Guidance and navigation control (GNC) antibody-like proteins and methods of making and using the same

Abstract

The present application provides multispecific antibody-like proteins that can comprise one or more binding domains, including a first binding domain (D1), a second binding domain (D2), a third binding domain (D3), a fourth binding domain (D4), a fifth binding domain (D5), or a sixth binding domain (D6). The multispecific antibody-like proteins disclosed herein can be monospecific, bispecific, trispecific, tetraspecific, pentaspecific, or hexaspecific. The binding domains, such as D1, D2, D3, D4, D5, and D6, each independently can have a binding affinity specific for a T cell activating receptor, an immune cell receptor, an immune checkpoint molecule, a costimulatory factor, a leukocyte receptor, a tumor antigen, a tumor associated antigen (TAA), a histiocyte receptor, a cancer cell receptor, or a combination thereof.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 991,042, filed March 17, 2020, pursuant to 35 USC119(e), the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This application generally relates to the technical field of multispecific antibodies for cancer immunotherapy, and more specifically to the preparation and use of guidance and navigation control (GNC) antibodies that have multiple binding activities against surface molecules of both immune cells and tumor cells. Background Technology

[0004] Cancer cells have developed a variety of strategies to evade the immune system. There is an urgent need to improve the functionality, specificity, potency, and efficacy of biotherapeutic agents. Various resistance mechanisms also hinder the success of targeted therapy in cancer treatment. Tumor plasticity has become a pattern of evasion of targeted therapy in various cancers, including prostate and lung adenocarcinoma, as well as melanoma and basal cell carcinoma. Mechanisms that interfere with the formation of a robust anti-tumor immune response are considered to include at least the following categories: 1) defective tumor antigen processing or presentation; 2) lack of activation mechanisms; 3) inhibitory mechanisms and immunosuppressive states; and 4) resistant tumor cells (4). To overcome these evasion and resistance mechanisms, new therapeutic strategies are designed to promote the incorporation of multiple immune effector factors into combined immunotherapy strategies, including but not limited to T-cell conjugates, checkpoint inhibitors, and innate immunity. However, such combined therapy strategies typically involve two or more independent biopharmaceutical products, requiring the manufacture of separate biopharmaceuticals and approval of the clinical safety and efficacy of each product. Combined therapy may target immune cells or tumor cells, or both. For example, there are antibody therapies using bispecific antibodies targeting CD3 and CD19, or CAR-T cell therapies comprising engineered T cells expressing anti-CD19 chimeric antibodies. A common side effect of these immunotherapies is cytokine release syndrome, indicating insufficient immune regulation. In this context, novel strategies are needed to overcome tumor plasticity—the heterogeneous and dynamic expression of tumor antigens and / or resistant tumor cells—while simultaneously achieving additional immune regulation.

[0005] To this end, platforms of multispecific antibodies, also known as guidance and navigation control (GNC), have been established to facilitate the multiplex targeting of T cell engagers, costimulators, checkpoint inhibitors, and tumor antigens (see Applicant’s applications, WO / 2019 / 005641, WO 2019191120, and PCT / US20 / 59230, incorporated herein in their entirety). Furthermore, tetraspecific GNC (tetraGNC) antibodies can be used to make GNC-T cell therapies for the treatment of liquid and solid tumors. Despite the multifunctional GNC molecules, epitope-negative tumor cells can remain untargeted and thus evade immunotherapy. For example, expression of NKG2D ligands is tightly regulated to prevent autoimmune tissue damage, and thus normal tissues generally do not express NKG2D ligands. Thus, the use of NKG2D receptors can be an effective targeting mechanism for cancer immunotherapy through innate immune recognition processes. In this context, there is an apparent need for further development of multispecific antibody related cell therapies. While multispecific single drugs remain highly desirable and cost effective, the design, expression, and manufacture of effective and stable multispecific antibodies other than tetraspecific GNC antibodies are technically challenging. SUMMARY

[0006] The following summary is illustrative only and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent to those skilled in the art from the following detailed description, the drawings, and the claims.

[0007] The present application provides proteins having binding specificity, such as multispecific antibody-like proteins, which can include multispecific antibodies, fragments of these binding proteins can include, but are not limited to, scFv domains, Fab regions, Fc domains, VH, VL, light chains, heavy chains, variable regions, and complementarity determining regions (CDRs), as well as methods of making and methods of using the multispecific antibody-like proteins and fragments thereof.

[0008] In one embodiment, the multispecific antibody-like protein can be a multispecific antibody, a monoclonal antibody, an isolated monoclonal antibody, or a humanized antibody.

[0009] In one embodiment, the protein can comprise various domains and regions, such as binding domains. In one embodiment, the multispecific antibody-like protein can comprise one or more binding domains, including a first binding domain (D1), a second binding domain (D2), a third binding domain (D3), a fourth binding domain (D4), a fifth binding domain (D5), or a sixth binding domain (D6). The multispecific antibody-like proteins disclosed herein can be monospecific, bispecific, trispecific, tetraspecific, pentaspecific, or hexaspecific.

[0010] In an embodiment, the binding domains, such as D1, D2, D3, D4, D5, and D6, can each independently have specific binding affinity for a T cell activation receptor, an immune cell receptor, an immune checkpoint molecule, a costimulatory factor, a leukocyte receptor, a tumor antigen, a tumor associated antigen (TAA), a histiocyte receptor, a cancer cell receptor, or a combination thereof.

[0011] In an embodiment, the T cell activation receptor can comprise CD3. In an embodiment, the immune checkpoint receptor can comprise PD-L1, PD-1, TIGIT, TIM-3, LAG-3, CTLA4, BTLA, VISTA, PD-L2, CD160, LOX-1, siglec-15, CD47, HVEM SIRPalpha, CSF1R, CD73, Siglec-15, CD47, or a combination thereof. In an embodiment, the costimulatory receptor can comprise 4-1BB, CD28, OX40, GITR, CD40L, CD40, ICOS, LIGHT, CD27, CD30, or a combination thereof. In an embodiment, the tumor associated antigen can comprise EGFR, HER2, HER3, EGRFVIII, CD19, BCMA, CD20, CD33, CD123, CD22, CD30, ROR1, CEA, LMP1, LMP2A, mesothelin, PSMA, EpCAM, phosphatidylinositol protein glycan 3, gpA33, GD2, TROP2, NKG2D ligand, CD39, CLDN18.2, DLL3, HLA-G, FcRH5, GPRC5D, LIV-1, MUC1, CD138, CD70, uPAR, CD38, or a combination thereof.

[0012] In an embodiment, the binding domain of the T cell activation receptor is adjacent to the binding domain of the tumor associated antigen (TAA).

[0013] In an embodiment, D1, D3, D4, D5, and D6 can independently be a scFv domain, a receptor, or a ligand. In an embodiment, at least one, two, three, four, or five of D1, D3, D4, D5, and D6 in the hexa-specific antibody-like protein comprises a scFv domain. In an embodiment, D1, D3, D4, D5, and D6 can each be a scFv domain.

[0014] In an embodiment, at least one, two, three, four, or five of D1, D3, D4, D5, and D6 in the hexa-specific antibody-like protein comprises a receptor. In an embodiment, D1, D3, D4, D5, and D6 can each be a receptor.

[0015] In one embodiment, at least one, two, three, four, or five of D1, D3, D4, D5, and D6 in the hexa-specific antibody-like protein comprises a ligand. In one embodiment, D1, D3, D4, D5, and D6 can each be a ligand.

[0016] In one embodiment, the scFv domain can comprise a VH connected to a VL in a VH-VL or VL-VH orientation. In one embodiment, the scFv domain can comprise a disulfide bond between the VL and the VH. In one embodiment, the disulfide bond is between VL100 and VH44 of the scFv domain. In one embodiment, the scFv domain can comprise a substitution R19S (Kabat) in the VH. In one embodiment, the multi-specific antibody-like protein can comprise an Fc region. In one embodiment, the Fc region is engineered to eliminate effector cell functions including, but not limited to, ADCC, ADCP, or CDC. In one embodiment, the Fc region comprises at least one mutation at L234A, L235A, G237A, or K322A (Eu numbering). In one embodiment, the Fc region comprises mutations at L234A / L235A / G237A / K322A. In one embodiment, the Fc region comprises mutations at L234A / L235A / K322A (Eu numbering).

[0017] Domains and regions can be connected by linkers. In one embodiment, the linker can comprise (G x S y ) n Linker, wherein n, x, and y are each independently an integer from 1 to 10. In one embodiment, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0018] In one aspect, the present application provides a hexa-specific antibody-like protein. In one embodiment, the hexa-specific antibody-like protein having an N-terminus and a C-terminus can comprise, in order from the N-terminus to the C-terminus, a first binding domain (D1) at the N-terminus, a Fab region that can comprise a light chain as a second binding domain (D2), an Fc region, a third binding domain (D3) having binding affinity to PD-L1, and a fourth binding domain (D4) at the C-terminus having binding affinity to 4-1BB, wherein the light chain can comprise a fifth binding domain (D5) covalently linked to the C-terminus and a sixth binding domain (D6) covalently linked to the N-terminus, wherein D1, D2, D5, and D6 can each independently have binding affinity to a tumor associated antigen (TAA) or CD3.

[0019] In an embodiment, the hexa-specific antibody-like protein can have D1 or D2 with binding affinity for CD3. In an embodiment, the hexa-specific antibody-like protein can have D1 with binding affinity for CD3. In an embodiment, the hexa-specific antibody-like protein can have D2 with binding affinity for CD3.

[0020] In an embodiment, the hexa-specific antibody-like protein can include D1 with binding specificity for CD3, D2 with binding specificity for EGFR, EGFRvIII, CD20, mesothelin, Claudin 18.2, HER2, CD33, or a combination thereof, D3 with binding specificity for PD-L1, D4 with binding specificity for 4-1BB, and D5 and D6 each independently with binding specificity for a tumor associated antigen.

[0021] In an embodiment, the hexa-specific antibody-like protein can include D1 with binding specificity for CD3, D2 with binding specificity for a tumor associated antigen, D3 with binding specificity for PD-L1, D4 with binding specificity for 4-1BB, and D5 and D6 each independently with binding specificity for NKG2D ligand, HER3, CD19, or a combination thereof.

[0022] In an embodiment, the hexa-specific antibody-like protein can include D1 with binding specificity for EGFR, D2 with binding specificity for CD3, D3 with binding specificity for PD-L1, D4 with binding specificity for 4-1BB, and D5 with binding specificity for CD19, and D6 with binding specificity for HER3.

[0023] In an embodiment, the hexa-specific antibody-like protein can include D1 with binding specificity for EGFR, D2 with binding specificity for CD3, D3 with binding specificity for PD-L1, D4 with binding specificity for 4-1BB, and D5 with binding specificity for HER3, and D6 with binding specificity for CD19.

[0024] In an embodiment, the hexa-specific antibody-like protein can include D1 with binding specificity for CD3, D2 with binding specificity for EGFR, D3 with binding specificity for PD-L1, D4 with binding specificity for 4-1BB, and D5 with binding specificity for HER3, and D6 with binding specificity for CD19.

[0025] In one embodiment, the hexa-specific antibody-like protein can comprise an amino acid sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identity to SEQ ID NO. 176, 178, 106, 108, 332, 334, 324, 326, 328, or 330.

[0026] In one aspect, the present application provides a tetra- or penta-specific antibody-like protein. In one embodiment, the antibody-like protein having an N-terminus and a C- terminus can comprise, in order from the N-terminus to the C-terminus, a first binding domain (D1) at the N-terminus, a Fab region as a second binding domain (D2) that can comprise a light chain, wherein the light chain can optionally include a fifth binding domain (D5) covalently linked to the C-terminus or a sixth binding domain (D6) covalently linked to the N-terminus, an Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminus. In one embodiment, the multi-specific antibody-like protein comprises an amino acid sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO. 110, 112, 116, 118, 122, 124, 128, 130, 134, 136, 140, 142, 146, 148, 152, 154, 158, 160, 164, 166, 170, 172, 112, 114, 118, 120, 124, 126, 130, 132, 136, 138, 142, 144, 148, 150, 154, 156, 160, 162, 166, 168, 172, 174, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 302, 304, 306, or 308.

[0027] In one embodiment, the multi-specific antibody-like protein can be tetra-specific. In one embodiment, the multi-specific antibody-like protein can be penta-specific. In one embodiment, D2, D5, and D6 can each independently have a binding affinity to a tumor associated antigen (TAA).

[0028] In one embodiment, the tetra-specific antibody-like protein can have D1 having a binding specificity to CD3, D2 having a binding specificity to a tumor associated antigen, D3 having a binding specificity to PD-L1, and D4 having a binding specificity to 4-1BB.

[0029] In an embodiment, a five-specific antibody-like protein can have a D1 having binding specificity for CD3, a D2 and a D5 each independently having binding specificity for a tumor associated antigen, a D3 having binding specificity for PD-L1, and a D4 having binding specificity for 4-1BB.

[0030] In an embodiment, a five-specific antibody-like protein can have a D1 having binding specificity for CD3, a D2 and a D5 each independently having binding specificity for a tumor associated antigen, a D3 having binding specificity for PD-L1, and a D4 having binding specificity for 4-1BB.

[0031] In an embodiment, a five-specific antibody-like protein can have a D1 having binding specificity for CD3, a D2 having binding specificity for a tumor associated antigen, a D3 having binding specificity for PD-L1, a D4 having binding specificity for 4-1BB, and a D5 having binding specificity for HER3.

[0032] In an embodiment, a five-specific antibody-like protein can have a D1 having binding specificity for CD3, a D2 having binding specificity for EGFR or EGFRvIII, a D3 having binding specificity for PD-L1, a D4 having binding specificity for 4-1BB, and a D5 having binding specificity for HER3.

[0033] In an embodiment, a five-specific antibody-like protein can have a D1 having binding specificity for CD3, a D2 having binding specificity for CD20, a D3 having binding specificity for PD-L1, a D4 having binding specificity for 4-1BB, and a D5 having binding specificity for CD19.

[0034] In an embodiment, a five-specific antibody-like protein can have a D1 and a D6 each independently having binding specificity for a tumor associated antigen, a D2 having binding specificity for CD3, a D3 having binding specificity for PD-L1, and a D4 having binding specificity for 4-1BB.

[0035] In an embodiment, a five-specific antibody-like protein can have a D1 having binding specificity for EGFR, a D2 having binding specificity for CD3, a D3 having binding specificity for PD-L1, a D4 having binding specificity for 4-1BB, and a D6 having binding specificity for CD19.

[0036] In one aspect, the present application provides a multispecific antibody-like protein having at least one binding domain as a receptor. In one embodiment, the nuclease is NKG2D.

[0037] In one embodiment, the multispecific antibody-like protein having an N-terminus and a C-terminus can comprise, in order from the N-terminus to the C-terminus, optionally a first binding domain (D1) at the N-terminus, a second binding domain (D2) that can comprise a light chain, wherein the light chain optionally can include a fifth binding domain (D5) covalently linked to the C-terminus, a sixth binding domain (D6) covalently linked to the N-terminus, or both, an Fc region, optionally a third binding domain (D3), and optionally a fourth binding domain (D4) at the C-terminus, wherein at least one of D1, D2, D3, D4, D5, and D6 is NKG2D, and wherein each of D1, D2, D3, D4, D5, and D6 independently can have a binding affinity specific for a T cell activating receptor, an immune cell receptor, an immune checkpoint molecule, a costimulatory factor, a leukocyte receptor, a tumor antigen, a tumor associated antigen (TAA), a histiocyte receptor, a cancer cell receptor, or a combination thereof.

