of SEQ ID NO: 88; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 89; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 91, a vlCDR2 having an amino acid sequence of SEQ ID NO: 92, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 93; or (8) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 95; vhCDR2 having an amino acid sequence of SEQ ID NO: 96; and vhCDR3 having an amino acid sequence of SEQ ID NO: 97; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 99, vlCDR2 having an amino acid sequence of SEQ ID NO: 100, and vlCDR3 having an amino acid sequence of SEQ ID NO: 101; or (9) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 103; a vhCDR2 having an amino acid sequence of SEQ ID NO: 104; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 105; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 107, a vlCDR2 having an amino acid sequence of SEQ ID NO: 108, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 109; or (10) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 111; a vhCDR2 having an amino acid sequence of SEQ ID NO: 112; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 113; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 115, a vlCDR2 having an amino acid sequence of SEQ ID NO: 116, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 117; or (11) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 119; vhCDR2 having an amino acid sequence of SEQ ID NO: 120; and vhCDR3 having an amino acid sequence of SEQ ID NO: 121; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 123, vlCDR2 having an amino acid sequence of SEQ ID NO: 124, and vlCDR3 having an amino acid sequence of SEQ ID NO: 125; or (12) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 127; a vhCDR2 having an amino acid sequence of SEQ ID NO: 128; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 129; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 131, a vlCDR2 having an amino acid sequence of SEQ ID NO: 132, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 133; or (13) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 135; a vhCDR2 having an amino acid sequence of SEQ ID NO: 136; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 137; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 139, a vlCDR2 having an amino acid sequence of SEQ ID NO: 140, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 141; or (14) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 143; a vhCDR2 having an amino acid sequence of SEQ ID NO: 144; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 115; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 147, a vlCDR2 having an amino acid sequence of SEQ ID NO: 149, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 149; or (15) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 151; a vhCDR2 having an amino acid sequence of SEQ ID NO: 152; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 153; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 155, a vlCDR2 having an amino acid sequence of SEQ ID NO: 156, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 157; or (16) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 159; vhCDR2 having an amino acid sequence of SEQ ID NO: 160; and vhCDR3 having an amino acid sequence of SEQ ID NO: 161; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 163, vlCDR2 having an amino acid sequence of SEQ ID NO: 164, and vlCDR3 having an amino acid sequence of SEQ ID NO: 165; or (17) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 167; a vhCDR2 having an amino acid sequence of SEQ ID NO: 168; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 169; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 171, a vlCDR2 having an amino acid sequence of SEQ ID NO: 172, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 173; or (18) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 175; a vhCDR2 having an amino acid sequence of SEQ ID NO: 176; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 177; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 179, a vlCDR2 having an amino acid sequence of SEQ ID NO: 180, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 181; or (19) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 183; vhCDR2 having an amino acid sequence of SEQ ID NO: 184; and vhCDR3 having an amino acid sequence of SEQ ID NO: 185; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 187, vlCDR2 having an amino acid sequence of SEQ ID NO: 188, and vlCDR3 having an amino acid sequence of SEQ ID NO: 189; or (20) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 191; vhCDR2 having an amino acid sequence of SEQ ID NO: 192; and vhCDR3 having an amino acid sequence of SEQ ID NO: 193; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 195, vlCDR2 having an amino acid sequence of SEQ ID NO: 196, and vlCDR3 having an amino acid sequence of SEQ ID NO: 197; or (21) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 199; vhCDR2 having an amino acid sequence of SEQ ID NO: 200; and vhCDR3 having an amino acid sequence of SEQ ID NO: 201; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 203, vlCDR2 having an amino acid sequence of SEQ ID NO: 204, and vlCDR3 having an amino acid sequence of SEQ ID NO: 205; or (22) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 381; vhCDR2 having an amino acid sequence of SEQ ID NO: 382; and vhCDR3 having an amino acid sequence of SEQ ID NO: 383; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 385, vlCDR2 having an amino acid sequence of SEQ ID NO: 386, and vlCDR3 having an amino acid sequence of SEQ ID NO: 387; or (23) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 389; vhCDR2 having an amino acid sequence of SEQ ID NO: 390; and vhCDR3 having an amino acid sequence of SEQ ID NO: 391; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 393, vlCDR2 having an amino acid sequence of SEQ ID NO: 394, and vlCDR3 having an amino acid sequence of SEQ ID NO: 395; or (24) (i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 10; a vhCDR2 having an amino acid sequence of SEQ ID NO: 11; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 12; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 14, a vlCDR2 having an amino acid sequence of SEQ ID NO: 15, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 16; or (25) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 405; a vhCDR2 having an amino acid sequence of SEQ ID NO: 406; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 407; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 409, a vlCDR2 having an amino acid sequence of SEQ ID NO: 410, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 411; or (26) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 413; vhCDR2 having an amino acid sequence of SEQ ID NO: 414; and vhCDR3 having an amino acid sequence of SEQ ID NO: 415; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 417, vlCDR2 having an amino acid sequence of SEQ ID NO: 418, and vlCDR3 having an amino acid sequence of SEQ ID NO: 419; or (27) i) VH2, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 421; vhCDR2 having an amino acid sequence of SEQ ID NO: 422; and vhCDR3 having an amino acid sequence of SEQ ID NO: 423; and (ii) VL2, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 425, vlCDR2 having an amino acid sequence of SEQ ID NO: 426, and vlCDR3 having an amino acid sequence of SEQ ID NO:
427.
45. The heterodimeric antibody of claim 43, wherein VH2 and VL2 are selected from the following: (1) (i) VH2 having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 400; or (2) (i) VH2 having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 35; or (3) (i) VH2 having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 43; or (4) (i) VH2 having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 51; or (5) (i) VH2 having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 59; or (6) (i) VH2 having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 67; or (7) (i) VH2 having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 90; or (8) (i) VH2 having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 98; or (9) (i) VH2 having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 106; or (10) (i) VH2 having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 114; or (11) (i) VH2 having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 122; or (12) (i) VH2 having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 130; or (13) (i) VH2 having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 138; or (14) (i) VH2 having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 146; or (15) (i) VH2 having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 154; or (16) (i) VH2 having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 162; or (17) (i) VH2 having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 170; or (18) (i) VH2 having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 178; or (19) (i) VH2 having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 186; or (20) (i) VH2 having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 194; or (21) (i) VH2 having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 202; or (22) (i) VH2 having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 384; or (23) (i) VH2 having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 392; or (24) (i) VH2 having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 13; or (25) (i) VH2 having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 408; or (26) (i) VH2 having the amino acid sequence of SEQ ID NO: 412; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 416; or (27) (i) VH2 having the amino acid sequence of SEQ ID NO:420; and (ii) VL2 having the amino acid sequence of SEQ ID NO:
424.
46. The heterodimeric antibody according to any one of claims 35 to 45, wherein VH1 comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
43.
47. The heterodimeric antibody according to claim 46, wherein VH1 comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; wherein VL1 comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; wherein VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and wherein VL2 comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:44, vlCDR2 having the amino acid sequence of SEQ ID NO:45, and vlCDR3 having the amino acid sequence of SEQ ID NO:
46.
48. The heterodimeric antibody according to any one of claims 35 to 45, wherein VH1 comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 396; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
400.
49. The heterodimeric antibody according to claim 48, wherein VH1 comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; wherein VL1 comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; wherein VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 397; a vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and wherein VL2 comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:401, vlCDR2 having the amino acid sequence of SEQ ID NO:402, and vlCDR3 having the amino acid sequence of SEQ ID NO:
403.
50. The heterodimeric antibody according to any one of claims 35 to 49, wherein the first Fc domain and the second Fc domain are each variant Fc domains.
51. A heterodimeric antibody as described in claim 50, wherein one of the first Fc domain and the second Fc domain comprises the heterodimerization variant T366W, and the other of the first Fc domain and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V, wherein the numbering is according to EU numbering.
52. The heterodimeric antibody of claim 51, wherein the first Fc domain comprises the heterodimerization variant T366W, and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V.