[0038] In one embodiment, the multispecific antibody-like protein comprising NKG2D can be monospecific, bispecific, trispecific, tetraspecific, or pentaspecific.

[0039] In one embodiment, the multispecific antibody-like protein comprising NKG2D can have a D2 comprising a dimer linked to a CL and a CH1, wherein the dimer is NKG2D. In one embodiment, the multispecific antibody-like protein comprising NKG2D can comprise an amino acid sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO. 196 or 198.

[0040] In one embodiment, the multispecific antibody-like protein comprising NKG2D can have D1, D2, D3, D4, D5, and D6, each of which independently can have binding specificity for an antigen selected from EGFR, HER2, HER3, EGFRvIII, ROR1, CD3, CD28, CEA, LMP1, LMP2A, mesothelin, PSMA, EpCAM, Syndecan 3, gpA33, GD2, TROP2, NKG2D, NKG2D ligand, BCMA, CD19, CD20, CD33, CD123, CD22, CD30, PD-L1, PD1, OX40, 4-1BB, GITR, TIGIT, TIM-3, LAG-3, CTLA4, CD40, CD40L, VISTA, ICOS, BTLA, LIGHT, HVEM, CSF1R, CD73, CD39, CLDN18.2, DLL3, HLA-G, FcRH5, GPRC5D, LIV-1, MUC1, CD138, CD70, CD16, uPAR, Siglec-15, CD47, CD38, NKp46, PD-L2, CD160, LOX-1, SIRPa, CD27, and wherein the Fc domain comprises a human IgG Fc domain.

[0041] In one embodiment, the multispecific antibody-like protein comprising NKG2D can have D2, D5, and D6, each of which independently has binding specificity for a tumor associated antigen. In one embodiment, the multispecific antibody-like protein comprising NKG2D can have D2 having binding specificity for a tumor associated antigen. In one embodiment, the multispecific antibody-like protein comprising NKG2D can have D1, D2, D3, and D4, each of which independently has binding specificity for NKG2D ligand, CD3, PD-L1, 4-1BB, or a combination thereof.

[0042] In one embodiment, the multispecific antibody-like protein comprising NKG2D can comprise an amino acid sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity to SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 78, 80, 82, 84, 86, 88, 30, or 32.

[0043] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for a NKG2D ligand, D2 has binding specificity for CD3, D3 has binding specificity for PD-L1, and D4 has binding specificity for 4-1BB.

[0044] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for a NKG2D ligand, D2 has binding specificity for CD3, D3 has binding specificity for 4-1BB, and D4 has binding specificity for PD-L1.

[0045] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for a NKG2D ligand, D2 has binding specificity for CD3, D3 has binding specificity for 4-1BB, and D4 has binding specificity for PD-L1.

[0046] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for a NKG2D ligand, D2 has binding specificity for CD3, D3 has binding specificity for 4-1BB, and D4 has binding specificity for PD-L1.

[0047] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for a NKG2D ligand, D2 has binding specificity for CD3, D3 has binding specificity for 4-1BB, and D4 has binding specificity for PD-L1.

[0048] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for a NKG2D ligand, D2 has binding specificity for CD3, D3 has binding specificity for 4-1BB, and D4 has binding specificity for PD-L1.

[0049] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for a NKG2D ligand, D2 has binding specificity for CD3, D3 has binding specificity for 4-1BB, and D4 has binding specificity for PD-L1.

[0050] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for a NKG2D ligand, D2 has binding specificity for CD3, D3 has binding specificity for 4-1BB, and D4 has binding specificity for PD-L1.

[0051] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for CD3, D2 has binding specificity for a NKG2D ligand, and D6 has binding specificity for CD19.

[0052] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for CD3, D2 has binding specificity for a NKG2D ligand, D3 has binding specificity for PD-L1, and D4 has binding specificity for 4-1BB.

[0053] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for CD3, D2 has binding specificity for a NKG2D ligand, D3 has binding specificity for PD-L1, D4 has binding specificity for 4-1BB, and D6 has binding specificity for a tumor associated antigen.

[0054] In one embodiment, the multispecific antibody-like protein comprising NKG2D has binding specificity for CD3, D2 has binding specificity for a NKG2D ligand, D3 has binding specificity for PD-L1, D4 has binding specificity for 4-1BB, and D6 has binding specificity for CD19.

[0055] In a second aspect, the present application provides an isolated nucleic acid sequence encoding an amino acid sequence of the multispecific antibody-like protein disclosed herein.

[0056] In a third aspect, the present application provides an expression vector. In one embodiment, the expression vector comprises an isolated nucleic acid sequence disclosed herein.

[0057] In another aspect, the present application provides a host cell comprising an isolated nucleic acid sequence disclosed herein. In one embodiment, the host cell is a prokaryotic cell. In one embodiment, the host cell is a eukaryotic cell.

[0058] In another aspect, the present application provides a method of producing a multispecific antibody-like protein or fragment thereof. In one embodiment, the method can comprise the steps of culturing a host cell comprising an isolated nucleic acid sequence such that a DNA sequence encoding a multispecific antibody or monomer is expressed, and purifying the multispecific antibody, wherein the isolated nucleic acid sequence encodes an amino acid of a multispecific antibody-like protein or fragment thereof disclosed herein.

[0059] In another aspect, the present application provides an immunoconjugate. In one embodiment, the immunoconjugate can comprise a cytotoxic agent or an imaging agent linked to the multispecific antibody of claim 30 via a linker, wherein the linker can comprise a covalent bond, such as an ester bond, ether bond, amide bond, disulfide bond, imide bond, sulfone bond, phosphate bond, phosphor ester bond, peptide bond, hydrophobic poly(ethylene glycol) linker, or a combination thereof. In one embodiment, the cytotoxic agent or the imaging agent can comprise a chemotherapeutic agent, a growth inhibitory agent, a cytotoxic agent from the class of calicheamicins, an antimitotic agent, a toxin, a radioisotope, a therapeutic agent, or a combination thereof.

[0060] In another aspect, the present application provides a pharmaceutical composition. In one embodiment, the pharmaceutical composition can comprise a pharmaceutically acceptable carrier and the multispecific antibody-protein or fragment thereof, the immunoconjugate, or both disclosed herein. In one embodiment, the pharmaceutical composition can further comprise a therapeutic agent selected from a radioisotope, a radionuclide, a toxin, a chemotherapeutic agent, or a combination thereof.

[0061] In another aspect, the present application provides a method for treating or preventing a cancer, an autoimmune disease, or an infectious disease in a subject. In one embodiment, the method comprises the step of administering a pharmaceutical composition, which can comprise the purified multispecific antibody-like protein or fragment thereof. In one embodiment, the method can comprise administering to the subject an effective amount of the purified multispecific antibody-like protein, the immunoconjugate, or the pharmaceutical composition disclosed herein.

[0062] In one embodiment, the method can further comprise co-administering an effective amount of a therapeutic agent, wherein the therapeutic agent comprises an antibody, a chemotherapeutic agent, an enzyme, an anti-estrogen agent, a receptor tyrosine kinase inhibitor, a kinase inhibitor, a cell cycle inhibitor, a checkpoint inhibitor, a DNA, RNA, or protein synthesis inhibitor, a RAS inhibitor, an inhibitor of PD1, PD-L1, CTLA4, 4-1BB, OX40, GITR, ICOS, LIGHT, TIM3, LAG3, TIGIT, CD40, CD27, HVEM, BTLA, VISTA, B7H4, CSF1R, NKG2D ligand, CD73, or a combination thereof.

[0063] In one embodiment, the subject is a human. In one embodiment, the subject is a mammal. In one embodiment, the subject is a chimpanzee. In one embodiment, the subject is a pet animal.

[0064] In another aspect, the present application provides a solution comprising an effective concentration of a purified multispecific antibody-like protein or fragment thereof, immunoconjugate, or pharmaceutical composition disclosed herein. In one embodiment, the solution is the plasma of a human subject. BRIEF DESCRIPTION OF DRAWINGS

[0065] The foregoing and other features of the present disclosure will become more apparent from the following description and accompanying drawings. It should be understood that the drawings are only illustrative of several embodiments arranged in accordance with the present disclosure and thus should not be considered as limiting the scope of the present disclosure, which will be described with additional features and details by using the accompanying drawings, in which:

[0066] Figure 1 Configurations of hexa-specific GNC antibodies with Fab regions or dimeric receptors as D2 binding domains and 5 antigen binding domains added to the heavy chain (D1, D3 and D4) and light chain (D5 and D6) are described with different structures selected from scFv based on variable sequences and receptors and ligands encoded by non-variable sequences;

[0067] Figure 2 Analytical SEC results are shown demonstrating the stability and high quality of purified tetra-specific GNC antibodies comprising NKG2D receptors and 41BBL (A-C) and purified NKG2D penta-specific GNC (D);

[0068] Figure 3 TDCC assays are shown measuring comparative potencies of 4 tetra-specific GNC antibodies (SI-49E1, SI-49E2, SI-49E3, SI-49E4) and 2 bispecific control antibodies (SI-49X1 and SI-49X2) lacking a PD-L1 and a41 BB domain in targeting the MICA expressing MDA-MB-231 cell line;

[0069] Figure 4 TDCC assays are shown measuring comparative potencies of one NKG2D-aMSLN penta-specific GNC (SI-49P1 ), two aMSLN tetra-specific GNC (SI-51 E4 and SI-51 E1 ) and one NKG2D-aMSLN tri-specific GNC (SI-51 X1, control) in targeting the MICA and mesothelin expressing MDA-MB-231 cells;

[0070] Figure 5 TDCC assays are shown measuring comparative potencies of a group of tetra-specific GNC antibodies with three part 1 binding domains and a single part 2 binding specificity to multiple tumor antigens in targeting cervical cancer cells (Hela);

[0071] Figure 6 TDCC assay showing the comparative potency of a multi-specific GNC antibody having identical EGFR binding specificity for all molecules and identical HER3 binding specificity for SI-1 and SI-1P2 in targeting EGFR-expressing MDA-MB-231 breast cancer cells in the presence (SI-1P2, SI-55E1 and SI-55E2) and absence of partial 1 binding specificity (SI-1);

[0072] Figure 7 TDCC assay showing the comparative potency of a tetra-specific GNC containing additional disulfide bonds in all of its scFv domains (SI-50E6, stapled) and not containing additional disulfide bonds (SI-50E1) compared to a bi-specific GNC antibody (SI-50X1) in targeting EGFR-expressing MDA-MB-231 breast cancer cells; and

[0073] Figure 8 A class of multi-specific GNC antibodies having any combination of three partial 1 binding specificities for CD3, PD-L1 and 4-1BB from D1, D3 and D4 and partial 2 binding specificities for three tumor antigens from D2, D5 and D6 are described by using a modular cloning system. DETAILED DESCRIPTION

[0074] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments can be utilized, and other changes can be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and with reference to the attached drawings, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.

[0075] The present disclosure provides, inter alia, isolated antibodies; methods of making such antibodies, bispecific or multi-specific molecules, antibody-drug conjugates and / or immunoconjugates consisting of such antibodies or antigen-binding fragments; pharmaceutical compositions containing antibodies, bispecific or multi-specific molecules, antibody-drug conjugates and / or immunoconjugates; methods of making molecules and compositions; and methods of using the molecules and compositions disclosed herein to treat cancer.

[0076] The present application relates to methods of making and using multispecific GNC antibodies, in particular tetra-, penta-, and hexaGNC (tetraGNC, pentaGNC, hexaGNC) antibodies. In general, GNC proteins such as GNC antibodies are characterized by comprising two moieties: moiety 1 for engaging immune cells, e.g., activating T cells, while moiety 2 targets tumor cells. GNC antibodies retain multiple antigen binding domains for engaging immune cells, e.g., anti-CD3 for T cell activation, anti-4-1BB for co-stimulation, and anti-PD-L1 for inhibiting immune checkpoints. To improve the efficacy of antibody therapy in treating cancer, GNC antibodies are designed to be structurally stable and compact while retaining the characteristic features of the two moieties in GNC antibodies. This improvement allows for additional binding specificity to a second tumor-associated antigen on the same or different tumor cells. GNC antibodies contain Fc domains that allow for FcRn-mediated recycling and half-life extension, and protein A-based facile purification. If desired, Fc receptor-mediated immunity can be incorporated. Due to the increased number of antigen binding domains (AgBDs), GNC antibodies are generally larger than IgG antibodies, which provides spatial flexibility for binding T cells and tumor cells. GNC antibodies can be effective antibody therapeutics for treating cancer by targeting one or more tumor antigens including, but not limited to, BCMA, CD19, CD20, CD33, CD123, CD22, CD30, ROR1, CEA, HER2, HER3, EGFR, EGFRvIII, LMP1, LMP2A, mesothelin, PSMA, EpCAM, Glypican 3, gpA33, GD2, TROP2. Multispecific T cell engaging antibodies, such as tetra- and pentaGNC antibodies, have unique advantages over conventional immunotherapies. They demonstrate CD3 on T cells crosslinking functionality with tumor-associated antigens (TAAs), which redirect and direct them to kill tumor cells without the need to remove T cells from patients and / or genetically modify them to be specific for tumor cells prior to re-introducing them into patients (also known as chimeric antigen receptor T cells, or CAR-T therapy). GNC protein-mediated antibody therapy or T cell therapy does not involve genetic modification of T cells, which can have the risk of transforming modified T cells into clonally expanded, i.e., T cell leukemia.

[0077] The present application discloses comprises a GNC antibody as Figure 1The tetra-, penta-, and hexa-specific GNC antibodies of the heavy (HC) and light (LC) chains shown. The hexa-specific GNC antibodies can be constructed with Fab regions or dimeric receptors as the D2 binding domain and 5 antigen binding domains added to the heavy (D1, D3, and D4) and light (D5 and D6) chains with different structures selected from variable sequence-based antibody fragments (e.g., scFv) and non-variable sequence-encoded receptors and ligands. The VH and VL of the Fab regions can be replaced with non-Fab dimers with or without binding specificity. In one embodiment, the Fc domains of both chains are engineered to contain complementary mutations, also known as "knobs-into-holes," to enhance the formation of heterodimers. The hexa-specific GNC antibodies comprise 6 independent binding specificities to at least 6 antigens expressed by immune effector cells or target cancer cells. The species of hexa-specific GNC antibodies are designed for treating cancer as a single pharmaceutical compared to conventional combination therapy to improve efficacy and reduce manufacturing costs. As such, the treatment simplifies the clinical administration of SOPs, alleviates logistical concerns regarding multivariate dosing, and makes the patient more affordable.

[0078] The term "antibody" is used in the broadest sense and specifically covers single monoclonal antibodies (including agonist and antagonist antibodies), antibody compositions with polyepitopic specificity, and antibody fragments (e.g., Fab, F(ab')2, and Fv) so long as they exhibit the desired biological activity. In some embodiments, the antibody can be a monoclonal, polyclonal, chimeric, ScFv, bispecific or bi-functional, human and humanized antibody and active fragments thereof. Examples of active fragment molecules that bind to known antigens include Fab, F(ab')2, scFv, and Fv fragments, including products of an Fab immunoglobulin expression library and epitope-binding fragments of any of the above antibodies and fragments. In some embodiments, the antibody can include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain a binding site that immunospecifically binds an antigen. The immunoglobulin can be of any type (IgG, IgM, IgD, IgE, IgA, and IgY) or class (IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclasses of immunoglobulin molecules. In one embodiment, the antibody can be an intact antibody and any antigen binding fragment derived from an intact antibody. A typical antibody is a heterotetrameric protein comprising two heavy (H) chains and two light (L) chains. Each heavy chain is comprised of a heavy chain variable domain (abbreviated VH) and a heavy chain constant domain. Each light chain is comprised of a light chain variable domain (abbreviated VL) and a light chain constant domain. The VH and VL regions can be further subdivided into domains of hypervariable complementarity determining regions (CDR) and more conserved regions called framework regions (FR). Each variable domain (VH or VL) is generally composed of three CDRs and four FRs, arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, from amino-terminus to carboxy-terminus. Within the variable regions of the light and heavy chains are binding regions that interact with an antigen.

[0079] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure can be made by the hybridoma method first described by Kohler & Milstein, Nature, 256: 495 (1975), or can be made by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567).

[0080] The monoclonal antibodies can include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical with or homologous to a corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81 : 6851-6855

[1984] ).

[0081] Monoclonal antibodies can be produced using a variety of methods, including mouse hybridoma or phage display (see Siegel. Transfus. Clin. Biol. 9: 15-22 (2002) for a review) or molecular cloning of antibodies directly from primary B cells (see Tiller. New Biotechnol. 28: 453-7 (201 1 )). In the present disclosure, some antibodies were produced by immunizing rabbits with both human PD-L1 protein and cells transiently expressing human PD-L1 on the cell surface. Rabbits are known to produce antibodies with high affinity, diversity, and specificity (Weber et al., Exp. Mol. Med. 49:e305). B cells from the immunized animals were cultured in vitro and screened for the production of anti-PD-L1 antibodies. In addition to immunizing rabbits and then performing B cell culture, other common strategies for antibody production and discovery include immunizing other animals (e.g., mice) and then performing hybridomas and / or display on phage, yeast, or mammalian cells; or using synthetic variable gene libraries for display. Using recombinant DNA technology, antibody variable genes are isolated, the resulting antibodies are recombinantly expressed, and further screened for desired characteristics, such as the ability to inhibit PD-L1 binding to PD-1, the ability to bind non-human primate PD-L1, and the ability to enhance human T cell activation. This general approach to antibody discovery is similar to that described by Seeber et al. (PLOS One. 9: e86184 (2014)).

[0082] The term "antigen or epitope binding portion or fragment" refers to antibody fragments that are capable of binding to an antigen. These fragments can have the antigen binding function and other functions of the intact antibody. Examples of binding fragments include, but are not limited to, single-chain Fv fragments (scFv), which are composed of the VL and VH domains of a single arm of an antibody connected in a single polypeptide chain by a synthetic linker, or Fab fragments, which are monovalent fragments composed of the VL, constant light (CL), VH, and constant heavy 1 (CH1 ) domains. Antibody fragments are produced using conventional methods known to those skilled in the art. Antibody fragments can be screened for utility using the same techniques as used for intact antibodies.

[0083] "Antigen or epitope binding fragments" can be derived from the antibodies of the present disclosure by a number of techniques known in the art. For example, a purified monoclonal antibody can be cleaved with an enzyme such as pepsin, and subjected to HPLC gel filtration. The appropriate fractions containing the Fab fragments are then collected and concentrated by membrane filtration or the like. For further description of general techniques for isolating active fragments of antibodies, see, e.g., Khaw, B. A. et al., J. Nucl. Med. 23: 101 1 -1019 (1982); Rousseaux et al., Methods Enzymology, 121 :663-69, Academic Press, 1986.

[0084] Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen.

[0085] A Fab fragment can contain the constant domain of the light chain and the first constant domain of the heavy chain (CH1). A Fab' fragment differs from a Fab fragment by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains carry free thiol groups. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are known.

[0086] "Fv" is the minimum antibody fragment that contains a complete antigen- recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen binding specificity to the antibody.

[0087] The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.

[0088] Depending on the amino acid sequences of the constant domains of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes) e.g., IgG-1, IgG-2, IgG-3, and IgG-4; IgA-1 and IgA-2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0089] A "humanized antibody" refers to a type of engineered antibody having CDRs derived from a non-human donor immunoglobulin, with the remaining immunoglobulin-derived portions of the molecule derived from a human immunoglobulin(s). In addition, framework support residues can be changed to maintain binding affinity. Methods of obtaining "humanized antibodies" are well known to those skilled in the art (see, e.g., Queen et al., Proc. Natl Acad Sci USA, 86: 10029-10032 (1989); Hodgson et al., Bio / Technology, 9: 421 (1991)).

[0090] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein and are defined to refer to a biomolecule composed of amino acids connected by peptide bonds.

[0091] The terms "a," "an," and "the" as used herein are defined as meaning "one or more" and include the plural unless the context requires otherwise.

[0092] "Isolated" refers to a biomolecule that is free of at least some of the components with which it naturally occurs. In describing various polypeptides disclosed herein, "isolated" refers to a polypeptide that has been identified and separated and / or recovered from a cell or cell culture from which it was expressed. Typically, an isolated polypeptide will have been produced by at least one purification step. An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen binding specificities.

[0093] "Recombinant" refers to the production of an antibody in an exogenous host cell using recombinant nucleic acid technology.

[0094] The term "antigen" refers to an entity or fragment thereof that can induce an immune response in an organism, particularly an animal, more particularly a mammal including a human. The term includes an immunogen and its region responsible for antigenicity or antigenic determinant.

[0095] Further, as used herein, the term "immunogenic" refers to a substance that elicits or enhances an immune response in a human or animal against an immunogenic agent, T cells, or other reactive immune cells or immune responses in an animal. An immune response occurs when an individual produces sufficient antibodies, T cells, and other reactive immune cells against an administered immunogenic composition of the disclosure to ameliorate or alleviate the condition being treated.

[0096] “Specific binding” or “specifically binds to” or “specific for” a particular antigen or epitope means binding that is significantly different from non-specific interaction. For example, specific binding can be measured by determining the binding of a molecule compared to the binding of a control molecule, which is typically a similarly structured molecule that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0097] The term “affinity” refers to a measure of the attraction between two polypeptides, e.g., antibody / antigen, receptor / ligand, etc. The inherent attraction between two polypeptides can be expressed as the binding affinity equilibrium dissociation constant (KD) for a particular interaction. The KD binding affinity constant can be measured, for example, by Bio-Layer Interferometry, where KD is the ratio of kdis (dissociation rate constant) to kon (association rate constant), as KD = kdis / kon.

[0098] Specific binding to a particular antigen or epitope can be exhibited, for example, by an antibody having 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 , or at least about 10 -10 M, at least about 10 -11 M, at least about 10 -12 M or more, where KD refers to the equilibrium dissociation constant for a particular antibody-antigen interaction. Typically, a multispecific antibody that specifically binds to an antigen has a KD for the antigen or epitope that is 20, 50, 100, 500, 1000, 5,000, 10,000, or more times greater than that of a control molecule.

[0099] In addition, for example, specific binding to a particular antigen or epitope can be exhibited by an antibody having a KA or Ka for the antigen or epitope that is at least 20, 50, 100, 500, 1000, 5,000, 10,000, or more times greater than that of a control for the epitope, where KA or Ka refers to the association rate for a particular antibody-antigen interaction.

[0100] “Homology” between two sequences is determined by sequence identity. If the two sequences to be compared with each other differ in length, sequence identity preferably relates to the percentage of nucleotide residues of the shorter sequence that are identical with nucleotide residues of the longer sequence. Sequence identity can be routinely determined by using computer programs. Deviations occurring in the comparison between a given sequence and the above-mentioned sequences of the present disclosure can be caused, for example, by additions, deletions, substitutions, insertions or recombination.

[0101] The present disclosure can be more readily understood by reference to the following detailed description of specific embodiments and examples included herein. Although the present disclosure has been described in reference to particular details of certain embodiments of the disclosure, these details are not intended to limit the scope of the disclosure and are presented only for the purpose of illustration.

[0102] Examples

[0103] Example 1. Methods and assays

[0104] Expression and purification

[0105] DNA sequences encoding heavy and light chains were cloned from custom gene fragments into pTT5 vectors using restriction cloning and / or Gibson assembly. Plasmid DNA was transiently transfected in ExpiCHO cells (Thermo A29133) to produce multispecific GNC proteins according to the manufacturer’s instructions. Titer was measured after 7-9 days using a ForteBio Octet instrument with Protein A sensors.

[0106] GNC proteins were purified by Protein A chromatography (Cytiva, 17549853), washed with Phosphate Buffered Saline (PBS), and eluted with 50 mM sodium acetate, pH 3.6, then immediately neutralized with 1 / 5 of 1 M sodium acetate, pH 7.0. Analytical size exclusion chromatography (aSEC) was performed to assess protein quality after affinity purification. aSEC was performed using an Acquity Arc Waters with an XBridge BEH SEC 7.8 x 300 mm, 3.5 pm column. Preparative SEC steps were further polished proteins using a Superdex 200 Increase 10 / 300 GL column. All subsequent assays were performed by aSEC with at least 90% of the protein of interest.

[0107] T cell dependent toxicity assay

[0108] T cell dependent cytotoxicity (TDCC) assays are based on methods outlined by Nazarian et al. (2014). Target cells from established cancer cell lines (ADCC) are first transduced with a luciferase expression gene to generate luciferase positive target cells. These target cells are subsequently grown in cell culture flasks, when expanded to an appropriate number, they are removed, counted, and replated into 384 well (Corning 3570) plates at appropriate densities according to previous growth characteristics using a BioTek EL406 liquid dispenser. For adherent cell lines, cells are allowed to adhere to the plates overnight in a CO2 controlled jacketed tissue culture incubator. Next, PBMCs or previously expanded T cells (dynabeads) are plated at appropriate effector to target cell ratios (typically 5: 1) and serially diluted test T cell targeting agents are added to the plates. The 96 well dilution block is automatically punched into 384 well quadrants (Opentrons OT-2 liquid handling robot) and the assay samples are run in quadruplicate. TDCC assay plates are incubated for 72-96 hours. Cell viability curves are read using Promega Bright-Glo luciferase detection kit. Briefly, 20 uL of sample is added to the TDCC assay plates and incubated for ~ 15 min, then the resulting luminescence is measured on a BMG Clariostar microplate reader. Killing curves and EC50 values are analyzed and graphed in GraphPad software.

[0109] SEC-MALS

[0110] Analytical size exclusion chromatography (SEC) in combination with multi-angle light scattering (MALS) and absorbance (UV) and / or refractive index (RI) concentration detectors was analyzed. SEC-MALS is commonly used during analytical characterization of antibodies and early clinical trials to support FDA IND submissions. Acquity Arc Waters with XBridge BEH SEC 7.8 x 300 mm, 3.5 pm column. MALS assembly uses Wyatt miniDAWN TREOS / Optilab T-rEX system. The molecular weight can be determined from the measurement of the change in solution refractive index, n, with molecular concentration change (Ac) by measuring the dn / dc (= An / Ac) value using the Optilab T-rEX differential refractometer. The intensity of light scattered by the molecules, measured by the miniDAWN TREOS multi-angle light scattering (MALS) detector, is directly proportional to the molar mass.

[0111] OCTET

[0112] The ForteBio Octet platform applies Bio-Layer Interferometry (BLI) as a label-free technology to measure protein-protein interactions. It is an optical analysis technique that analyzes the interference pattern of white light reflected from two surfaces: a layer of immobilized protein on the biosensor tip and an internal reference layer. Any change in the number of molecules bound to the biosensor tip causes a shift in the interference pattern that can be measured in real time. In this method, binding between an antibody immobilized on the surface of an Anti-Human IgG Fc Capture (AHC) biosensor tip and an antigen in solution increases the optical thickness at the biosensor tip, resulting in a shift in wavelength, Δλ, that directly reflects changes in the thickness of the biological layer. The interaction of these two molecules is measured in real time, providing the ability to monitor binding specificity, binding and dissociation rates, or concentration with precision and accuracy. Unbound molecules, changes in the refractive index of the surrounding medium, or changes in flow rate do not affect the interference pattern. A simple assay of GNC protein binding to target antigen can be performed on the Octet system using AHC tips to immobilize the GNC protein and purified antigen as the analyte at a single concentration (e.g., 100 nM) or a series of concentrations (e.g., seven 1 :2 serial dilutions starting at 200 nM).

[0113] Dynamic light scattering (DLS) Tm

[0114] The hydrodynamic radius (Rh) of antibody samples (1 mg / ml) was measured by using a DynaPro Plate Reader (Wyatt Technology, Santa Barbara, CA) at a ramping rate of 0.26 °C / min from 25 °C to 75 °C in 1 °C increments. A total of 3 acquisitions of 5 seconds each were collected at each temperature. The DYNAMICS 7.8.1.3 software (Wyatt Technologies) was used to calculate the radius and the starting temperature at which the Rh began to change significantly as well as the midpoint of the transition curve (Tm).

[0115] Quantitative flow cytometry (qFACS)

[0116] CountBright Absolute Counting Beads (Thermo C36950) were used for calibration and quantification of the respective receptor numbers on various tumor cell lines using the primary antibody panitumumab (EGFR), anti-HER3 from MM111 (HER3), PL221G5 (PD-L1), TF 3H8-1 (CEA), and trastuzumab (HER2) as previously described (Wang L et al. Curr Protoc. Cytom. 2016).

[0117] Example 2. GNC antibodies with NKG2D as one of the binding domains

[0118] NKG2D is a major recognition receptor for the detection and elimination of transformed and infected cells, as its ligands are induced during cellular stress that is a consequence of infection or genomic stress such as cancer. In humans, NKG2D is encoded by the KLRK1 gene, which is located in the NK- gene complex (NKC), which is expressed by NK cells, gd T cells, and CD8 + T cells. The human NKG2D receptor complex assembles into a hexameric structure, while NKG2D itself forms a homodimer of its extracellular domain for ligand binding. In NK cells, NKG2D acts as an activating receptor, which is itself able to trigger cytotoxicity. The function of NKG2D on CD8 + T cells is to send a costimulatory signal to activate them. Major histocompatibility complex class I polypeptide-related sequence A gene (MICA) encodes a membrane-bound protein that stimulates as a ligand in essentially all human natural killer (NK), gd T, and CD8 + T cells. The MICA protein is absent in most cells, but can be induced by infection and oncogenic transformation, and is often expressed in epithelial tumors. Upon binding to MICA, NKG2D activates NK and gd T cells for cytolysis against infected cells and tumor cells expressing MICA. Thus, membrane-bound MICA acts as a signal during the early immune response against infections or spontaneously arising tumors. On the other hand, human tumor cells spontaneously release a soluble form of MICA, leading to downregulation of NKG2D, which in turn severely impairs the anti-tumor immune response of NK and CD8 + T cells. This is thought to contribute to tumor immune evasion, and also impairs host resistance to infection, which can be neutralized by free NKG2D. In this case, according to the definition of GNC proteins, NKG2D is one of the cytotoxic cell binding moieties (from Applicant’s application number PCT / US2018 / 039160, incorporated herein in its entirety).