53. The heterodimeric antibody according to any one of claims 50 to 52, wherein the first Fc domain and the second Fc domain each comprise one or more ablation variants.
54. The heterodimeric antibody of claim 53, wherein the one or more ablation variants comprise L234A / L235A / D265S, wherein numbering is according to EU numbering.
55. The heterodimeric antibody of any one of claims 50 to 54, wherein the first Fc domain or the second Fc domain comprises the purification variant H435R / Y436F, wherein the numbering is according to EU numbering.
56. The heterodimeric antibody of claim 55, wherein the second Fc domain comprises the purified variant H435R / Y436F.
57. A heterodimeric antibody according to any one of claims 50 to 54, wherein the first Fc domain comprises amino acid substitutions L234A / L235A / D265S / LT366W, and the second Fc domain comprises amino acid substitutions L234A / L235A / D265S / T366S / L368A / Y407V / H435R / Y436F, wherein numbering is according to EU numbering.
58. The heterodimeric antibody of any one of claims 51 to 57, wherein the first Fc domain and the second Fc domain each further comprise the amino acid substitution M252Y / S254T / T256E, wherein the numbering is according to EU numbering.
59. The heterodimeric antibody of claim 51, wherein the first Fc domain and the second Fc domain comprise a set of heterodimerization skew variants selected from the following heterodimerization variants: S364K / E357Q:L368D / K370S; S364K:L368D / K370S; S364K:L368E / K370S; D401K:T411E / K360E / Q362E; and T366W:T366S / L368A / Y407V, wherein numbering is according to EU numbering.
60. The heterodimeric antibody of claim 59, wherein the first Fc domain and the second Fc domain comprise the heterodimerization skew variant S364K / E357Q:L368D / K370S, wherein the numbering is according to EU numbering.
61. A heterodimeric antibody according to any one of claims 50, 59 or 60, wherein the first Fc domain and the second Fc domain each comprise one or more ablation variants.
62. The heterodimeric antibody of claim B25, wherein the one or more ablation variants comprise E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.
63. The heterodimeric antibody of any one of claims B14 or 59-62, wherein one of the first monomer or the second monomer further comprises a pI variant.
64. The heterodimeric antibody of claim 63, wherein the CH1-hinge-CH2-CH3 of the second monomer comprises the pI variant N208D / Q295E / N384D / Q418E / N421D, wherein the numbering is according to EU numbering.
65. The heterodimeric antibody according to any one of claims 50 or 59-64, wherein the CH1-hinge-CH2-CH3 of the second monomer comprises the amino acid variants E233P / L234V / L235A / G236del / S267K / L368D / K370S / N208D / Q295E / N384D / Q418E / N421D, wherein the first Fc domain comprises the amino acid variants E233P / L234V / L235A / G236del / S267K / S364K / E357Q, And the numbering is based on EU numbering.
66. The heterodimeric antibody of any one of claims 59-65, wherein the first variant Fc domain and the second variant Fc domain each further comprise amino acid variants 428L / 434S.
67. The heterodimeric antibody of any one of claims 35 to 66, wherein the scFv linker is selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 456), and GGGSGGS GGCPPCGGSGG (SEQ ID NO: 457).
68. A heterodimeric antibody, comprising: a) a first monomer, which comprises, from N-terminus to C-terminus, VH1-CH1-first domain linker-scFv-second domain linker-CH2-CH3, wherein VH1 is the first variable heavy domain, and CH2-CH3 is the first Fc domain; b) a second monomer comprising, from N-terminus to C-terminus, VH1-CH1-hinge-CH2-CH3, wherein CH2-CH3 is a second Fc domain; and c) a light chain comprising from N-terminus to C-terminus VL1-CL, wherein VL1 is the first variable light domain and CL is the constant light domain, wherein the scFv comprises a second VH domain (VH2), a scFv linker and a second variable light domain (VL2) wherein each of the VH1 and the VL1 together form a first antigen binding domain (ABD), and the VH2 and the VL2 form a second ABD, and wherein one of the first ABD and the second ABD binds human CD28 and the other of the first ABD and the second ABD binds PSMA.
69. The heterodimeric antibody of claim 68, wherein the first ABD binds human CD28 and the second ABD binds PSMA.
70. The heterodimeric antibody of claim 68, wherein the first ABD binds PSMA and the second ABD binds human CD28.
71. The heterodimeric antibody of any one of claims 68 to 70, wherein the scFv comprises VH2-scFv linker-VL2 from N-terminus to C-terminus.
72. The heterodimeric antibody of any one of claims 68 to 70, wherein the scFv comprises VL2-scFv linker-VH2 from N-terminus to C-terminus.
73. The heterodimeric antibody of any one of claims 68 to 72, wherein the first ABD binds to human PSMA, and wherein VH1 and VL1 are selected from the following: (1) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; or (2) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 210; or (3) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 226; or (4) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 234; or (5) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 242; or (6) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 250; or (7) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 258; or (8) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 266; or (9) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 274; or (10) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 282; or (11) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 290; or (12) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 298; or (13) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 306; or (14) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 314; or (15) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 322; or (16) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 330; or (17) (i) VH1, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
338.
74. The heterodimeric antibody of claim 73, wherein VH1 and VL1 are selected from the following: (1) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; (2) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 207; vhCDR2 having an amino acid sequence of SEQ ID NO: 208; and vhCDR3 having an amino acid sequence of SEQ ID NO: 209; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 211, vlCDR2 having an amino acid sequence of SEQ ID NO: 212, and vlCDR3 having an amino acid sequence of SEQ ID NO: 213; or (3) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 223; vhCDR2 having an amino acid sequence of SEQ ID NO: 224; and vhCDR3 having an amino acid sequence of SEQ ID NO: 225; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 227, vlCDR2 having an amino acid sequence of SEQ ID NO: 228, and vlCDR3 having an amino acid sequence of SEQ ID NO: 229; or (4) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 231; vhCDR2 having an amino acid sequence of SEQ ID NO: 232; and vhCDR3 having an amino acid sequence of SEQ ID NO: 233; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 235, vlCDR2 having an amino acid sequence of SEQ ID NO: 236, and vlCDR3 having an amino acid sequence of SEQ ID NO: 237; or (5) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 239; vhCDR2 having an amino acid sequence of SEQ ID NO: 240; and vhCDR3 having an amino acid sequence of SEQ ID NO: 241; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 243, vlCDR2 having an amino acid sequence of SEQ ID NO: 244, and vlCDR3 having an amino acid sequence of SEQ ID NO: 245; or (6) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 247; vhCDR2 having an amino acid sequence of SEQ ID NO: 248; and vhCDR3 having an amino acid sequence of SEQ ID NO: 249; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 251, vlCDR2 having an amino acid sequence of SEQ ID NO: 252, and vlCDR3 having an amino acid sequence of SEQ ID NO: 253; or (7) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 255; vhCDR2 having an amino acid sequence of SEQ ID NO: 256; and vhCDR3 having an amino acid sequence of SEQ ID NO: 257; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 259, vlCDR2 having an amino acid sequence of SEQ ID NO: 260, and vlCDR3 having an amino acid sequence of SEQ ID NO: 261; or (8) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 263; vhCDR2 having an amino acid sequence of SEQ ID NO: 264; and vhCDR3 having an amino acid sequence of SEQ ID NO: 265; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 267, vlCDR2 having an amino acid sequence of SEQ ID NO: 268, and vlCDR3 having an amino acid sequence of SEQ ID NO: 269; or (9) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 271; vhCDR2 having an amino acid sequence of SEQ ID NO: 212; and vhCDR3 having an amino acid sequence of SEQ ID NO: 273; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 275, vlCDR2 having an amino acid sequence of SEQ ID NO: 276, and vlCDR3 having an amino acid sequence of SEQ ID NO: 277; or (10) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 279; vhCDR2 having an amino acid sequence of SEQ ID NO: 280; and vhCDR3 having an amino acid sequence of SEQ ID NO: 281; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 283, vlCDR2 having an amino acid sequence of SEQ ID NO: 284, and vlCDR3 having an amino acid sequence of SEQ ID NO: 285; or (11) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 287; vhCDR2 having an amino acid sequence of SEQ ID NO: 288; and vhCDR3 having an amino acid sequence of SEQ ID NO: 289; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 291, vlCDR2 having an amino acid sequence of SEQ ID NO: 292, and vlCDR3 having an amino acid sequence of SEQ ID NO: 293; or (12) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 295; vhCDR2 having an amino acid sequence of SEQ ID NO: 296; and vhCDR3 having an amino acid sequence of SEQ ID NO: 297; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 299, vlCDR2 having an amino acid sequence of SEQ ID NO: 300, and vlCDR3 having an amino acid sequence of SEQ ID NO: 301; or (13) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 303; vhCDR2 having an amino acid sequence of SEQ ID NO: 304; and vhCDR3 having an amino acid sequence of SEQ ID NO: 305; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 307, vlCDR2 having an amino acid sequence of SEQ ID NO: 308, and vlCDR3 having an amino acid sequence of SEQ ID NO: 309; or (14) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 311; vhCDR2 having an amino acid sequence of SEQ ID NO: 312; and vhCDR3 having an amino acid sequence of SEQ ID NO: 313; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 315, vlCDR2 having an amino acid sequence of SEQ ID NO: 316, and vlCDR3 having an amino acid sequence of SEQ ID NO: 317; or (15) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 319; vhCDR2 having an amino acid sequence of SEQ ID NO: 320; and vhCDR3 having an amino acid sequence of SEQ ID NO: 321; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 323, vlCDR2 having an amino acid sequence of SEQ ID NO: 324, and vlCDR3 having an amino acid sequence of SEQ ID NO: 325; or (16) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 327; vhCDR2 having an amino acid sequence of SEQ ID NO: 328; and vhCDR3 having an amino acid sequence of SEQ ID NO: 329; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 331, vlCDR2 having an amino acid sequence of SEQ ID NO: 332, and vlCDR3 having an amino acid sequence of SEQ ID NO: 333; or (17) (i) VH1, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 335; vhCDR2 having an amino acid sequence of SEQ ID NO: 336; and vhCDR3 having an amino acid sequence of SEQ ID NO: 337; and (ii) VL1, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 339, vlCDR2 having an amino acid sequence of SEQ ID NO: 340, and vlCDR3 having an amino acid sequence of SEQ ID NO:
341.