[0119] GNC antibodies with NKG2D ligand binding specificity contain a common core antibody domain, whose Fc region may or may not have effector function. Four-specific GNC antibodies have been generated with the NKG2D dimer as one of the binding domains on the heavy chain (HC) (Table 1). These antibodies have two additional scFv domains, including a binding domain to 4-1BB (a TNF superfamily receptor typically expressed on activated T cells) (SI-49E1, SI-49E2, SI-49E3, SI-49E4, Table 1); or an additional scFv plus 41BBL (trimeric form), which is typically found on antigen-presenting cells (APCs) and binds to 4-1BB (SI-49E11, SI-49E12, SI-49E13, Table 1). The four binding domains (D1 to D4) are fused via the G / S linker region and expressed as a single heavy chain (HC or chain A or chain 1). Figure 1 As defined, these types of tetraspecific GNC antibodies are characterized by one scFv (D1) located at the N-terminus of the VH domain (D2 or Fab), two scFvs (D3 and D4) consecutively linked to the Fc region, and the light chain (LC) containing only the native VL domain (D2 or Fab). To generate pentaspecific GNC antibodies with NKG2D binding specificity, one strategy is to modify the N (D6) or C (D5) terminus of the LC with an additional NKG2D tandem repeat homodimer. Figure 1). Five D5-pentaspecific GNC antibodies were generated with NKG2D dimers as the light chain binding domain (SI-49P1, SI-49P2, SI-49P3, SI-49P4, and SI-49P5, Table 2). These D5-pentaspecific GNC antibodies are characterized by a single cancer targeting moiety (D2) combined with four cytotoxic binding moieties, namely anti-CD3, anti-PD-L1, anti-4-1BB, and NKG2D. Table 3 lists information of exemplary cancer targeting moieties and cytotoxic binding moieties as independent binding domains. According to this definition, PD-L1 is not classified as a cancer targeting moiety even though it is expressed on cancer cells as an immune checkpoint marker. Although these D5-pentaspecific GNC antibodies consist of core antibody binding domains with an additional 3 scFv binding regions on the HC and one NKG2D tandem repeat homodimer on the LC, for a total of 5 different specificities, the configuration can be diversified. For example, a pentaspecific GNC antibody can have a core antibody binding domain with an additional 2 scFv binding regions plus one TNF superfamily (trimeric form) domain and one NKG2D tandem repeat homodimer, for a total of 5 different specificities. Because NKG2D and 41BBL are not typical antigen binding domain structures, i.e., Fab or scFv, such GNC antibodies with Fab in the core can be referred to elsewhere as GNC molecules or GNC proteins with the same meaning. In addition, domain structures can be engineered to stabilize those multispecific GNC proteins. For example, each scFv domain can have a variant that is knitted by a disulfide bond at vL100 and vH44 and a variant that is not knitted, which is selected to stabilize the overall structure.

[0120] Analytical SEC showed that the purified tetraspecific GNC antibodies containing NKG2D receptor and 41BBL (SI-49E1, SI-49E2, SI-49E3, SI-49E4, SI-49E11, SI-49E12, and SI-49E13) were stable and of high quality (2D). Figure 2 A-2C) and several D5-pentaspecific GNC from LC with NKG2D binding specificity (2D), including SI-49E1, SI-49E2, SI-49E3, SI-49E4, SI-49E11, SI-49E12, SI-49E13, SI-49P1, SI-49P2, SI-49P3, and SI-49P4. The results demonstrate that these atypical GNC antibodies can be easily purified and remain stable.

[0121] Example 3. Comparative potency of GNC antibodies with NKG2D as one of the binding domains

[0122] In NK cells, NKG2D acts as an activating receptor, which is itself capable of triggering cytotoxicity, whereas in CD8 +On T cells, the function of NKG2D is to send a costimulatory signal to activate them. NKG2D forms homodimers, with its extracellular domain used for ligand binding. This feature qualifies NKG2D as a GNC form of non-variable sequence-based binding domain, and additional binding domains can be added to generate a class of multispecific NKG2D-GNC proteins. In one GNC form, a single NKG2D monomer is incorporated into the D2 position of the heavy and light chains, and the NKG2D monomers form a dimeric NKG2D receptor upon HC / LC dimerization. Thus, NKG2D can bind its ligands as a multispecific antibody-like protein GNC molecule receptor. In other GNC forms, NKG2D tandem repeats are designed by adding (GxSy)nlinkers between the single NKG2D monomers, and the NKG2D monomers all dimerize and form functional dimeric receptors. This NKG2D tandem dimer structure can be located at D1, D3, D4, D5, or D6.

[0123] To assess the effect of the position of NKG2D in the four-specific GNC antibodies, SI-49E1, SI-49E2, SI-49E3, SI-49E4 were used in TDCC assays Figure 3 ) using MICA-expressing MDA-MB-231 cell line, all 4 NKG2D four-specific GNC antibodies showed higher potency than control antibodies (bispecific NKG2D-aCD3-Fc antibody SI-49X1 and bispecific Fc-aCD3-NKG2D antibody SI-49X2), both of which lack anti-PD-L1 and anti-4-1BB scFv. The results suggest that the binding specificity to PD-L1 and / or 4-1BB contributes to the toxicity. The minor differences between the 4 NKG2D four-specific GNC antibodies can significantly reflect their differences in configuration and accessibility to immune cells.

[0124] To assess the effect of the position of NKG2D in the five-specific GNC antibodies, SI-49P1, SI-49P2, SI-49P3, SI-49P4, and SI-49P5 (Table 2) were used in TDCC assays Figure 4) NKG2D-aMSLN penta-specific GNC antibody SI-49P1 showed higher cell killing than tetra-specific GNC control antibodies SI-51E4 and SI-51E1 and NKG2D-aMesothelin (aMSLN) control antibody SI-51X1. This observation supports the trend that adding and positioning NKG2D to tetra-specific GNC antibodies increases potency. The fact that control antibody SI-51X1 (tri-specific aNKG2D-LC / aCD3-aMSLN-Fc lacking aPD-L1 and a4-1BB domains) is less potent indicates that both aPD-L1 and a4-1BB domains can enhance toxicity. Cell killing potency is supported by penta-specific GNC > tetra-specific GNC > penta-specific GNC control antibodies.

[0125] To quantify the ability of NKG2D receptor domain dimer redirection of T cells to kill MICA-bearing tumor cells in the context of tetra- or penta-specific GNC antibodies, TDCC assays were performed with MDA-MB-231 target cells. Test articles included a control tetra-specific GNC with a negative control anti-FITC domain at D2 (SI-38E72, aCD3 x aFITC x aPD-L1 x a4-1BB), tetra-specific GNC antibodies with binding domains at different GNC positions (SI-49E1, SI-49E2, SI-49E3, SI-49E4, NKG2D x aCD3 x aPD-L1 x a4-1BB), and a penta-specific GNC with an additional aMSLN binding domain (SI-49P1, aCD3 x aMSLN x aPD-L1 x a4-1BB x NKG2D). The effector:target cell ratio (E:t) was 5:1, and purified T cells, target cells, and drug dilutions were incubated for 96 hours, after which luminescence values representing remaining tumor cells were read. Note that some experiments were performed at different time periods, and absolute EC50 values can vary somewhat. However, the results in Table 4 show that all tetra-specific GNC antibodies containing NKG2D domains had significantly higher TDCC potency than the corresponding tetra-specific GNC without NKG2D (SI-38E72), ranging from about 10-fold (SI-49E2) to more than 130-fold (SI-49E4). While differences between these tetra-specific GNC antibodies can be attributed to the configuration of the same set of 4 binding domains, the addition of an anti-TAA moiety increased the potency of SI-49P1 (penta-specific GNC antibody) by more than 600-fold. Thus, adding a cytotoxic binding moiety such as NKG2D can increase potency, while adding an anti-TAA binding moiety can specifically increase the potency of T cell-mediated tumor cell killing.

[0126] Example 4. Mutations to remove light chain contaminants

[0127] Antibody-based proteins are typically purified by protein A affinity chromatography, in which protein A resin is used to purify the protein within the Fc domain. H2 -C H3 The binding site at the interface captures the antibody. However, protein A also binds to V. H3 Family Fvs of V H Domains. This is not a problem for most antibody-based platforms because V H Domains are typically located on heavy chains. However, when V is present... H3 When the scFv is connected to a light chain, V H The domain can bind to protein A resin during purification, leading to heavy-chain-light-chain heterotetramer contamination by light-chain monomers and dimers. Therefore, when generating heavy-chain heterotetramers containing any V on the light chain... H3 When developing multispecific antibodies for a protein domain, a potential obstacle is the presence of additional contaminants in the protein A elution buffer. This is particularly problematic when light chains are expressed more efficiently than heavy chains, resulting in a significant amount of light chain contaminants being purified along with the desired protein assembly.

[0128] In order to reasonably destroy V H3 The family member protein A binds, and a structural approach is used to disrupt the binding interface. The crystal structure 1DEE (Graille M. et al., Proc. Nat. Acad. Sci. 2000.) shows V... H3 The residue R19 (Kabat number) directly contacts the two side chains of the protein A domain D. Specifically, it can eliminate the contacts with Q32 and D36, significantly weakening the interaction. Therefore, due to its shorter side chains, it does not form these interactions. Furthermore, S19 is naturally present in other VH family members, suggesting that its immunogenicity may be lower than other substitutes. Incorporating the mutant R19S (Kabat number) into the V-containing region of the GNC light chain... H3 The FR1 region of the VH domain of the scFv. Specifically, the six-specific GNC antibody SI-55-H11 has an R19S mutation in its light chain sequence encoding the anti-HER3 scFv domain at D5 and the anti-CD19 scFv domain at 6. The target residues are located at the protein A binding interface, therefore the R-to-S mutation disrupts the interaction with protein A. Eliminating protein A binding in the light chain scFv prevents light chain monomers and dimers from binding to protein A during purification. As a result, a more homogeneous product free of light chain contaminants can be obtained. Each light chain may contain up to two VH domains. H3 The six-specific GNC mutation in scFvs is particularly important in allowing for efficient purification of the desired product.

[0129] Example 5. Comparative potency of multi-specific GNC antibodies with different binding domain architecture

[0130] In the general scheme for multispecific GNC proteins (Figure 1), Figure 1 To assess how structural diversity of each binding domain influences the overall functionality of multispecific GNC antibodies, TDCC assays were performed to elicit T cell-mediated killing of pancreatic cancer cells (BxPC3). As listed in Table 5, three penta-specific GNC antibodies (SI-1P1, SI-55P9, and SI-55P10) and one hexa-specific GNC antibody (SI-55H11) were used to evaluate the changes in binding specificity to EGFR, HER3, CD19, CD3, and 4-1BB. All test articles contained an aPD-Ll scFv at the D3 position, which was unchanged in position or structure. For binding specificity to EGFR, changes included position (D1 vs. D2). For binding, changes included structure (stapled vs. unstapled) and position (D1 vs. D2). For binding specificity to 4-1BB, changes included structure and binding mechanism (variable sequence-based scFv vs. non-variable sequence-based ligand-receptor interaction via 41BBL, i.e., interaction of 4-1BB ligand trimer to 4-1BB receptor). For binding specificity to CD19, the change was a relevant humanized variable sequence. For binding specificity to HER3, the difference in the group was to facilitate a tetra-specific, penta-specific, or hexa-specific GNC antibody, as HER3 was not detectable on the surface of BXPC3 (see Table 9).

[0131] The TDCC assay was set up under the same conditions, e.g., effector: target cell ratio (E:t) of 5:1, purified T cells, target cells, and drug dilutions were incubated for 72 hours, and then luminescence values representing remaining tumor cells were read. Note that some experiments were performed at different time periods, and EC50 values can vary from one experiment to another within the margin of error. However, the potencies of these penta-specific and hexa-specific GNC antibodies were below 1 pM and within a 10-fold range, indicating that structural changes can more significantly improve manufacturing cost and feasibility than potency to kill BXPC3 cells. In this case, the composition of binding specificities remains a determinant for producing multispecific GNC antibodies that target specific forms of cancer.

[0132] Example 6. Compositions for part 1 and part 2 of multi-specific GNC antibodies

[0133] The ability to have up to 6 binding specificities, multispecific GNC antibodies can become the most potent antibody therapies with the highest killing of cancer cells, e.g., EC50values can drop from nM to pM or even fM range. Successful and highly potent multispecific GNC antibodies depend on the composition of the Part 1 and Part 2 antigens. Table 4 determines the comparative potency of the four Part 1 binding specificities (i.e., aCD3, aPD-L1, a4-1BB, and NKG2D) in four specific GNC antibodies using MDA-MB-231 cells as target breast cancer cells in a TDCC assay. The addition of a fourth Part 1 binding domain, a NKG2D dimeric receptor based on non-variable sequences, improved potency by about 10-130 fold compared to a control antibody (SI-38E72) containing three Part 1 binding domains (i.e., aCD3, aPD-L1, and a4-1BB as D1, D3, and D4 HCs, respectively), depending on the configuration. However, the addition of an anti-TAA moiety significantly increased the potency of a five specific GNC antibody (SI-55H11) up to 600 fold.

[0134] To evaluate Part 1 binding specificities in combination with three Part 1 binding domains, TDCC assays were performed using the breast cancer cell line MDA-MB-231 as target cells. All test articles included aCD3, aPD-L1, and a-4-1BB scFv in the D1, D3, and D4 positions, respectively. A four specific GNC antibody (SI-38E72) was used as a control in the absence of a Part 1 binding domain, with an a-FITC domain at D2 having no specificity for any tumor antigen. Other four specific GNC test articles contained various binding domains at D2 (SI-55E: aEGFR cetuximab; SI-55E2: aEGFR panitumumab; SI-50E1: aHER2 trastuzumab; and SI-51E1: aMesothelin amrubicin) and a five specific GNC antibody (SI-1P1) contained aEGFR cetuximab at D2 and aHER3 MM111 scFv at D5. The effector:target cell ratio (E:t) was 5:1 or 10:1, and purified T cells, target cells, and drug dilutions were incubated for 96 hours before luminescence values representing remaining tumor cells were read. Note that some experiments were performed at different time periods, and EC50values can vary but are within error. However, the results demonstrate that all GNC antibodies containing an aTAA domain at D2 caused significantly (20 to 100 fold) more potent TDCC compared to the control with aFITC at D2 (Table 6). The EC50of the five specific GNC antibody (SI-1P1) was similar to the four specific GNC, indicating that domains can be added to increase TAA selectivity while still maintaining potent TDCC.

[0135] Example 7. Screening of TAA using a four-specific GNC configuration with three part 1 bindings

[0136] The configuration of the three parts of the Part 1 binding domain fixed at D1, D3, and D4 (Table 6) can be used as the backbone HC to accurately identify new and / or potent Part 2 binding domains of TAAs. To assess the ability of multispecific GNC antibodies targeting different tumor antigens to elicit T cell-mediated killing, TDCC assays were performed using the cervical cancer cell line HeLa as target cells. All test articles included aCD3, aPD-L1, and a4-1BB scFvs at D1, D3, and D4, respectively, and a tetraspecific GNC antibody (SI-38E72) was used as a control with an aFITC domain at D2 that is not specific for any tumor antigen. Other tetraspecific GNC test articles contained various binding domains at D2 as listed in Table 7. The effector:target cell ratio (E:t) was 10:1, and purified T cells, target cells, and drug dilutions were incubated for 96 hours before luminescence values representing remaining tumor cells were read. Note that some experiments were performed at different times, so that EC50 values can vary but are within error. However, results from experiments on the same day show that two anti-EGFR tetraspecific GNC antibodies, SI-55E1 (Cet) and SI-55E2 (Pan), killed more than 50% of cancer cells with potencies of 13 pM and 9 pM, respectively. Figure 5 ). Other test articles (SI-51E1, SI-52E1, SI-50E2, SI-54E1, SI-55E3, SI-56E1, SI-57E1, and SI-38E17) were weakly cytotoxic to the seeded cells, less than 20%. Thus, their EC50 values are not comparable to those of SI-55E1 and SI-55E2. SI-55E3 carries an anti-EGFR binding domain at D2 or employs a Fab from nimotuzumab, which has a lower binding affinity for EGFR than does panitumumab for SI-55E1 and cetuximab for SI-55E2 (from Applicant’s application number PCT / US2020 / 059230, incorporated herein in its entirety). Surprisingly, SI-55E3 belongs to those that exhibited weak killing. This finding indicates that binding specificity and affinity play a role in multispecific GNC antibody-mediated TDCC.

[0137] Example 8. Comparative potency of same multi-specific GNC antibodies killing different cancer cells

[0138] To further characterize the comparative potency of SI-55E1 and SI-55E2, which have the same configuration of the part 1 binding domains and target EGFR, the MDA-MB-231 cell line was used in the TDCC assay. In the same day experiment, two additional antibodies that target both EGFR and HER3 were used: SI-1P2 is a penta-specific GNC antibody with the same configuration of part 1 binding domains as SI-55E1 and SI-55E2 plus an additional part 2 domain that binds HER3, while SI-1 is a bi-specific antibody against both EGFR and HER3 in the absence of any part 1 binding domains. The materials and methods for this TDCC assay were the same as described in Example 1. As shown in Table 6, SI-55E1, SI-55E2, and SI-1P2 exhibited comparable potency with overlapping dose-activity curves and their EC50values were calculated in the range of 17-29 fM. In contrast, SI-1 did not show any response at doses lower than nM in this same day experiment. This result supports the notion that the three part 1 binding domains (CD3, PD-L1, and 4-1BB) make a significant contribution to the potency of the multi-specific GNC antibodies. Figure 6

[0139] To measure the effect of the addition of part 1 binding domains such as anti-CD3, two tetra-specific GNC antibodies (SI-50E1 and SI-50E6) and one bi-specific GNC antibody (SI-50X1) were analyzed in the TDCC assay using the MDA-MB-231 cell line as target cells. All three antibodies have the same binding specificity for HER2 from trastuzumab (Table 6). SI-50E1 and SI-50E6 have the same configuration of part 1 and part 2 binding domains, however, the scFv domains of SI-50E6 are engineered with additional disulfide bonds for increased stability (i.e., stapled), while the scFv domains of SI-50E1 are not stapled. SI-50X1 is a bi-specific antibody that targets CD3 and HER2. The TDCC dose-response curves clearly show that all three GNC antibodies are potent with their EC50values in the range of fM (Table 6). The differences in the curves and EC values are due to the absence or presence of part 2 binding domains for PD-L1 and 4-1BB in the three antibodies. Figure 7

[0140] Example 9. Selection of TAA and assembly of part 2 binding domains for multi-specific GNC antibodies

[0141] ​​Antibody therapies employ a variety of strategies to directly or indirectly kill cancer cells, both mechanisms of action rely on binding to surface antigens. On the other hand, cancer cells evolve from antibodies, immune cells, or both to gain their ability to escape such recognition. With the ability to have up to 6 binding specificities, multispecific GNC antibodies show the highest potency by in vitro EC50 measurements in the pM and fM range. The highly potent multispecific GNC antibodies depend on the composition of the Part 1 and Part 2 antigens. In this context, the three parts of the Part 1 binding domains (CD3, PD-L1, and 4-1BB) in the configuration (D1, D3, and D4 of HC, respectively) provide the backbone of the multispecific GNC antibodies. This formatted GNC antibody allows the selection, screening, and optimization of TAA Figure 8

[0142] To demonstrate the importance of the TAA surface expression profile, quantitative flow cytometry (qFACS) was performed to quantify the approximate number of receptors per cell for various tumor targets. EGFR, HER2, and HER3 are members of the EGFR family whose expression is typically upregulated on solid tumors, and PD-L1 is a target of immune checkpoint signaling exploited by a portion of human cancers. However, no surface expression of HER3 and PD-L1 was detected in MDA-MB-232 cells and HeLa cells, respectively (Table 8). This observation can explain the lack of a combined lethal effect of SI-1P1 when simultaneously targeting EGFR and HER3 compared to SI-55E1, SI-55E2, and SI-50E1 (Table 6), which each target EGFR or HER2. It can also explain the failure of the control antibody (SI-38E72) to induce TDCC likely due to the absence of PD-L1 on HeLa cells (Table 7). Depending on the cancer cell’s evolution and dynamic expression profile, different types of cancer cells (such as those shown in Table 9) can be used to test TDCC for any candidate antibody.

[0143] ​To screen for TAAs, a modular cloning platform can be used to efficiently identify TAAs or epitopes of TAAs to assemble partial 2 binding domains of multispecific GNC antibodies. For example, TAA-Fc tetraspecific GNC-1 and TAA-Fc tetraspecific GNC-2 are two sets of tetraspecific GNC antibodies with paired identical binding specificities. The only difference is that all TAA-Fc tetraspecific GNC-2 antibodies have the pegged scFv domains D1, D3, and D4 of the HC (mutations of VH44→C and VL100→C). In this case, the HC is swapped to generate two sets of tetraspecific GNC antibodies. In another example, the LC can be swapped to generate multispecific GNC antibodies with binding domains added to the TAAs, such as SI-55P10 to SI-55H11 and SI-55E1 to SI-1P1. This modular cloning platform allows for the assembly of multispecific GNC antibodies with up to 3 TAAs starting from a single anti-TAA monoclonal antibody.

[0144] Example 10. Functionality of multi-specific GNC proteins with receptors at D2 position

[0145] To further demonstrate the flexibility of the GNC platform to accommodate different binding domains at each molecular position, a set of proteins were generated with the NKG2D receptor at the D2 position (Table 10). When the monomeric NKG2D binds to the D2 position of two GNC chains, the NKG2D monomer is predicted to dimerize upon chain association. SI-49R21 is a monospecific GNC (antibody-like protein) with the NKG2D receptor replacing the antibody VH / VL domains. SI-49R22 contains the same format except that its Fc domain also contains the knob-into-hole mutations (chain A: T366S / L368A / Y407V; and chain B: T366W) for heterodimerization. SI-49R23 is a monospecific protein with NKG2D fused directly to the antibody Fc domain, and SI-49R24 contains this same structure but additionally has the knob-into-hole mutations in the Fc. SI-49R19 is a bispecific GNC with an anti-CD3 scFv in D1 and NKG2D in D2, and SI-49R18 is a trispecific GNC additionally containing anti-CD19 at D6. SI-49E15 contains an anti-CD3 scFv at D1, NKG2D at D2, an anti-PD-L1 scFv at D3, and an anti-4-1BB scFv at D4; SI-49P6 contains the same domains as SI-49E15 and additionally contains an anti-CD19 scFv at D6. SI-49P7 has the same structure as SI-49P6 except that it contains a 4-1BB ligand trimer instead of an anti-4-1BB scFv at D4.

[0146] All proteins with NKG2D in D2 were successfully expressed and purified. To verify the functionality of the NKG2D receptor in D2 position, Octet binding was performed. GNC proteins were loaded onto AHC sensors at 5 pg / ml, followed by binding to 1 :2 serial dilutions of human MICA (Acro, MIA-H5221) (highest concentration 100 nM). The global fit of the 1 : 1 binding model gave the binding affinity (KD values) shown in Table 11. The mono-, bi-, tri-, tetra- and penta-specific GNC proteins with NKG2D in D2 showed to retain strong binding to the NKG2D ligand MICA as evidenced by the KD values at 20 nM.

[0147] Example 11. Antigen binding independent of GNC position, humanization, or domain format

[0148] To further demonstrate the adaptability of the GNC platform, a set of hexa-specific GNC proteins targeting the same antigens (CD3 x EGFR x PD-L1 x 4-1BB x CD19 x HER3) was generated. The whole set contains an anti-PD-L1 scFv in D3, an anti-4-1BB scFv in D4, an anti-HER3 scFv in D5, an anti-CD19 scFv in D6. Two molecules (SI-77H4 and SI-77H5) contain an anti-CD3 scFv in D1 and an anti-EGFR Fab in D2, differing in that the anti-EGFR domain of SI-77H4 is humanized, while the anti-EGFR domain of SI-77H5 retains the mouse sequence. Two molecules (SI-55H11 and SI-55H12) contain an anti-EGFR scFv in D1 and an anti-CD3 Fab in D2, differing in that the D2 VH / VL contains a disulfide-stapled in SI-55H11 (VH-44C, VL-100C), but not in SI-55H12. This set thus allowed to elucidate whether D1 / D2 positioning influences protein expression properties or binding affinity towards tumor-associated antigens.

[0149] Proteins were transiently expressed in ExpiCHO cells as described in Example 1. After about 8 days, GNC titers were measured using Protein A sensors on an Octet platform (Table 12). The results showed that the hexa-specific GNC proteins were well expressed (>30 pg / ml) regardless of the orientation and format of the anti-EGFR and anti-CD3 domains. After the first Protein A purification step, all proteins had similar low levels of aggregation with 72-85% percent of the protein of interest (Table 12). Subsequently, the affinity of the anti-EGFR domains for human EGFR was assessed by loading the GNC proteins onto AHC sensors and using a single concentration (100 nM) of His-tagged human EGFR (expressed in-house) as the analyte. As shown in Table 12, the orientation and format of the anti-EGFR and anti-CD3 domains did not significantly affect the EGFR binding affinity (KD values within about 2-fold). Thus, regardless of the position of the anti-TAA and anti-CD3 domains between D1 and D2, the GNC proteins retained full functionality.

[0150] Table

[0151] Table 1. Generation and characterization of a class of tetra-specific GNC (tetraGNC) antibodies with added binding domains and Fab domains (D1 to D4) on the heavy chain (HC). NKG2D in D1, D3, D4, D5, and D6 are used as dimerizing tandem repeats, while NKG2D in D2 is a monomer that dimerizes upon chain association.

[0152]

[0153]

[0154] Table 2. Generation and characterization of penta- and hexa-specific GNC (pentaGNC and hexaGNC) antibodies, including their sequence identification numbers (SEQ ID), binding specificities of each domain from D1 to D6.

[0155]

[0156]

[0157] Table 3. Annotation of binding specificities, domain structures, sources, and sequence identification numbers (SEQ ID) of the binding domains.

[0158]

[0159]

[0160] Table 4. Comparative potency of multispecific GNC molecules with NKG2D receptor dimers as additional binding moieties to immune cells to kill breast cancer cells (MDA-MB-231) in TDCC assays.

[0161]

[0162] Table 5. Comparative potency of multispecific GNC antibodies (e.g., scFv or ligands) with the same binding specificity but with different domain structures to kill pancreatic cancer cells (BXPC-3) in TDCC assays.

[0163]

[0164] a 284A10, see Applicant’s application No. PCT / US2018 / 039143;

[0165] a SI-huBU12, see Applicant’s application No. PC / US2020 / 059230.

[0166] Table 6. Comparative potency of multispecific GNC antibodies targeting at least one of these tumor antigens EGFR, HER2, HER3 or MSLN to kill breast cancer cells (MDA-MB-231) in TDCC assays.

[0167]

[0168] Table 7. Comparative potency of tetraspecific GNC antibodies targeting one additional tumor antigen to kill cervical cancer cells (Hela) in TDCC assays.

[0169]

[0170]

[0171] Table 8. qFACS analysis of normal T lymphocytes and cancer cell surface tumor antigen and PD-L1 expression.

[0172] \Antibody cells\ Panitumumab aEGFR Trastuzumab aHER2 MM111 aHER3 PL221G5 aPD-L1 T lymphocytes 0.00 0.00 0.00 2000.00 MDA-MB-231 63858.26 15403.43 0.00 25456.74 BxPC3 101584.25 1575.51 0.00 11608.69 HeLa 24908.49 10459.99 45441.51 0.00

[0173] Table 9. Potency of multispecific GNC antibodies determined by surface expression of tumor antigens on cancer cells.

[0174]

[0175] Table 10. Production and characterization of mono-, bi-, tri-, tetra- and penta- specific GNC antibodies, including their sequence identification numbers (SEQ ID), binding specificity of each domain from D1 to D6.

[0176] Sample ID SEQ ID D1 D2 D3 D4 D5 D6 SI-49R21 195-198 NKG2D SI-49R22* 199-204 NKG2D SI-49R23** 205-206 NKG2D SI-49R24*** 207-210 NKG2D SI-49R19 183-186 aCD3-alt NKG2D SI-49R18 187-190 aCD3-alt NKG2D SI-BU12 SI-49E15 191-194 aCD3-alt NKG2D aPD-L1 a4-1BB SI-49P6 77-80 aCD3-alt NKG2D aPD-L1 a4-1BB SI-BU12 SI-49P7 81-84 aCD3-alt NKG2D aPD-L1 41BBL SI-BU12

[0177] * SI-49R22 contains a heterodimeric Fc with knob-into-hole mutations (chain A: T366S / L368A / Y407V; and chain B: T366W)

[0178] ** SI-49R23 lacks CH1 / CL domains

[0179] *** SI-49R24 contains a heterodimeric Fc with knob-into-hole mutations (chain A: T366S / L368A / Y407V; and chain B: T366W) and lacks CH1 / CL domains

[0180] Table 11. Comparative binding affinities of selected multispecific GNCs to NKG2D receptor at D2 position for NKG2D ligand MICA.

[0181] Sample ID MICA K D (nM)]]> SI-49R21 8.95 SI-49R22 1.93 SI-49R23 14.9 SI-49R24 17.7 SI-49R19 3.93 SI-49R18 5.11 SI-49E15 3.34 SI-49P6 8.7 SI-49P7 11.2

[0182] Table 12. Characterization of representative hexa-specific GNC antibodies comprising anti-EGFR and anti-CD3 domains at D1 (scFv) or D2 (Fab).