75. The heterodimeric antibody of claim 73, wherein VH1 and VL1 are selected from the following: (1) (i) VH1 having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 218; or (2) (i) VH1 having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 210; or (3) (i) VH1 having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 226; or (4) (i) VH1 having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 234; or (5) (i) VH1 having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 242; or (6) (i) VH1 having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 250; or (7) (i) VH1 having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 258; or (8) (i) VH1 having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 266; or (9) (i) VH1 having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 274; or (10) (i) VH1 having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 282; or (11) (i) VH1 having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 290; or (12) (i) VH1 having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 298; or (13) (i) VH1 having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 306; or (14) (i) VH1 having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 314; or (15) (i) VH1 having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 322; or (16) (i) VH1 having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 330; or (17) (i) VH1 having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1 having the amino acid sequence of SEQ ID NO:
338.
76. The heterodimeric antibody of any one of claims 68 to 75, wherein the second ABD binds to human CD28, and wherein VH2 and VL2 are selected from the following: (1) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 400; or (2) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 35; or (3) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 43; or (4) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 51; or (5) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 59; or (6) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 67; or (7) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 90; or (8) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 98; or (9) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 106; or (10) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 114; or (11) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 122; or (12) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 130; or (13) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 138; or (14) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 146; or (15) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 154; or (16) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 162; or (17) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 170; or (18) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 178; or (19) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 186; or (20) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 194; or (21) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 202; or (22) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 384; or (23) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 392; or (24) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 13; or (25) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 408; or (26) (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 412; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 416; or (27) (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 420; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
424.
77. The heterodimeric antibody of claim 76, wherein VH2 and VL2 are selected from the following: (1) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 397; vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 401, vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and vlCDR3 having an amino acid sequence of SEQ ID NO: 403; or (2) (i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 32; a vhCDR2 having an amino acid sequence of SEQ ID NO: 33; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 34; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 36, a vlCDR2 having an amino acid sequence of SEQ ID NO: 37, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 38; or (3) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 44, a vlCDR2 having an amino acid sequence of SEQ ID NO: 45, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 46; or (4) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 48; a vhCDR2 having an amino acid sequence of SEQ ID NO: 49; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 50; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 52, a vlCDR2 having an amino acid sequence of SEQ ID NO: 53, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 54; or (5) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 56; a vhCDR2 having an amino acid sequence of SEQ ID NO: 57; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 58; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 60, a vlCDR2 having an amino acid sequence of SEQ ID NO: 61, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 62; or (6) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 64; vhCDR2 having an amino acid sequence of SEQ ID NO: 65; and vhCDR3 having an amino acid sequence of SEQ ID NO: 66; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 68, vlCDR2 having an amino acid sequence of SEQ ID NO: 69, and vlCDR3 having an amino acid sequence of SEQ ID NO: 70; or (7) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 87; a vhCDR2 having an amino acid sequence of SEQ ID NO: 88; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 89; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 91, a vlCDR2 having an amino acid sequence of SEQ ID NO: 92, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 93; or (8) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 95; vhCDR2 having an amino acid sequence of SEQ ID NO: 96; and vhCDR3 having an amino acid sequence of SEQ ID NO: 97; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 99, vlCDR2 having an amino acid sequence of SEQ ID NO: 100, and vlCDR3 having an amino acid sequence of SEQ ID NO: 101; or (9) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 103; a vhCDR2 having an amino acid sequence of SEQ ID NO: 104; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 105; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 107, a vlCDR2 having an amino acid sequence of SEQ ID NO: 108, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 109; or (10) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 111; a vhCDR2 having an amino acid sequence of SEQ ID NO: 112; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 113; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 115, a vlCDR2 having an amino acid sequence of SEQ ID NO: 116, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 117; or (11) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 119; vhCDR2 having an amino acid sequence of SEQ ID NO: 120; and vhCDR3 having an amino acid sequence of SEQ ID NO: 121; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 123, vlCDR2 having an amino acid sequence of SEQ ID NO: 124, and vlCDR3 having an amino acid sequence of SEQ ID NO: 125; or (12) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 127; a vhCDR2 having an amino acid sequence of SEQ ID NO: 128; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 129; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 131, a vlCDR2 having an amino acid sequence of SEQ ID NO: 132, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 133; or (13) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 135; a vhCDR2 having an amino acid sequence of SEQ ID NO: 136; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 137; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 139, a vlCDR2 having an amino acid sequence of SEQ ID NO: 140, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 141; or (14) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 143; a vhCDR2 having an amino acid sequence of SEQ ID NO: 144; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 115; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 147, a vlCDR2 having an amino acid sequence of SEQ ID NO: 149, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 149; or (15) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 151; a vhCDR2 having an amino acid sequence of SEQ ID NO: 152; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 153; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 155, a vlCDR2 having an amino acid sequence of SEQ ID NO: 156, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 157; or (16) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 159; vhCDR2 having an amino acid sequence of SEQ ID NO: 160; and vhCDR3 having an amino acid sequence of SEQ ID NO: 161; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 163, vlCDR2 having an amino acid sequence of SEQ ID NO: 164, and vlCDR3 having an amino acid sequence of SEQ ID NO: 165; or (17) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 167; a vhCDR2 having an amino acid sequence of SEQ ID NO: 168; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 169; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 171, a vlCDR2 having an amino acid sequence of SEQ ID NO: 172, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 173; or (18) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 175; a vhCDR2 having an amino acid sequence of SEQ ID NO: 176; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 177; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 179, a vlCDR2 having an amino acid sequence of SEQ ID NO: 180, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 181; or (19) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 183; vhCDR2 having an amino acid sequence of SEQ ID NO: 184; and vhCDR3 having an amino acid sequence of SEQ ID NO: 185; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 187, vlCDR2 having an amino acid sequence of SEQ ID NO: 188, and vlCDR3 having an amino acid sequence of SEQ ID NO: 189; or (20) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 191; vhCDR2 having an amino acid sequence of SEQ ID NO: 192; and vhCDR3 having an amino acid sequence of SEQ ID NO: 193; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 195, vlCDR2 having an amino acid sequence of SEQ ID NO: 196, and vlCDR3 having an amino acid sequence of SEQ ID NO: 197; or (21) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 199; vhCDR2 having an amino acid sequence of SEQ ID NO: 200; and vhCDR3 having an amino acid sequence of SEQ ID NO: 201; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 203, vlCDR2 having an amino acid sequence of SEQ ID NO: 204, and vlCDR3 having an amino acid sequence of SEQ ID NO: 205; or (22) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 381; vhCDR2 having an amino acid sequence of SEQ ID NO: 382; and vhCDR3 having an amino acid sequence of SEQ ID NO: 383; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 385, vlCDR2 having an amino acid sequence of SEQ ID NO: 386, and vlCDR3 having an amino acid sequence of SEQ ID NO: 387; or (23) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 389; vhCDR2 having an amino acid sequence of SEQ ID NO: 390; and vhCDR3 having an amino acid sequence of SEQ ID NO: 391; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 393, vlCDR2 having an amino acid sequence of SEQ ID NO: 394, and vlCDR3 having an amino acid sequence of SEQ ID NO: 395; or (24) (i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 10; a vhCDR2 having an amino acid sequence of SEQ ID NO: 11; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 12; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 14, a vlCDR2 having an amino acid sequence of SEQ ID NO: 15, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 16; or (25) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 405; a vhCDR2 having an amino acid sequence of SEQ ID NO: 406; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 407; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 409, a vlCDR2 having an amino acid sequence of SEQ ID NO: 410, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 411; or (26) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 413; vhCDR2 having an amino acid sequence of SEQ ID NO: 414; and vhCDR3 having an amino acid sequence of SEQ ID NO: 415; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 417, vlCDR2 having an amino acid sequence of SEQ ID NO: 418, and vlCDR3 having an amino acid sequence of SEQ ID NO: 419; or (27) i) VH2, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 421; vhCDR2 having an amino acid sequence of SEQ ID NO: 422; and vhCDR3 having an amino acid sequence of SEQ ID NO: 423; and (ii) VL2, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 425, vlCDR2 having an amino acid sequence of SEQ ID NO: 426, and vlCDR3 having an amino acid sequence of SEQ ID NO:
427.
78. The heterodimeric antibody of claim 76, wherein VH2 and VL2 are selected from the following: (1) (i) VH2 having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 400; or (2) (i) VH2 having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 35; or (3) (i) VH2 having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 43; or (4) (i) VH2 having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 51; or (5) (i) VH2 having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 59; or (6) (i) VH2 having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 67; or (7) (i) VH2 having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 90; or (8) (i) VH2 having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 98; or (9) (i) VH2 having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 106; or (10) (i) VH2 having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 114; or (11) (i) VH2 having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 122; or (12) (i) VH2 having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 130; or (13) (i) VH2 having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 138; or (14) (i) VH2 having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 146; or (15) (i) VH2 having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 154; or (16) (i) VH2 having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 162; or (17) (i) VH2 having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 170; or (18) (i) VH2 having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 178; or (19) (i) VH2 having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 186; or (20) (i) VH2 having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 194; or (21) (i) VH2 having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 202; or (22) (i) VH2 having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 384; or (23) (i) VH2 having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 392; or (24) (i) VH2 having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 13; or (25) (i) VH2 having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 408; or (26) (i) VH2 having the amino acid sequence of SEQ ID NO: 412; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 416; or (27) (i) VH2 having the amino acid sequence of SEQ ID NO:420; and (ii) VL2 having the amino acid sequence of SEQ ID NO:
424.
79. The heterodimeric antibody according to any one of claims 68 to 78, wherein VH1 comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
43.
80. The heterodimeric antibody according to claim C12, wherein VH1 comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; wherein VL1 comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; wherein VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and wherein VL2 comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:44, vlCDR2 having the amino acid sequence of SEQ ID NO:45, and vlCDR3 having the amino acid sequence of SEQ ID NO:
46.
81. The heterodimeric antibody according to any one of claims 68 to 78, wherein VH1 comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 396; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
400.
82. The heterodimeric antibody according to claim 81, wherein VH1 comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; wherein VL1 comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; wherein VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 397; a vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and wherein VL2 comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:401, vlCDR2 having the amino acid sequence of SEQ ID NO:402, and vlCDR3 having the amino acid sequence of SEQ ID NO:
403.
83. The heterodimeric antibody of any one of claims 68 to 81, wherein the first Fc domain and the second Fc domain are each variant Fc domains.
84. A heterodimeric antibody as described in claim 83, wherein one of the first Fc domain and the second Fc domain comprises the heterodimerization variant T366W, and the other of the first Fc domain and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V, wherein the numbering is according to EU numbering.
85. A heterodimeric antibody as described in claim 84, wherein the first Fc domain comprises the heterodimerization variant T366W, and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V.
86. A heterodimeric antibody according to any one of claims 83 to 85, wherein the first Fc domain and the second Fc domain each comprise one or more ablation variants.
87. The heterodimeric antibody of claim 86, wherein the one or more ablation variants comprise L234A / L235A / D265S, wherein numbering is according to EU numbering.
88. A heterodimeric antibody according to any one of claims 83 to 87, wherein the first Fc domain or the second Fc domain comprises the purification variant H435R / Y436F, wherein the numbering is according to EU numbering.
89. The heterodimeric antibody of claim 88, wherein the second Fc domain comprises the purified variant H435R / Y436F.
90. A heterodimeric antibody according to any one of claims 83 to 89, wherein the first Fc domain comprises amino acid substitutions L234A / L235A / D265S / LT366W, and the second Fc domain comprises amino acid substitutions L234A / L235A / D265S / T366S / L368A / Y407V / H435R / Y436F, wherein numbering is according to EU numbering.
91. The heterodimeric antibody of any one of claims 84 to 90, wherein the first Fc domain and the second Fc domain each further comprise the amino acid substitution M252Y / S254T / T256E, wherein the numbering is according to EU numbering.
92. The heterodimeric antibody of claim 83, wherein the first Fc domain and the second Fc domain comprise a set of heterodimerization skew variants selected from the following heterodimerization variants: S364K / E357Q:L368D / K370S; S364K:L368D / K370S; S364K:L368E / K370S; D401K:T411E / K360E / Q362E; and T366W:T366S / L368A / Y407V, wherein the numbering is according to EU numbering.
93. The heterodimeric antibody of claim 91, wherein the first Fc domain and the second Fc domain comprise the heterodimerization skew variant S364K / E357Q:L368D / K370S, wherein the numbering is according to EU numbering.
94. A heterodimeric antibody according to any one of claims 83, 92 or 93, wherein the first Fc domain and the second Fc domain each comprise one or more ablation variants.
95. The heterodimeric antibody of claim 94, wherein the one or more ablation variants comprise E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.
96. The heterodimeric antibody of any one of claims 83 or 91-95, wherein one of the first monomer or the second monomer further comprises a pi variant.
97. The heterodimeric antibody of claim 96, wherein the CH1-hinge-CH2-CH3 of the second monomer comprises the pI variant N208D / Q295E / N384D / Q418E / N421D, wherein the numbering is according to EU numbering.
98. The heterodimeric antibody according to any one of claims 83 or 92-97, wherein the CH1-hinge-CH2-CH3 of the second monomer comprises the amino acid variants E233P / L234V / L235A / G236del / S267K / L368D / K370S / N208D / Q295E / N384D / Q418E / N421D, wherein the first Fc domain comprises the amino acid variants E233P / L234V / L235A / G236del / S267K / S364K / E357Q, And the numbering is based on EU numbering.