[0183]

[0184] * SI-55H11 D2 contains a disulfide-stapled between VH and VL (VH-44C, VL-100C)

[0185] SEQUENCE LISTING

[0186]

[0187]

[0188]

[0189]

[0190]

[0191] CDRs underlined in amino acid sequences

[0192] Chain A: HC or Chain 1

[0193] Chain B: LC or Chain 2

[0194] >SEQ ID 1 SI-49E1 chain A nt

[0195]

[0196] >SEQ ID 2 SI-49E1 chain A aa

[0197] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVVDGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKGLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0198] >SEQ ID 3 SI-49E1 chain B nt

[0199] GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0200] >SEQ ID 4 SI-49E1 chain B aa

[0201] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0202] >SEQ ID 5 SI-49E2 chain Ant

[0203]

[0204] >SEQ ID 6 SI-49E2 chain A aa

[0205] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVVDGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKGLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC Q STYLGTDYVGGA FGGGTKVEIKGGGGSGGGGSGEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIK <​​​GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0208] >SEQ ID 8 SI-49E2 chain B aa

[0209] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0210] >SEQ ID 9 SI-49E3 chain A nt

[0211]

[0212] >SEQ ID 10 SI-49E3 chain A aa

[0213] DVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSTGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKGLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIYEASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0214] >SEQ ID 11 SI-49E3 chain B nt

[0215] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0216] >SEQ ID 12 SI-49E3 chain B aa

[0217] DIQMTQSPSTLSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0218] >SEQ ID 13 SI-49E4 chain A nt

[0219]

[0220] >SEQ ID 14 SI-49E4 Chain A aa

[0221] DIQMTQSPSTLSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSTGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKGLEWIG VITGRDITYYA RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SWAKG WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINC DGGSSAITSNNI WYQQKPGKAPKLLIYQASESISSWLA GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC EASKLAS FGGGTKVEIKGGGGSGGGGSGFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0222] >SEQ ID 15 SI-49E4 chain B nt

[0223] GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0224] >SEQ ID 16 SI-49E4 chain B aa

[0225] DVVMTQSPSSVSASVGDRVTITC QGYFYFISRTYVNS WYQQKPGKAPKLLIY QASESISSWLA GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC EASKLAS FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0226] >SEQ ID 17 SI-49E11 chain A nt

[0227]

[0228] >SEQ ID 18 SI-49E11 chain A aa

[0229] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVVDGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS QGYFYFISRTYVNS WVRQAPGKGLEWIG TNAMS RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VITGRDITYYASWAKG WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS DGGSSAITSNNI WVRQAPGKGLEWIA ​ RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ​WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIKGGGGSGGGGSGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGSTGSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGL

[0230] >SEQ ID 19 SI-49E11 chain B nt

[0231] GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0232] >SEQ ID 20 SI-49E11 chain B aa

[0233] DVVMTQSPSTLSASVGDRVTINC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0234] >SEQ ID 21 SI-49E12 chain A nt

[0235]

[0236] >SEQ ID 22 SI-49E12 chain A aa

[0237] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVVDGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS ​ WVRQAPGKGLEWIG ​ RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ​WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGSTGSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGGGGSGGGGSGEVQLLESGGGLVQPGGSLRLSCAASGFSFS ​ WVRQAPGKGLEWIA ​RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ​ WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIK

[0238] >SEQ ID 23 SI-49E12 chain B nt

[0239] GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0240] >SEQ ID 24 SI-49E12 chain B aa

[0241] DVVMTQSPSTLSASVGDRVTINC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0242] >SEQ ID 25 SI-49E13 chain A nt

[0243]

[0244] >SEQ ID 26 SI-49E13 chain A aa

[0245] REGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGSTGSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLSTGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS ​ ​ WVRQAPGKGLEWIA ​ RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ​WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS ​ WVRQAPGKGLEWIG ​ RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ​ WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIKGGGGSGGGGSGFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0246] >SEQ ID 27 SI-49E13 chain B nt

[0247] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0248] >SEQ ID 28 SI-49E13 chain B aa

[0249] DIQMTQSPSTLSASVGDRVTITC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0250] >SEQ ID 29 SI-49E14 chain A nt

[0251]

[0252] >SEQ ID 30 SI-49E14 chain A aa

[0253] DIQMTQSPSTLSASVGDRVTITC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS ​ WVRQAPGKGLEWIA ​ RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ​ WGQGTLVTVSTGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS ​ WVRQAPGKGLEWIG ​ ​ RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ​WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIKGGGGSGGGGSGFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0254] >SEQ ID 31 SI-49E14 Chain B nt

[0255]

[0256] >SEQ ID 32 SI-49E14 Chain B aa

[0257] REGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGSTGSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0258] >SEQ ID 33 SI-1P1 Chain A nt

[0259]

[0260] >SEQ ID 34 SI-1P1 chain A aa

[0261] DVVMTQSPSTLSASVGDRVTINC ​ WYQQKPGKAPKLLIY ​ GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC ​ FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS ​ WVRQAPGKGLEWIG ​ RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ​ WGQGTLVTVSTGGGGSGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLT NYGVH WVRQSPGKGLEWLG VIWSGGNTDYNTPFTS RLSINKDNSKSQVFFKMNSLQSNDTAIYYCAR ALTYYDYEFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTL AS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNI RTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0262] >SEQ ID 35 SI-1P1 chain B nt

[0263]

[0264] >SEQ ID 36 SI-1P1 chain B aa

[0265] DILLTQSPVILSVSPGERVSFSC RASQSIGTNIH WYQQRTNGSPRLLIK YASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQSALTQPASVSGSPGQSITISC TGTSSDVGGYNFVS WYQQHPGKAPKLMIY DVSDRPS GVSDRFSGSKSGNTASLIISGLQADDEADYYC SSYGSSSTHVI FGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLRLSCAASGFTFS SYWMS WVRQAPGKGLEWVA NINRDGSASYYVDSVKG RFTISRDDAKNSLYLQMNSLRAEDTAVYYCAR D RGVGYFDL WGRGTLVTVSS

[0266] >SEQ ID 37 SI-1P2 chain A nt

[0267]

[0268] >SEQ ID 38 SI-1P2 chain A aa

[0269] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLT NYGVH WVRQSPGKGLEWLG VIWSGGNTDYNTPFTS RLSINKDNSKSQVFFKMNSLQSNDTAIYYCAR ALTYYDYEFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTL AS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNI RTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0270] >SEQ ID 39 SI-1P2 chain B nt

[0271]

[0272] >SEQ ID 40 SI-1P2 chain B aa

[0273] DILLTQSPVILSVSPGERVSFSC RASQSIGTNIH WYQQRTNGSPRLLIK YASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQSALTQPASVSGSPGQSITISC TGTSSDVGGYNFVS WYQQHPGKAPKLMIY DVSDRPS GVSDRFSGSKSGNTASLIISGLQADDEADYYC SSYGSSSTHVI FGCGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLRLSCAASGFTFS SYWMS WVRQAPGKCLEWVA NINRDGSASYYVDSVKG RFTISRDDAKNSLYLQMNSLRAEDTAVYYCAR D RGVGYFDL WGRGTLVTVSS

[0274] >SEQ ID 41 SI-1P4 chain A nt

[0275]

[0276] >SEQ ID 42 SI-1P4 chain A aa

[0277] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGGSVS SGDYYWT WIRQSPGKGLEWIG HIYYSGNTNYNPSLKS RLTISIDTSKTQFSLKLSSVTAADTAIYYCVR DRVTGAFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTL AS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNI RTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0278] >SEQ ID 43 SI-1P4 chain B nt

[0279]

[0280] >SEQ ID 44 SI-1P4 chain B aa

[0281] DIQMTQSPSSLSASVGDRVTITC QASQDISNYLN WYQQKPGKAPKLLIY DASNLET GVPSRFSGSGSGTDFTFTISSLQPEDIATYFC QHFDHLPLA FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQSALTQPASVSGSPGQSITISC TGTSSDVGGYNFVS WYQQHPGKAPKLMIY DVSDRPS GVSDRFSGSKSGNTASLIISGLQADDEADYYC SSYGSSSTHVI FGCGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLRLSCAASGFTFS SYWMS WVRQAPGKCLEWVA NINRDGSASYYVDSVKG RFTISRDDAKNSLYLQMNSLRAEDTAVYYCAR D RGVGYFDL WGRGTLVTVSS

[0282] >SEQ ID 45 SI-39P1 chain A nt

[0283]

[0284] >SEQ ID 46 SI-39P1 chain A aa

[0285] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKGLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSSGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSIT SDFAWN WIRQFPGNKLEWMG YISYSGNTRYNPSLKS RISITRDTSKNQFFLQLNSVTIEDTATYYCVT AGRGFPY WGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY CASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSQSLVESGGGLVQPGGSLRLSCAASGFSFS SNYWIC WVRQAPGKGLEWIA CIYVGSSGDTYYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DSSSYYMFNL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSALVMTQSPSTLSASVGDRVTINC INTENDED IDTYLA WYQQKPGKAPKLLIF YASDLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGGYYTSSADTRGA FGGGTKVEIK

[0286] >SEQ ID 47 SI-39P1 chain B nt

[0287]

[0288] >SEQ ID 48 SI-39P1 chain B aa

[0289] DILMTQSPSSMSVSLGDTVSITC HSSQDINSNIG WLQQRPGKSFKGLIY HGTNLDD EVPSRFSGSGSGADYSLTISSLESEDFADYYC VQYAQFPWT FGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQSALTQPASVSGSPGQSITISC TGTSSDVGGYNFVS WYQQHPGKAPKLMIY DVSDRPS GVSDRFSGSKSGNTASLIISGLQADDEADYYC SSYGSSSTHVI FGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLRLSCAASGFTFS SYWMS WVRQAPGKGLEWVA NINRDGSASYVDSVKG RFTISRDDAKNSLYLQMNSLRAEDTAVYYCAR D RGVGYFDL WGRGTLVTVSS

[0290] >SEQ ID 49 SI-38P5 chain A nt

[0291]

[0292] >SEQ ID 50 SI-38P5 chain A aa

[0293] DVVMTQSPSTLSASVGDRVTINC DISCUSSION WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKGLEWIG VITGRDITYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSITE WGQGTLVTVSTGGGGSGGGGSQVQLQQPGAELVKPGASVKMSCKASGYTFT SYNMH WVKQTPGRGLEWIG AIYPGNGDTSYNQKFKG KATLTADKSSSTAYMQLSSLTSEDSAVYYCAR STYYGGDWYFNV WGAGTTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY CASH TLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQ NIRTYLS WYQQKPGKAPKLLIY LISTEN GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC STYLE DOVE FGGGTKVEIK

[0294] >SEQ ID 51 SI-38P5 chain B nt

[0295]

[0296] >SEQ ID 52 SI-38P5 chain B aa

[0297] QIVLSQSPAILSASPGEKVTMTC RASSSVSYIH WFQQKPGSSPKPWIY ATSNLAS GVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYSFS SSWIG WVRQAPGKGLEWMG IIYPDDSDTRYSPSFQG QVTISADKSIRTAYLQWSSLKASDTAMYYCAR HVTMIWGVIIDF WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSAIQLTQSPSSLSASVGDRVTITC QUESTIONS WYQQKPGKAPKLLIY DASSLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQ FNSYPFT FGPGTKVDIK <00010捌捌>>SEQ ID 53 SI-38P6 chain A nt

[0299]

[0300] >SEQ ID 54 SI-38P6 chain A aa

[0301] DVVMTQSPSTLSASVGDRVTINC DISCUSSION WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSITE WGQGTLVTVSTGGGGSGGGGSQVQLQQPGAELVKPGASVKMSCKASGYTFT SYNMH WVKQTPGRGLEWIG AIYPGNGDTSYNQKFKG KATLTADKSSSTAYMQLSSLTSEDSAVYYCAR STYYGGDWYFNV WGAGTTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY CASH TLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQ NIRTYLS WYQQKPGKAPKLLIY LISTEN GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC STYLE DOVE FGCGTKVEIK

[0302] >SEQ ID 55 SI-38P6 chain B nt

[0303]

[0304] >SEQ ID 56 SI-38P6 chain B aa

[0305] QIVLSQSPAILSASPGEKVTMTC RASSSVSYIH WFQQKPGSSPKPWIY ATSNLAS GVPVRFSGSGSGTSYSLTISRVEAEDAATYYC QQWTSNPPT FGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYSFS SSWIG WVRQAPGKCLEWMG IIYPDDSDTRYSPSFQG QVTISADKSIRTAYLQWSSLKASDTAMYYCAR HVTMIWGVIIDF WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSAIQLTQSPSSLSASVGDRVTITC QUESTIONS WYQQKPGKAPKLLIY DASSLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQ FNSYPFT FGCGTKVDIK

[0306] >SEQ ID 57 SI-49P1 chain A nt

[0307]

[0308] >SEQ ID 58 SI-49P1 chain A aa

[0309] EIVMTQSPSTLSASVGDRVIITC DISCUSSION WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGAEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKLTVLGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSITE WGQGTLVTVSTGGGGSGGGGSQVQLQQSGPELEKPGASVKISCKASGYSFT GYTMN WVKQSHGKSLEWIG COLOR SYNQKFRG KATLTVDKSSSTAYMDLLSLTSEDSAVYFCAR GGYDGRGFDY WGSGTPVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY CASTLE AS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHM QWVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNI RTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0310] >SEQ ID 59 SI-49P1 chain B nt

[0311]

[0312] >SEQ ID 60 SI-49P1 chain B aa

[0313] DIELTQSPAIMSASPGEKVTMTC SASSSVSYMH WYQQKSGTSPKRWIY DTSKLAS GVPGRFSGSGSGNSYSLTISSVEAEDDATYYC QQWSKHPLT FGSGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0314] >SEQ ID 61 SI-49P2 chain A nt

[0315]

[0316] >SEQ ID 62 SI-49P2 chain A aa

[0317] EIVMTQSPSTLSASVGDRVIITC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGAEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKLTVLGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQQPGAELVRPGASVKLSCKASGYTFT SYWIN WVKQRPGQGLEWIG NIYPSDSYTNYNQKFKD KATLTVDKSSSTAYMQLSSPTSEDSAVYYCTR SWRGNSFDY WGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLA S GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHM QWVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIR TYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0318] >SEQ ID 63 SI-49P2 chain B nt

[0319]

[0320] >SEQ ID 64 SI-49P2 chain B aa

[0321] DIVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLT WYQQKPGQPPKLLIY WASTRES GVPDRFTGSGSGTDFTLTISSVQAEDLAVYYC QNDYSYPFT FGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRT

[0322] >SEQ ID 65 SI-49P3 chain A nt

[0323]

[0324] >SEQ ID 66 SI-49P3 chain A aa

[0325] EIVMTQSPSTLSASVGDRVIITC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGAEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKLTVLGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIK DTYIH WVRQAPGKGLEWVA RIYPTNGYTRYADSVKG RFTISADTSKNTAYLQMNSLRAEDTAVYYCSR WGGD GFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLN WYQQKPGKAPKLLIY KAST LAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHM QWVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQN IRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0326] >SEQ ID 67 SI-49P3 chain B nt

[0327]

[0328] >SEQ ID 68 SI-49P3 chain B aa

[0329] DIQMTQSPSSLSASVGDRVTITC RASQDVNTAVA WYQQKPGKAPKLLIY SASFLYSGVPS RFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0330] >SEQ ID 69 SI-49P4 chain A nt

[0331]

[0332] >SEQ ID 70 SI-49P4 chain A aa

[0333] EIVMTQSPSTLSASVGDRVIITC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGAEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKLTVLGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSIT SDFA WNWIRQFPGNKLEWMG YISYSGNTRYNPSLKS RISITRDTSKNQFFLQLNSVTIEDTATYYCVT AGRGFP YWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHM QWVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTY LS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0334] >SEQ ID 71 SI-49P4 chain B nt

[0335]