99. The heterodimeric antibody of any one of claims 90-98, wherein the first variant Fc domain and the second variant Fc domain each further comprise amino acid variants 428L / 434S.
100. The heterodimeric antibody according to any one of claims 68 to 99, wherein the scFv linker is selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 456) and GGGSGGS GGCPPCGGSGG (SEQ ID NO: 457).
101. A heterodimeric antibody, comprising: a) a first monomer comprising, from N-terminus to C-terminus, VH1-CH1-hinge-CH2-CH3-domain linker-scFv, wherein VH1 is the first variable heavy domain, and CH2-CH3 is the first Fc domain; b) a second monomer comprising, from N-terminus to C-terminus, VH1-CH1-hinge-CH2-CH3, wherein VH1 is a first variable heavy domain and CH2-CH3 is a second Fc domain; and c) a light chain comprising from N-terminus to C-terminus VL1-CL, wherein VL1 is the first variable light domain and CL is the constant light domain, wherein the scFv comprises a second VH domain (VH2), a scFv linker and a second variable light domain (VL2) wherein each of the VH1 and the VL1 together form a first antigen binding domain (ABD), and the VH2 and the VL2 form a second ABD, and wherein one of the first ABD and the second ABD binds human CD28 and the other of the first ABD and the second ABD binds PSMA.
102. The heterodimeric antibody of claim 101, wherein the first ABD binds human CD28 and the second ABD binds PSMA.
103. The heterodimeric antibody of claim 101, wherein the first ABD binds PSMA and the second ABD binds human CD28.
104. The heterodimeric antibody of any one of claims 101 to 103, wherein the scFv comprises VH2-scFv linker-VL2 from N-terminus to C-terminus.
105. (Original) The heterodimeric antibody according to any one of claims 101 to 103, wherein the scFv comprises VL2-scFv linker-VH2 from N-terminus to C-terminus.
106. The heterodimeric antibody of any one of claims 101 to 105, wherein the first ABD binds to human PSMA, and wherein VH1 and VL1 are selected from the following: (1) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; or (2) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 210; or (3) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 226; or (4) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 234; or (5) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 242; or (6) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 250; or (7) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 258; or (8) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 266; or (9) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 274; or (10) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 282; or (11) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 290; or (12) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 298; or (13) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 306; or (14) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 314; or (15) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 322; or (16) (i) VH1 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 330; or (17) (i) VH1, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
338.
107. The heterodimeric antibody of claim 106, wherein VH1 and VL1 are selected from the following: (1) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; (2) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 207; vhCDR2 having an amino acid sequence of SEQ ID NO: 208; and vhCDR3 having an amino acid sequence of SEQ ID NO: 209; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 211, vlCDR2 having an amino acid sequence of SEQ ID NO: 212, and vlCDR3 having an amino acid sequence of SEQ ID NO: 213; or (3) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 223; vhCDR2 having an amino acid sequence of SEQ ID NO: 224; and vhCDR3 having an amino acid sequence of SEQ ID NO: 225; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 227, vlCDR2 having an amino acid sequence of SEQ ID NO: 228, and vlCDR3 having an amino acid sequence of SEQ ID NO: 229; or (4) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 231; vhCDR2 having an amino acid sequence of SEQ ID NO: 232; and vhCDR3 having an amino acid sequence of SEQ ID NO: 233; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 235, vlCDR2 having an amino acid sequence of SEQ ID NO: 236, and vlCDR3 having an amino acid sequence of SEQ ID NO: 237; or (5) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 239; vhCDR2 having an amino acid sequence of SEQ ID NO: 240; and vhCDR3 having an amino acid sequence of SEQ ID NO: 241; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 243, vlCDR2 having an amino acid sequence of SEQ ID NO: 244, and vlCDR3 having an amino acid sequence of SEQ ID NO: 245; or (6) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 247; vhCDR2 having an amino acid sequence of SEQ ID NO: 248; and vhCDR3 having an amino acid sequence of SEQ ID NO: 249; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 251, vlCDR2 having an amino acid sequence of SEQ ID NO: 252, and vlCDR3 having an amino acid sequence of SEQ ID NO: 253; or (7) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 255; vhCDR2 having an amino acid sequence of SEQ ID NO: 256; and vhCDR3 having an amino acid sequence of SEQ ID NO: 257; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 259, vlCDR2 having an amino acid sequence of SEQ ID NO: 260, and vlCDR3 having an amino acid sequence of SEQ ID NO: 261; or (8) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 263; vhCDR2 having an amino acid sequence of SEQ ID NO: 264; and vhCDR3 having an amino acid sequence of SEQ ID NO: 265; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 267, vlCDR2 having an amino acid sequence of SEQ ID NO: 268, and vlCDR3 having an amino acid sequence of SEQ ID NO: 269; or (9) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 271; vhCDR2 having an amino acid sequence of SEQ ID NO: 212; and vhCDR3 having an amino acid sequence of SEQ ID NO: 273; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 275, vlCDR2 having an amino acid sequence of SEQ ID NO: 276, and vlCDR3 having an amino acid sequence of SEQ ID NO: 277; or (10) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 279; vhCDR2 having an amino acid sequence of SEQ ID NO: 280; and vhCDR3 having an amino acid sequence of SEQ ID NO: 281; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 283, vlCDR2 having an amino acid sequence of SEQ ID NO: 284, and vlCDR3 having an amino acid sequence of SEQ ID NO: 285; or (11) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 287; vhCDR2 having an amino acid sequence of SEQ ID NO: 288; and vhCDR3 having an amino acid sequence of SEQ ID NO: 289; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 291, vlCDR2 having an amino acid sequence of SEQ ID NO: 292, and vlCDR3 having an amino acid sequence of SEQ ID NO: 293; or (12) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 295; vhCDR2 having an amino acid sequence of SEQ ID NO: 296; and vhCDR3 having an amino acid sequence of SEQ ID NO: 297; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 299, vlCDR2 having an amino acid sequence of SEQ ID NO: 300, and vlCDR3 having an amino acid sequence of SEQ ID NO: 301; or (13) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 303; vhCDR2 having an amino acid sequence of SEQ ID NO: 304; and vhCDR3 having an amino acid sequence of SEQ ID NO: 305; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 307, vlCDR2 having an amino acid sequence of SEQ ID NO: 308, and vlCDR3 having an amino acid sequence of SEQ ID NO: 309; or (14) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 311; vhCDR2 having an amino acid sequence of SEQ ID NO: 312; and vhCDR3 having an amino acid sequence of SEQ ID NO: 313; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 315, vlCDR2 having an amino acid sequence of SEQ ID NO: 316, and vlCDR3 having an amino acid sequence of SEQ ID NO: 317; or (15) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 319; vhCDR2 having an amino acid sequence of SEQ ID NO: 320; and vhCDR3 having an amino acid sequence of SEQ ID NO: 321; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 323, vlCDR2 having an amino acid sequence of SEQ ID NO: 324, and vlCDR3 having an amino acid sequence of SEQ ID NO: 325; or (16) (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 327; vhCDR2 having an amino acid sequence of SEQ ID NO: 328; and vhCDR3 having an amino acid sequence of SEQ ID NO: 329; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 331, vlCDR2 having an amino acid sequence of SEQ ID NO: 332, and vlCDR3 having an amino acid sequence of SEQ ID NO: 333; or (17) (i) VH1, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 335; vhCDR2 having an amino acid sequence of SEQ ID NO: 336; and vhCDR3 having an amino acid sequence of SEQ ID NO: 337; and (ii) VL1, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 339, vlCDR2 having an amino acid sequence of SEQ ID NO: 340, and vlCDR3 having an amino acid sequence of SEQ ID NO:
341.