[0336] >SEQ ID 72 SI-49P4 Chain B aa

[0337] DILMTQSPSSMSVSLGDTVSITC HSSQDINSNIG WLQQRPGKSFKGLIY HGTNLDD EVPSRFSGSGSGADYSLTISSLESEDFADYYC VQYAQFPWT FGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0338] >SEQ ID 73 SI-49P5 Chain A nt

[0339]

[0340] >SEQ ID 74 SI-49P5 chain A aa

[0341] EIVMTQSPSTLSASVGDRVIITC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGAEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKLTVLGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTIT DSNIH WVRQAPGQSLEWIG YIYPYNGGTDYNQKFKN RATLTVDNPTNTAYMELSSLRSEDTAFYYCVN GNPWLA YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHM QWVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTY LS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0342] >SEQ ID 75 SI-49P5 chain B nt

[0343]

[0344] >SEQ ID 76 SI-49P5 chain B aa

[0345] DIQLTQSPSTLSASVGDRVTITC RASESLDNYGIRFLT WFQQKPGKAPKLLMY AASNQGS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQTKEVPWS FGQGTKVEVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0346] >SEQ ID 77 SI-49P6 chain A nt

[0347]

[0348] >SEQ ID 78 SI-49P6 chain A aa

[0349] EIVMTQSPSTLSASVGDRVIITC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGAEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKLTVLGSTGSGSKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR S AFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKCLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0350] >SEQ ID 79 SI-49P6 chain B nt

[0351]

[0352] >SEQ ID 80 SI-49P6 chain B aa

[0353] ENVLTQSPASLSASPGERVTITC SASSSVSYMH WYQQKPGQAPKLWIY DTSKLAS GVPSRFSGSGSGNDHTLTISSMEPEDFATYYC FQGSVYPFT FGQGTKLEIKGSTGSGSKPGSGEGSTKGQVTLKESGPGLVQPGQTLRLTCAFSGFSLS TSGMGVG WIRQPPGKGLEWLA HIWWDDDKRYNPALKS RLTISKDTSKNQVYLQMNSLDAEDTAVYYCAR MELWSYYFDY WGQGTLVTVSSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0354] >SEQ ID 81 SI-49P7 chain A nt

[0355]

[0356] >SEQ ID 82 SI-49P7 chain A aa

[0357] EIVMTQSPSTLSASVGDRVIITC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGAEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKLTVLGSTGSGSKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR S AFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGSTGSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGL

[0358] >SEQ ID 83 SI-49P7 chain B nt

[0359]

[0360] >SEQ ID 84 SI-49P7 chain B aa

[0361] ENVLTQSPASLSASPGERVTITC SASSSVSYMH WYQQKPGQAPKLWIY DTSKLAS GVPSRFSGSGSGNDHTLTISSMEPEDFATYYC FQGSVYPFT FGQGTKLEIKGSTGSGSKPGSGEGSTKGQVTLKESGPGLVQPGQTLRLTCAFSGFSLS TSGMGVG WIRQPPGKGLEWLA HIWWDDDKRYNPALKS RLTISKDTSKNQVYLQMNSLDAEDTAVYYCAR MELWSYYFDY WGQGTLVTVSSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0362] >SEQ ID 85 SI-49P10 chain A nt <000

[0364] >SEQ ID 86 SI-49P10 chain A aa

[0365] EIVMTQSPSTLSASVGDRVIITC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGAEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKLTVLGSTGSGSKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR S AFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKCLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0366] >SEQ ID 87 SI-49P10 chain B nt

[0367]

[0368] >SEQ ID 88 SI-49P10 chain B aa

[0369] DIQMTQSPSSLSASVGDRVTITC QASQDISNYLN WYQQKPGKAPKLLIY DASNLET GVPSRFSGSGSGTDFTFTISSLQPEDIATYFC QHFDHLPLA FGGGTKVEIKGSTGSGSKPGSGEGSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0370] >SEQ ID 97 SI-38E17 chain A nt

[0371]

[0372] >SEQ ID 98 SI-38E17 chain A aa

[0373]

[0374] >SEQ ID 99 SI-38E17 Chain B nt

[0375] GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0376] >SEQ ID 100 SI-38E17 Chain B aa

[0377] AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0378] >SEQ ID 105 SI-55H11 chain A nt

[0379]

[0380] >SEQ ID 106 SI-55H11 chain A aa

[0381]

[0382] >SEQ ID 107 SI-55H11 chain B nt

[0383]

[0384] >SEQ ID 108 SI-55H11 chain B aa

[0385] ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWIYDTSKLASGVPSRFSGSGSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQVTLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLIISGLQADDEADYYCSSYGSSSTHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLSLSCAASGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCARDRGVGYFDLWGRGTLVTVSS

[0386] >SEQ ID 109 SI-50E1 chain A nt

[0387]

[0388] >SEQ ID 110 SI-50E1 chain A aa

[0389] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIK DTYIH WVRQAPGKGLEWVA RIYPTNGYTRYADSVKG RFTISADTSKNTAYLQMNSLRAEDTAVYYCSR WGGDGFYAMD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KAST LAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QQGYSWGNVDNV FGGGTKVEIK SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQN IRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0390] >SEQ ID 111 SI-50E1 and SI-50E6 chain B nt

[0391] GATATCCAGATGACCCAGTCCCCGAGCTCCCTGTCCGCCTCTGTGGGCGATAGGGTCACCATCACCTGCCGTGCCAGTCAGGATGTGAATACTGCTGTAGCCTGGTATCAACAGAAACCAGGAAAAGCTCCGAAACTACTGATTTACTCGGCATCCTTCCTCTACTCTGGAGTCCCTTCTCGCTTCTCTGGCTCCAGATCTGGGACGGATTTCACTCTGACCATCAGCAGTCTGCAGCCGGAAGACTTCGCAACTTATTACTGTCAGCAACATTATACTACTCCTCCCACGTTCGGACAGGGTACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0392] >SEQ ID 112 SI-50E1 and SI-50E6 Chain B aa

[0393] DIQMTQSPSSLSASVGDRVTITC RASQDVNTAVA WYQQKPGKAPKLLIY SASFLYS GVPSRFSGSRSGTDFTLTISSLQPEDFATYYC QQHYTTPPT FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0394] >SEQ ID 113 SI-50E6 chain A nt

[0395]

[0396] >SEQ ID 114 SI-50E6 chain A aa

[0397] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIK DTYIH WVRQAPGKGLEWVA RIYPTNGYTRYADSVKG RFTISADTSKNTAYLQMNSLRAEDTAVYYCSR WGGDGFYAMDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KAST LAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQN IRTYLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0398] >SEQ ID 115 SI-50E2 chain A nt

[0399]

[0400] >SEQ ID 116 SI-50E2 chain A aa

[0401]

[0402] >SEQ ID 117 SI-50E2 and SI-50E7 Chain B nt

[0403] GACATCCAGATGACACAATCTCCTAGCAGTCTGAGCGCAAGTGTTGGAGATCGTGTCACCATCACATGCAAGGCCAGCCAGGATGTGAGCATTGGAGTCGCCTGGTATCAGCAGAAACCCGGCAAGGCACCCAAGCTGCTGATCTACTCGGCCAGTTACAGATACACTGGCGTACCTTCGAGGTTTAGTGGTAGCGGTTCTGGAACCGATTTCACCCTCACCATTAGCTCCCTCCAACCCGAGGACTTCGCCACCTACTACTGCCAGCAATACTACATCTACCCTTACACGTTCGGCCAAGGCACTAAGGTCGAGATTAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0404] >SEQ ID 118 SI-50E2 and SI-50E7 Chain B aa

[0405] DIQMTQSPSSLSASVGDRVTITC KASQDVSIGVA WYQQKPGKAPKLLIY SASYRYT GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQYYIYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0406] >SEQ ID 119 SI-50E7 chain A nt

[0407]

[0408] >SEQ ID 120 SI-50E7 chain A aa

[0409]

[0410] >SEQ ID 121 SI-51E1 chain A nt

[0411]

[0412] >SEQ ID 122 SI-51E1 chain A aa

[0413]

[0414] >SEQ ID 123 SI-51E1 and SI-51E4 Chain B nt

[0415] GACATCGAGCTCACTCAGTCTCCAGCAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTGCCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGTCAGGCACCTCCCCCAAAAGATGGATTTATGACACATCCAAACTGGCTTCTGGAGTCCCAGGTCGCTTCAGTGGCAGTGGGTCTGGAAACTCTTACTCTCTCACAATCAGCAGCGTGGAGGCTGAAGATGATGCAACTTATTACTGCCAGCAGTGGAGTAAGCACCCTCTCACGTTCGGATCCGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0416] >SEQ ID 124 SI-51E1 and SI-51E4 Chain B aa

[0417] DIELTQSPAIMSASPGEKVTMTC SASSSVSYMH WYQQKSGTSPKRWIY DTSKLAS GVPGRFSGSGSGNSYSLTISSVEAEDDATYYC QQWSKHPLTFGSGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0418] >SEQ ID 125 SI-51E4 Chain A nt

[0419]

[0420] >SEQ ID 126 SI-51E4 Chain A aa

[0421] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQQSGPELEKPGASVKISCKASGYSFT GYTMN WVKQSHGKSLEWIG LITPYNGASSYNQKFRG KATLTVDKSSSTAYMDLLSLTSEDSAVYFCAR GGYDGRGFDY WGSGTPVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTL AS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNI RTYLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0422] >SEQ ID 127 SI-52E1 chain A nt

[0423]

[0424] >SEQ ID 128 SI-52E1 chain A aa

[0425] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSEVQLLQSGPELEKPGASVMISCKASGSSFT GYNMN WVRQNIGKSLEWIG AIDPYYGGTSYNQKFKG RATLTVDKSSSTAYMHLKSLTSEDSAVYYCVS GMEY WGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0426] >SEQ ID 129 SI-52E1 and SI-52E4 chain B nt

[0427] GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGATCTAGTCAGAGTCTTGTACACCGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATTCACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGTTCTCAAAGTACACATGTTCCTCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0428] >SEQ ID 130 SI-52E1 and SI-52E4 Chain B aa

[0429] EIVMTQSPATLSVSPGERATLSC RSSQSLVH RNGNTYLHWYLQKPGQSPKLLIH KVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDLGVYFC SQSTHVPPLT FGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0430] >SEQ ID 131 SI-52E4 chain A nt

[0431]

[0432] >SEQ ID 132 SI-52E4 chain A aa

[0433] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSEVQLLQSGPELEKPGASVMISCKASGSSFT GYNMN WVRQNIGKSLEWIG AIDPYYGGTSYNQKFKG RATLTVDKSSSTAYMHLKSLTSEDSAVYYCVS GMEY WGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTYLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0434] >SEQ ID 133 SI-53E1 chain A nt

[0435]

[0436] >SEQ ID 134 SI-53E1 chain A aa

[0437] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQQPGAELVRPGASVKLSCKASGYTFT SYWIN WVKQRPGQGLEWIG NIYPSDSYTNYNQKFKD KATLTVDKSSSTAYMQLSSPTSEDSAVYYCTR SWRGNSFDY WGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLA S GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIR TYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0438] >SEQ ID 135 SI-53E1 and SI-53E3 chain B nt

[0439] GACATTGTGATGACACAGTCTCCATCCTCCCTGACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAAACAGTGGAAATCAAAAGAACTACTTGACCTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAACTGTTGATCTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGAACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGAATGATTATAGTTATCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0440] >SEQ ID 136 SI-53E1 and SI-53E3 chain B aa

[0441] DIVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLT WYQQKPGQPPKLLIY WASTRES GVPDRFTGSGSGTDFTLTISSVQAEDLAVYYC QNDYSYPFT FGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0442] >SEQ ID 137 SI-53 E3 chain A nt

[0443]

[0444] >SEQ ID 138 SI-53E3 chain A aa

[0445] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQQPGAELVRPGASVKLSCKASGYTFT SYWIN WVKQRPGQGLEWIG NIYPSDSYTNYNQKFKD KATLTVDKSSSTAYMQLSSPTSEDSAVYYCTR SWRGNSFDY WGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLA S GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIR TYLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0446] >SEQ ID 139 SI-54E1 chain A nt

[0447]

[0448] >SEQ ID 140 SI-54E1 chain A aa

[0449] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQQPGAELVKPGASVKMSCKASGYTFT SYNMH WVKQTPGRGLEWIG AIYPGNGDTSYNQKFKG KATLTADKSSSTAYMQLSSLTSEDSAVYYCAR STYYGGDWYFNV WGAGTTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KAS TLAS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIK SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSS QASQ NIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0450] >SEQ ID 141 SI-54E1 and SI-54E3 chain B nt

[0451] CAGATCGTGCTGAGCCAGAGCCCCGCCATCCTGAGCGCCAGCCCCGGCGAGAAGGTGACCATGACCTGCCGGGCCAGCAGCAGCGTGAGCTACATCCACTGGTTCCAGCAGAAGCCCGGCAGCAGCCCCAAGCCCTGGATCTACGCCACCAGCAACCTGGCCAGCGGCGTGCCCGTGCGGTTCAGCGGCAGCGGCAGCGGCACCAGCTACAGCCTGACCATCAGCCGGGTGGAGGCCGAGGACGCCGCCACCTACTACTGCCAGCAGTGGACCAGCAACCCCCCCACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0452] >SEQ ID 142 SI-54E1 and SI-54E3 chain B aa

[0453] QIVLSQ SPAILSASPG EKVTMTC RASSSVSYIH WFQQKPGSSPKPWIY ATSNLAS GVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0454] >SEQ ID 143 SI-54E3 chain A nt

[0455]

[0456] >SEQ ID 144 SI-54E3 chain A aa

[0457]

[0458] >SEQ ID 145 SI-55E1 chain A nt

[0459]

[0460] >SEQ ID 146 SI-55E1 chain A aa

[0461] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLT NYGVH WVRQSPGKGLEWLG VIWSGGNTDYNTPFTS RLSINKDNSKSQVFFKMNSLQSNDTAIYYCAR ALTYYDYEFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTL AS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIK SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSS QASQNI RTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0462] >SEQ ID 147 SI-55E1 and SI-55E8 chain B nt

[0463] GACATCTTGCTGACTCAGTCTCCAGTCATCCTGTCTGTGAGTCCAGGAGAAAGAGTCAGTTTCTCCTGCAGGGCCAGTCAGAGTATTGGCACAAACATACACTGGTATCAGCAAAGAACAAATGGTTCTCCAAGGCTTCTCATAAAGTATGCTTCTGAGTCTATCTCTGGGATTCCTTCCAGGTTTAGTGGCAGTGGATCAGGGACAGATTTTACTCTTAGCATCAACAGTGTGGAGTCTGAAGATATTGCAGATTATTACTGTCAACAAAATAATAACTGGCCAACCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0464] >SEQ ID 148 SI-55E1 and SI-55E8 Chain B aa

[0465] DILLTQSPVILSVSPGERVSFSC RASQSIGTNIH WYQQRTNGSPRLLIK YASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0466] >SEQ ID 149 SI-55E8 chain A nt

[0467]

[0468] >SEQ ID 150 SI-55E8 chain A aa

[0469] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLT NYGVH WVRQSPGKGLEWLG VIWSGGNTDYNTPFTS RLSINKDNSKSQVFFKMNSLQSNDTAIYYCAR ALTYYDYEFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTL AS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNI RTYLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0470] >SEQ ID 151 SI-55E2 chain A nt