108. The heterodimeric antibody of claim 106, wherein VH1 and VL1 are selected from the following: (1) (i) VH1 having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 218; or (2) (i) VH1 having the amino acid sequence of SEQ ID NO: 206; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 210; or (3) (i) VH1 having the amino acid sequence of SEQ ID NO: 222; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 226; or (4) (i) VH1 having the amino acid sequence of SEQ ID NO: 230; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 234; or (5) (i) VH1 having the amino acid sequence of SEQ ID NO: 238; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 242; or (6) (i) VH1 having the amino acid sequence of SEQ ID NO: 246; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 250; or (7) (i) VH1 having the amino acid sequence of SEQ ID NO: 254; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 258; or (8) (i) VH1 having the amino acid sequence of SEQ ID NO: 262; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 266; or (9) (i) VH1 having the amino acid sequence of SEQ ID NO: 270; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 274; or (10) (i) VH1 having the amino acid sequence of SEQ ID NO: 278; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 282; or (11) (i) VH1 having the amino acid sequence of SEQ ID NO: 286; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 290; or (12) (i) VH1 having the amino acid sequence of SEQ ID NO: 294; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 298; or (13) (i) VH1 having the amino acid sequence of SEQ ID NO: 302; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 306; or (14) (i) VH1 having the amino acid sequence of SEQ ID NO: 310; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 314; or (15) (i) VH1 having the amino acid sequence of SEQ ID NO: 318; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 322; or (16) (i) VH1 having the amino acid sequence of SEQ ID NO: 326; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 330; or (17) (i) VH1 having the amino acid sequence of SEQ ID NO: 334; and (ii) VL1 having the amino acid sequence of SEQ ID NO:
338.
109. The heterodimeric antibody of any one of claims 101 to 108, wherein the second ABD binds to human CD28, and wherein VH2 and VL2 are selected from the following: (1) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 400; or (2) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 35; or (3) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 43; or (4) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 51; or (5) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 59; or (6) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 67; or (7) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 90; or (8) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 98; or (9) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 106; or (10) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 114; or (11) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 122; or (12) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 130; or (13) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 138; or (14) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 146; or (15) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 154; or (16) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 162; or (17) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 170; or (18) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 178; or (19) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 186; or (20) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 194; or (21) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 202; or (22) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 384; or (23) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 392; or (24) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 13; or (25) (i) VH2 comprising vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 comprising vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 408; or (26) (i) a VH comprising vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of a VH having the amino acid sequence of SEQ ID NO: 412; and (ii) a VL comprising vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of a VL having the amino acid sequence of SEQ ID NO: 416; or (27) (i) VH2, which comprises vhCDR1, vhCDR2 and vhCDR3, wherein the vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 420; and (ii) VL2, which comprises vlCDR1, vlCDR2 and vlCDR3, wherein the vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
424.
110. The heterodimeric antibody of claim 109, wherein VH2 and VL2 are selected from the following: (1) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 397; vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 401, vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and vlCDR3 having an amino acid sequence of SEQ ID NO: 403; or (2) (i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 32; a vhCDR2 having an amino acid sequence of SEQ ID NO: 33; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 34; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 36, a vlCDR2 having an amino acid sequence of SEQ ID NO: 37, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 38; or (3) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 44, a vlCDR2 having an amino acid sequence of SEQ ID NO: 45, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 46; or (4) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 48; a vhCDR2 having an amino acid sequence of SEQ ID NO: 49; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 50; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 52, a vlCDR2 having an amino acid sequence of SEQ ID NO: 53, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 54; or (5) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 56; a vhCDR2 having an amino acid sequence of SEQ ID NO: 57; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 58; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 60, a vlCDR2 having an amino acid sequence of SEQ ID NO: 61, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 62; or (6) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 64; vhCDR2 having an amino acid sequence of SEQ ID NO: 65; and vhCDR3 having an amino acid sequence of SEQ ID NO: 66; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 68, vlCDR2 having an amino acid sequence of SEQ ID NO: 69, and vlCDR3 having an amino acid sequence of SEQ ID NO: 70; or (7) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 87; a vhCDR2 having an amino acid sequence of SEQ ID NO: 88; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 89; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 91, a vlCDR2 having an amino acid sequence of SEQ ID NO: 92, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 93; or (8) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 95; vhCDR2 having an amino acid sequence of SEQ ID NO: 96; and vhCDR3 having an amino acid sequence of SEQ ID NO: 97; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 99, vlCDR2 having an amino acid sequence of SEQ ID NO: 100, and vlCDR3 having an amino acid sequence of SEQ ID NO: 101; or (9) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 103; a vhCDR2 having an amino acid sequence of SEQ ID NO: 104; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 105; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 107, a vlCDR2 having an amino acid sequence of SEQ ID NO: 108, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 109; or (10) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 111; a vhCDR2 having an amino acid sequence of SEQ ID NO: 112; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 113; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 115, a vlCDR2 having an amino acid sequence of SEQ ID NO: 116, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 117; or (11) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 119; vhCDR2 having an amino acid sequence of SEQ ID NO: 120; and vhCDR3 having an amino acid sequence of SEQ ID NO: 121; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 123, vlCDR2 having an amino acid sequence of SEQ ID NO: 124, and vlCDR3 having an amino acid sequence of SEQ ID NO: 125; or (12) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 127; a vhCDR2 having an amino acid sequence of SEQ ID NO: 128; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 129; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 131, a vlCDR2 having an amino acid sequence of SEQ ID NO: 132, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 133; or (13) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 135; a vhCDR2 having an amino acid sequence of SEQ ID NO: 136; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 137; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 139, a vlCDR2 having an amino acid sequence of SEQ ID NO: 140, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 141; or (14) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 143; a vhCDR2 having an amino acid sequence of SEQ ID NO: 144; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 115; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 147, a vlCDR2 having an amino acid sequence of SEQ ID NO: 149, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 149; or (15) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 151; a vhCDR2 having an amino acid sequence of SEQ ID NO: 152; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 153; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 155, a vlCDR2 having an amino acid sequence of SEQ ID NO: 156, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 157; or (16) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 159; vhCDR2 having an amino acid sequence of SEQ ID NO: 160; and vhCDR3 having an amino acid sequence of SEQ ID NO: 161; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 163, vlCDR2 having an amino acid sequence of SEQ ID NO: 164, and vlCDR3 having an amino acid sequence of SEQ ID NO: 165; or (17) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 167; a vhCDR2 having an amino acid sequence of SEQ ID NO: 168; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 169; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 171, a vlCDR2 having an amino acid sequence of SEQ ID NO: 172, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 173; or (18) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 175; a vhCDR2 having an amino acid sequence of SEQ ID NO: 176; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 177; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 179, a vlCDR2 having an amino acid sequence of SEQ ID NO: 180, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 181; or (19) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 183; vhCDR2 having an amino acid sequence of SEQ ID NO: 184; and vhCDR3 having an amino acid sequence of SEQ ID NO: 185; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 187, vlCDR2 having an amino acid sequence of SEQ ID NO: 188, and vlCDR3 having an amino acid sequence of SEQ ID NO: 189; or (20) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 191; vhCDR2 having an amino acid sequence of SEQ ID NO: 192; and vhCDR3 having an amino acid sequence of SEQ ID NO: 193; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 195, vlCDR2 having an amino acid sequence of SEQ ID NO: 196, and vlCDR3 having an amino acid sequence of SEQ ID NO: 197; or (21) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 199; vhCDR2 having an amino acid sequence of SEQ ID NO: 200; and vhCDR3 having an amino acid sequence of SEQ ID NO: 201; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 203, vlCDR2 having an amino acid sequence of SEQ ID NO: 204, and vlCDR3 having an amino acid sequence of SEQ ID NO: 205; or (22) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 381; vhCDR2 having an amino acid sequence of SEQ ID NO: 382; and vhCDR3 having an amino acid sequence of SEQ ID NO: 383; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 385, vlCDR2 having an amino acid sequence of SEQ ID NO: 386, and vlCDR3 having an amino acid sequence of SEQ ID NO: 387; or (23) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 389; vhCDR2 having an amino acid sequence of SEQ ID NO: 390; and vhCDR3 having an amino acid sequence of SEQ ID NO: 391; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 393, vlCDR2 having an amino acid sequence of SEQ ID NO: 394, and vlCDR3 having an amino acid sequence of SEQ ID NO: 395; or (24) (i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 10; vhCDR2 having an amino acid sequence of SEQ ID NO: 11; and vhCDR3 having an amino acid sequence of SEQ ID NO: 12; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 14, vlCDR2 having an amino acid sequence of SEQ ID NO: 15, and vlCDR3 having an amino acid sequence of SEQ ID NO: 16; or (25) i) a VH2 comprising: a vhCDR1 having an amino acid sequence of SEQ ID NO: 405; a vhCDR2 having an amino acid sequence of SEQ ID NO: 406; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 407; and (ii) a VL2 comprising: a vlCDR1 having an amino acid sequence of SEQ ID NO: 409, a vlCDR2 having an amino acid sequence of SEQ ID NO: 410, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 411; or (26) i) VH2 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 413; vhCDR2 having an amino acid sequence of SEQ ID NO: 414; and vhCDR3 having an amino acid sequence of SEQ ID NO: 415; and (ii) VL2 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 417, vlCDR2 having an amino acid sequence of SEQ ID NO: 418, and vlCDR3 having an amino acid sequence of SEQ ID NO: 419; or (27) i) VH2, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 421; vhCDR2 having an amino acid sequence of SEQ ID NO: 422; and vhCDR3 having an amino acid sequence of SEQ ID NO: 423; and (ii) VL2, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 425, vlCDR2 having an amino acid sequence of SEQ ID NO: 426, and vlCDR3 having an amino acid sequence of SEQ ID NO:
427.
111. The heterodimeric antibody of claim 109, wherein VH2 and VL2 are selected from the following: (1) (i) VH2 having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 400; or (2) (i) VH2 having the amino acid sequence of SEQ ID NO: 31; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 35; or (3) (i) VH2 having the amino acid sequence of SEQ ID NO: 39; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 43; or (4) (i) VH2 having the amino acid sequence of SEQ ID NO: 47; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 51; or (5) (i) VH2 having the amino acid sequence of SEQ ID NO: 55; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 59; or (6) (i) VH2 having the amino acid sequence of SEQ ID NO: 63; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 67; or (7) (i) VH2 having the amino acid sequence of SEQ ID NO: 86; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 90; or (8) (i) VH2 having the amino acid sequence of SEQ ID NO: 94; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 98; or (9) (i) VH2 having the amino acid sequence of SEQ ID NO: 102; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 106; or (10) (i) VH2 having the amino acid sequence of SEQ ID NO: 110; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 114; or (11) (i) VH2 having the amino acid sequence of SEQ ID NO: 118; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 122; or (12) (i) VH2 having the amino acid sequence of SEQ ID NO: 126; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 130; or (13) (i) VH2 having the amino acid sequence of SEQ ID NO: 134; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 138; or (14) (i) VH2 having the amino acid sequence of SEQ ID NO: 142; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 146; or (15) (i) VH2 having the amino acid sequence of SEQ ID NO: 150; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 154; or (16) (i) VH2 having the amino acid sequence of SEQ ID NO: 158; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 162; or (17) (i) VH2 having the amino acid sequence of SEQ ID NO: 166; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 170; or (18) (i) VH2 having the amino acid sequence of SEQ ID NO: 174; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 178; or (19) (i) VH2 having the amino acid sequence of SEQ ID NO: 182; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 186; or (20) (i) VH2 having the amino acid sequence of SEQ ID NO: 190; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 194; or (21) (i) VH2 having the amino acid sequence of SEQ ID NO: 198; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 202; or (22) (i) VH2 having the amino acid sequence of SEQ ID NO: 380; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 384; or (23) (i) VH2 having the amino acid sequence of SEQ ID NO: 388; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 392; or (24) (i) VH2 having the amino acid sequence of SEQ ID NO: 9; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 13; or (25) (i) VH2 having the amino acid sequence of SEQ ID NO: 404; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 408; or (26) (i) VH2 having the amino acid sequence of SEQ ID NO: 412; and (ii) VL2 having the amino acid sequence of SEQ ID NO: 416; or (27) (i) VH2 having the amino acid sequence of SEQ ID NO:420; and (ii) VL2 having the amino acid sequence of SEQ ID NO:
424.
112. The heterodimeric antibody according to any one of claims 101 to 111, wherein VH1 comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 39; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
43.
113. The heterodimeric antibody according to claim 112, wherein VH1 comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; wherein VL1 comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; wherein VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 40; a vhCDR2 having an amino acid sequence of SEQ ID NO: 41; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 42; and wherein VL2 comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:44, vlCDR2 having the amino acid sequence of SEQ ID NO:45, and vlCDR3 having the amino acid sequence of SEQ ID NO:
46.
114. The heterodimeric antibody according to any one of claims 101 to 111, wherein VH1 comprises vhCDR1, vhCDR2 and vhCDR3, and the vhCDR1, vhCDR2 and vhCDR3 respectively have: the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 214; VL1 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO: 218; VH2 comprises vhCDR1, vhCDR2 and vhCDR3, wherein vhCDR1, vhCDR2 and vhCDR3 respectively have the amino acid sequences of vhCDR1, vhCDR2 and vhCDR3 of VH having the amino acid sequence of SEQ ID NO: 396; and VL2 comprises vlCDR1, vlCDR2 and vlCDR3, wherein vlCDR1, vlCDR2 and vlCDR3 respectively have the amino acid sequences of vlCDR1, vlCDR2 and vlCDR3 of VL having the amino acid sequence of SEQ ID NO:
400.
115. The heterodimeric antibody according to claim 114, wherein VH1 comprises: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; wherein VL1 comprises: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; wherein VH2 comprises: a vhCDR1 having an amino acid sequence of SEQ ID NO: 397; a vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and a vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and wherein VL2 comprises: vlCDR1 having the amino acid sequence of SEQ ID NO:401, vlCDR2 having the amino acid sequence of SEQ ID NO:402, and vlCDR3 having the amino acid sequence of SEQ ID NO:
403.
116. The heterodimeric antibody according to any one of claims 111 to 115, wherein the first Fc domain and the second Fc domain are each variant Fc domains.
117. A heterodimeric antibody as described in claim 116, wherein one of the first Fc domain and the second Fc domain comprises the heterodimerization variant T366W, and the other of the first Fc domain and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V, wherein the numbering is according to EU numbering.
118. A heterodimeric antibody as described in claim 117, wherein the first Fc domain comprises the heterodimerization variant T366W, and the second Fc domain comprises the heterodimerization variant T366S / L368A / Y407V.
119. The heterodimeric antibody according to any one of claims 116 to 118, wherein the first Fc domain and the second Fc domain each comprise one or more ablation variants.
120. The heterodimeric antibody of claim 119, wherein the one or more ablation variants comprise L234A / L235A / D265S, wherein numbering is according to EU numbering.
121. The heterodimeric antibody of any one of claims 116 to 120, wherein the first Fc domain or the second Fc domain comprises the purification variant H435R / Y436F, wherein the numbering is according to EU numbering.
122. The heterodimeric antibody of claim 121, wherein the second Fc domain comprises the purified variant H435R / Y436F.
123. A heterodimeric antibody according to any one of claims 116 to 122, wherein the first Fc domain comprises amino acid substitutions L234A / L235A / D265S / LT366W, and the second Fc domain comprises amino acid substitutions L234A / L235A / D265S / T366S / L368A / Y407V / H435R / Y436F, wherein numbering is according to EU numbering.
124. The heterodimeric antibody of any one of claims 117 to 123, wherein the first Fc domain and the second Fc domain each further comprise the amino acid substitution M252Y / S254T / T256E, wherein the numbering is according to EU numbering.
125. The heterodimeric antibody of claim 116, wherein the first Fc domain and the second Fc domain comprise a set of heterodimerization skew variants selected from the following heterodimerization variants: S364K / E357Q:L368D / K370S; S364K:L368D / K370S; S364K:L368E / K370S; D401K:T411E / K360E / Q362E; and T366W:T366S / L368A / Y407V, wherein the numbering is according to EU numbering.
126. The heterodimeric antibody of claim 125, wherein the first Fc domain and the second Fc domain comprise the heterodimerization skew variant S364K / E357Q:L368D / K370S, wherein the numbering is according to EU numbering.
127. A heterodimeric antibody according to any one of claims 116, 125 or 126, wherein the first Fc domain and the second Fc domain each comprise one or more ablation variants.
128. The heterodimeric antibody of claim 127, wherein the one or more ablation variants comprise E233P / L234V / L235A / G236del / S267K, wherein the numbering is according to EU numbering.
129. The heterodimeric antibody of any one of claims 116 or 125-128, wherein one of the first monomer or the second monomer further comprises a pi variant.
130. The heterodimeric antibody of claim 129, wherein the CH1-hinge-CH2-CH3 of the second monomer comprises the pi variant N208D / Q295E / N384D / Q418E / N421D, wherein the numbering is according to EU numbering.
131. The heterodimeric antibody according to any one of claims 116 or 125-130, wherein the CH1-hinge-CH2-CH3 of the second monomer comprises the amino acid variants E233P / L234V / L235A / G236del / S267K / L368D / K370S / N208D / Q295E / N384D / Q418E / N421D, wherein the first Fc domain comprises the amino acid variants E233P / L234V / L235A / G236del / S267K / S364K / E357Q, And the numbering is based on EU numbering.
132. The heterodimeric antibody according to any one of claims 125-131, wherein the first variant Fc domain and the second variant Fc domain each further comprise amino acid variants 428L / 434S.
133. The heterodimeric antibody of any one of claims 101 to 132, wherein the scFv linker is selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443) and GGGSGGSGGCPPCGGSGG (SEQ ID NO: 457).
134. A heterodimeric antibody, comprising: a) a first monomer having an amino acid sequence of SEQ ID NO: 351; b) a second monomer having an amino acid sequence of SEQ ID NO: 352; and c) a light chain having the amino acid sequence of SEQ ID NO:
353.
135. A heterodimeric antibody, comprising: a) a first monomer having an amino acid sequence of SEQ ID NO: 342; b) a second monomer having an amino acid sequence of SEQ ID NO: 343; and c) a light chain having the amino acid sequence of SEQ ID NO:
344.
136. A bispecific antibody, comprising: A first antigen binding domain having: (i) VH1 having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 218; and A second antigen binding domain having: (i) VH2 having the amino acid sequence of SEQ ID NO:39; and (ii) VL2 having the amino acid sequence of SEQ ID NO:
43.
137. A bispecific antibody, comprising: A first antigen binding domain having: (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; and A second antigen binding domain having: (i) VH2, comprising: vhCDR1 having the amino acid sequence of SEQ ID NO:40; vhCDR2 having the amino acid sequence of SEQ ID NO:41; and vhCDR3 having the amino acid sequence of SEQ ID NO:42; and (ii) VL2, comprising: vlCDR1 having the amino acid sequence of SEQ ID NO:44, vlCDR2 having the amino acid sequence of SEQ ID NO:45, and vlCDR3 having the amino acid sequence of SEQ ID NO:
46.
138. A bispecific antibody, comprising: A first antigen binding domain having: (i) VH1 having the amino acid sequence of SEQ ID NO: 214; and (ii) VL1 having the amino acid sequence of SEQ ID NO: 218; and A second antigen binding domain having: (i) VH2 having the amino acid sequence of SEQ ID NO: 396; and (ii) VL2 having the amino acid sequence of SEQ ID NO:
400.
139. A bispecific antibody, comprising: A first antigen binding domain having: (i) VH1 comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 215; vhCDR2 having an amino acid sequence of SEQ ID NO: 216; and vhCDR3 having an amino acid sequence of SEQ ID NO: 217; and (ii) VL1 comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 219, vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and vlCDR3 having an amino acid sequence of SEQ ID NO: 221; and A second antigen binding domain having: (i) VH2, comprising: vhCDR1 having an amino acid sequence of SEQ ID NO: 397; vhCDR2 having an amino acid sequence of SEQ ID NO: 398; and vhCDR3 having an amino acid sequence of SEQ ID NO: 399; and (ii) VL2, comprising: vlCDR1 having an amino acid sequence of SEQ ID NO: 401, vlCDR2 having an amino acid sequence of SEQ ID NO: 402, and vlCDR3 having an amino acid sequence of SEQ ID NO:
403.
140. A nucleic acid composition, each comprising: a) a first nucleic acid encoding a first monomer according to any one of claims 35 to 135; b) a second nucleic acid encoding the second monomer of any one of claims 35-135; and c) a third nucleic acid encoding the light chain of any one of claims 35-135.
141. An expression vector composition, the expression vector composition comprising: a) a first expression vector comprising the first nucleic acid of claim 140; b) a second expression vector comprising the second nucleic acid of claim 140; and c) a third expression vector comprising the third nucleic acid of claim 140.
142. A host cell comprising the expression vector composition of claim 141.
143. A method for producing a heterodimeric antibody according to any one of claims 35-135, the method comprising culturing the host cell of claim F3 under conditions wherein the heterodimeric antibody is expressed and recovering the heterodimeric antibody.
144. A nucleic acid composition encoding the bispecific antibody of any one of claims 1-34 or 136-139.
145. An expression vector comprising the nucleic acid composition of claim 144.
146. A host cell comprising the expression vector of claim 145.
147. A method of making a bispecific antibody according to any one of claims 1-34 or 136-139, the method comprising culturing the host cell of claim 146 under conditions wherein the bispecific antibody is expressed and recovering the bispecific antibody.
148. A method of treating prostate cancer in a patient in need thereof, the method comprising administering to the patient a heterodimeric antibody according to any one of claims 35-135.
149. A method of treating prostate cancer in a patient in need thereof, the method comprising administering to the patient: a) a heterodimeric antibody according to any one of claims 35-135; and b) a bispecific antibody, wherein the bispecific antibody is anti-CD3 x anti-PSMA or anti-CD3 x anti-B7H3.
150. A method of treating prostate cancer in a patient in need thereof, the method comprising administering to the patient: a) a heterodimeric antibody according to any one of claims 35-135; and b) a bispecific antibody, wherein the bispecific antibody is anti-CD3 x anti-PSMA or anti-CD3 x anti-B7H3 or anti-CD3 x anti-hK2 or anti-CD3 x anti-TMEFF2.
151. A method of enhancing T cell proliferation in the presence of PSMA-expressing cells, the method comprising contacting the cells with a heterodimeric antibody according to any one of claims 35-135.
152. A method of inhibiting the growth or proliferation of a PSMA-expressing cell, the method comprising contacting the cell with the heterodimeric antibody of any one of claims 35-135.
153. The method of claim 151 or 152, wherein the PSMA-expressing cells are prostate cells.
154. A method of treating prostate cancer in a patient in need thereof, the method comprising administering to the patient the bispecific antibody of any one of claims 1-34 or 136-139.
155. A method of treating prostate cancer in a patient in need thereof, the method comprising administering to the patient: a) a first bispecific antibody according to any one of claims 1-34 or 136-139; and b) a second bispecific antibody, wherein the second bispecific antibody is anti-CD3 x anti-PSMA or anti-CD3 x anti-B7H3.
156. A method of treating prostate cancer in a patient in need thereof, the method comprising administering to the patient: a) a first bispecific antibody according to any one of claims 1-34 or 136-139; and b) a second bispecific antibody, wherein the bispecific antibody is anti-CD3 x anti-PSMA or anti-CD3 x anti-B7H3 or anti-CD3 x anti-hK2 or anti-CD3 x anti-TMEFF2.
157. A method of enhancing T cell proliferation in the presence of PSMA-expressing cells, the method comprising contacting the cells with the bispecific antibody of any one of claims 1-34 or 136-139.
158. A method of inhibiting the growth or proliferation of a PSMA-expressing cell, the method comprising contacting the cell with the bispecific antibody of any one of claims 1-34 or 136-139.
159. The method of claim 157 or 158, wherein the PSMA-expressing cells are prostate cells.