[0471]

[0472] >SEQ ID 152 SI-55E2 chain A aa

[0473] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGGSVS SGDYYWT WIRQSPGKGLEWIG HIYYSGNTNYNPSLKS RLTISIDTSKTQFSLKLSSVTAADTAIYYCVR DRVTGAFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTL AS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QQGYSWGNVDNV FGGGTKVEIK SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNI RTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0474] >SEQ ID 153 SI-55E2 and SI-55E9 chain B nt

[0475] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATCAGCAACTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTTCTGTCAACACTTTGATCATCTCCCGCTCGCTTTCGGCGGAGGGACCAAGGTGGAAATTAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0476] >SEQ ID 154 SI-55E2 and SI-55E9 Chain B aa

[0477] DIQMTQSPSSLSASVGDRVTITC QASQDISNYLN WYQQKPGKAPKLLIY DASNLET GVPSRFSGSGSGTDFTFTISSLQPEDIATYFC QHFDHLPLA FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0478] >SEQ ID 155 SI-55E9 chain A nt

[0479]

[0480] >SEQ ID 156 SI-55E9 Chain A aa

[0481] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGGSVS SGDYYWT WIRQSPGKGLEWIG HIYYSGNTNYNPSLKS RLTISIDTSKTQFSLKLSSVTAADTAIYYCVR DRVTGAFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTL AS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNI RTYLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0482] >SEQ ID 157 SI-55E3 chain A nt

[0483]

[0484] >SEQ ID 158 SI-55E3 chain A aa

[0485] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQQSGAEVKKPGSSVKVSCKASGYTFT NYYIY WVRQAPGQGLEWIG GINPTSGGSNFNEKFKT RVTITADESSTTAYMELSSLRSEDTAFYFCTR QGLWFDSDGRGFDF WGQGTTVTVSS

[0486] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY K ASTLAS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QA SQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0487] >SEQ ID 159 SI-55E3 and SI-55E10 chain B nt

[0488] GATATTCAAATGACTCAATCTCCTTCTTCTCTTTCTGCTTCTGTTGGTGATCGTGTTACTATTACTTGTCGTTCTTCTCAAAATATTGTTCATTCTAATGGTAATACTTATCTTGATTGGTATCAACAAACTCCTGGTAAAGCTCCTAAACTTCTTATTTATAAAGTTTCTAATCGTTTTTCTGGTGTTCCTTCTCGTTTTTCTGGTTCTGGTTCTGGTACTGATTTTACTTTTACTATTTCTTCTCTTCAACCTGAAGATATTGCTACTTATTATTGTTTTCAATATTCTCATGTTCCTTGGACTTTTGGTCAAGGTACTAAACTTCAAATTACTCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0489] >SEQ ID 160 SI-55E3 and SI-55E10 Chain B aa

[0490] DIQMTQSPSSLSASVGDRVTITC RSSQNIVHSNGNTYLD WYQQTPGKAPKLLIY KVSNRFS GVPSRFSGSGSGTDFTFTISSLQPEDIATYYC FQYSHVPWT FGQGTKLQITRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0491] >SEQ ID 161 SI-55E10 chain Ant

[0492]

[0493] >SEQ ID 162 SI-55E10 chain A aa

[0494] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQVQLQQSGAEVKKPGSSVKVSCKASGYTFT NYYIY WVRQAPGQGLEWIG GINPTSGGSNFNEKFKT RVTITADESSTTAYMELSSLRSEDTAFYFCTR QGLWFDSDGRGFDF WGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY K ASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QA SQNIRTYLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0495] >SEQ ID 163 SI-56E1 Chain A nt

[0496]

[0497] >SEQ ID 164 SI-56E1 chain A aa

[0498] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSEVQLVQSGAEVKKPGASVKVSCKASGYRFT NYWIH WVRQAPGQGLEWIG GINPGNNYATYRRKFQG RVTMTADTSTSTVYMELSSLRSEDTAVYYCTR EGYGNYGAWFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KAS TLAS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQ NIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0499] >SEQ ID 165 SI-56E1 and SI-56E3 chain B nt

[0500] GACGTTCAAGTGACCCAGAGCCCATCCAGCCTGAGCGCATCTGTAGGAGACCGGGTCACCATCACTTGTAGATCCAGTCAGAGTCTTGCAAACAGTTATGGGAACACCTTTTTGTCTTGGTATCTGCACAAACCAGGTAAAGCCCCACAATTGCTCATCTACGGAATCTCTAACAGATTTAGTGGTGTACCAGACAGGTTCAGCGGTTCCGGAAGTGGTACTGATTTCACCCTCACGATCTCGTCTCTCCAGCCAGAAGATTTCGCCACTTATTACTGTTTACAAGGTACACATCAGCCGTACACATTCGGTCAGGGTACTAAAGTAGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0501] >SEQ ID 166 SI-56E1 and SI-56E3 chain B aa

[0502] DVQVTQSPSSLSASVGDRVTITC RSSQSLANSYGNTFLS WYLHKPGKAPQLLIY GISNRFS GVPDRFSGSGSGTDFTLTISS LQPEDFATYYCLQGTHQPYT FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0503] >SEQ ID 167 SI-56 E3 chain A nt

[0504]

[0505] >SEQ ID 168 SI-56E3 chain A aa

[0506] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSEVQLVQSGAEVKKPGASVKVSCKASGYRFT NYWIH WVRQAPGQGLEWIG GINPGNNYATYRRKFQG RVTMTADTSTSTVYMELSSLRSEDTAVYYCTR EGYGNYGAWFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KAS TLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQ NIRTYLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0507] >SEQ ID 169 SI-57E1 chain A nt

[0508]

[0509] >SEQ ID 170 SI-57E1 chain A aa

[0510] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMSW VRQAPGKGLEWIG VITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQIQLQQSGPEVVKPGASVKISCKASGYTFT DYYIT WVKQKPGQGLE WIGWIYPGSGNTKYNEKFKG KATLTVDTSSSTAFMQLSSLTSEDTAVYFCAN YGNYWFAY WGQGTQVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QQGYSWGNVDNV FGGGTKVEIK SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPMW GQGTLVTVSS QASQNIRT YLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QSTYLGTDYVGGA FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS

[0511] >SEQ ID 171 SI-57E1 and SI-57E3 chain B nt

[0512] GACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCACCATCTCCTGCAAGGCCAGCCAAAGTGTTGATTTTGATGGTGATAGTTATATGAACTGGTACCAACAGAAACCAGGACAGCCACCCAAAGTCCTCATCTATGCTGCATCCAATCTAGAATCTGGGATCCCAGCCAGGTTTAGTGGCAGTGGGTCTGGGACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATTACTGTCAGCAAAGTAATGAGGATCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0513] >SEQ ID 172 SI-57E1 and SI-57E3 chain B aa

[0514] DIVLTQSPASLAVSLGQRATISC KASQSVDFDGDSYM NWYQQKPGQPPKVLIY AASNLES GIPARFSGSGSGTDFTLNIHPVEEEDAATYYC QQSNEDPWT FGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0515] >SEQ ID 173 SI-57 E3 chain A nt

[0516]

[0517] >SEQ ID 174 SI-57 E3 chain A aa

[0518] DVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGCGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKCLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSQIQLQQSGPEVVKPGASVKISCKASGYTFT DYYIT WVKQKPGQGLE WIGWIYPGSGNTKYNEKFKG KATLTVDTSSSTAFMQLSSLTSEDTAVYFCAN YGNYWFAY WGQGTQVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLNWYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRT YLSW YQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0519] >SEQ ID 175 SI-1H1 chain A nt

[0520]

[0521] >SEQ ID 176 SI-1H1 chain A aa

[0522] DIQMTQSPSSLSASVGDRVTITC QASQDISNYLN WYQQKPGKAPKLLIY DASNLET GVPSRFSGSGSGTDFTFTISSLQPEDIATYFC QHFDHLPLA FGGGTKVEIKGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGGSVS SGDYYWT WIRQSPGKGLEWIG HIYYSGNTNYNPSLKS RLTISIDTSKTQFSLKLSSVTAADTAIYYCVR DRVTGAF DI WGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTIS TNAMS WVRQAPGKGLEWIG VITGRDITYYASWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKGLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK

[0523] >SEQ ID 177 SI-1H1 chain B nt

[0524]

[0525] >SEQ ID 178 SI-1H1 chain B aa

[0526] QSALTQPASVSGSPGQSITISC TGTSSDVGGYNFVS WYQQHPGKAPKLMIY DVSDRPS GVSDRFSGSKSGNTASLIISGLQADDEADYYCSSYGS SSTHVI FGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLRLSCAASGFTFS SYWMS WVRQAPGKGLEWVA NINRDGSASYYVDSVKG RFTISRDDAKNSLYLQMNSLRAEDTAVYYCAR DRGVGYFDL WGRGTLVTVSSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINC QASESISSWLA WYQQKPGKAPKLLIY EASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGYFYFISRTYVNS FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVTLKESGPGLVQPGQTLRLTCAFSGFSLS TSGMGVG WIRQPPGKGLEWLA HIWWDDDKRYNPALKS RLTISKDTSKNQVYLQMNSLDAEDTAVYYCAR MELWSYYFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSENVLTQSPASLSASPGERVTITC SASSSVSYMH WYQQKPGQAPKLWIY DTSKLAS GVPSRFSGSGSGNDHTLTISSMEPEDFATYYC FQGSVYPFT FGQGTKLEIK

[0527] >SEQ ID 183 SI-49R19 chain A nt

[0528]

[0529] >SEQ ID 184 SI-49R19 chain A aa

[0530] EIVMTQSPSTLSASVGDRVIITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVLGSTGSGSKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0531] >SEQ ID 185 SI-49R19 chain B nt

[0532] TTCCTAAACTCATTATTCAACCAAGAAGTTCAAATTCCCTTGACCGAAAGTTACTGTGGCCCATGTCCTAAAAACTGGATATGTTACAAAAATAACTGCTACCAATTTTTTGATGAGAGTAAAAACTGGTATGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATACAGCAAAGAGGACCAGGATTTACTTAAACTGGTGAAGTCATATCATTGGATGGGACTAGTACACATTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAATAATTGAAATGCAGAAGGGAGACTGTGCACTCTATGCCTCGAGCTTTAAAGGCTATATAGAAAACTGTTCAACTCCAAATACGTACATCTGCATGCAAAGGACTGTGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0533] >SEQ ID 186 SI-49R19 chain B aa

[0534] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0535] >SEQ ID 187 SI-49R18 chain A nt

[0536]

[0537] >SEQ ID 188 SI-49R18 Chain A aa

[0538] EIVMTQSPSTLSASVGDRVIITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVLGSTGSGSKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0539] >SEQ ID 189 SI-49R18 Chain B nt

[0540]

[0541] >SEQ ID 190 SI-49R18 chain B aa

[0542] ENVLTQSPASLSASPGERVTITC SASSSVSYMH WYQQKPGQAPKLWIY DTSKLAS GVPSRFSGSGSGNDHTLTISSMEPEDFATYYC FQGSVYPFT FGQGTKLEIKGSTGSGSKPGSGEGSTKGQVTLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0543] >SEQ ID 191 SI-49E15 chain A nt

[0544]

[0545] >SEQ ID 192 SI-49E15 Chain A aa

[0546] EIVMTQSPSTLSASVGDRVIITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVLGSTGSGSKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCTASGFTIS TNAMS WVRQAPGKCLEWVG VITGRDITYYASWAKG RFTISRDTSKNTVYLQMNSLRAEDTAVYYCAR DGGSSAITSNNI WGQGTLVTVSTGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS SGYDMC WVRQAPGKCLEWIA CIAAGSAGITYDANWAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR S AFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITC QASQSISSHLN WYQQKPGKAPKLLIY KASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQGYSWGNVDNV FGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKCLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGCGTKVEIK

[0547] >SEQ ID 193 SI-49E15 chain B nt

[0548] TTCCTAAACTCATTATTCAACCAAGAAGTTCAAATTCCCTTGACCGAAAGTTACTGTGGCCCATGTCCTAAAAACTGGATATGTTACAAAAATAACTGCTACCAATTTTTTGATGAGAGTAAAAACTGGTATGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATACAGCAAAGAGGACCAGGATTTACTTAAACTGGTGAAGTCATATCATTGGATGGGACTAGTACACATTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAATAATTGAAATGCAGAAGGGAGACTGTGCACTCTATGCCTCGAGCTTTAAAGGCTATATAGAAAACTGTTCAACTCCAAATACGTACATCTGCATGCAAAGGACTGTGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0549] >SEQ ID 194 SI-49E15 Chain B aa

[0550] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0551] >SEQ ID 195 SI-49R21 Chain A nt

[0552]

[0553] >SEQ ID 196 SI-49R21 chain A aa

[0554] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0555] >SEQ ID 197 SI-49R21 chain B nt

[0556] TTCCTAAACTCATTATTCAACCAAGAAGTTCAAATTCCCTTGACCGAAAGTTACTGTGGCCCATGTCCTAAAAACTGGATATGTTACAAAAATAACTGCTACCAATTTTTTGATGAGAGTAAAAACTGGTATGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATACAGCAAAGAGGACCAGGATTTACTTAAACTGGTGAAGTCATATCATTGGATGGGACTAGTACACATTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAATAATTGAAATGCAGAAGGGAGACTGTGCACTCTATGCCTCGAGCTTTAAAGGCTATATAGAAAACTGTTCAACTCCAAATACGTACATCTGCATGCAAAGGACTGTGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0557] >SEQ ID 198 SI-49R21 chain B aa

[0558] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0559] >SEQ ID 199 SI-49R22 chain A nt

[0560]

[0561] >SEQ ID 200 SI-49R22 Chain A aa

[0562] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0563] >SEQ ID 201 SI-49R22 Chain B nt

[0564] TTCCTAAACTCATTATTCAACCAAGAAGTTCAAATTCCCTTGACCGAAAGTTACTGTGGCCCATGTCCTAAAAACTGGATATGTTACAAAAATAACTGCTACCAATTTTTTGATGAGAGTAAAAACTGGTATGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATACAGCAAAGAGGACCAGGATTTACTTAAACTGGTGAAGTCATATCATTGGATGGGACTAGTACACATTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAATAATTGAAATGCAGAAGGGAGACTGTGCACTCTATGCCTCGAGCTTTAAAGGCTATATAGAAAACTGTTCAACTCCAAATACGTACATCTGCATGCAAAGGACTGTGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0565] >SEQ ID 202 SI-49R22 chain B aa

[0566] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0567] >SEQ ID 203 SI-49R22 chain C nt

[0568]

[0569] >SEQ ID 204 SI-49R22 chain C aa

[0570] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0571] >SEQ ID 205 SI-49R23 chain Ant

[0572]

[0573] >SEQ ID 206 SI-49R23 chain A aa

[0574] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0575] >SEQ ID 207 SI-49R24 chain A nt

[0576]

[0577] >SEQ ID 208 SI-49R24 chain A aa

[0578] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0579] >SEQ ID 209 SI-49R24 chain B nt

[0580]

[0581] >SEQ ID 210 SI-49R24 chain B aa

[0582] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVASEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0583] >SEQ ID 217 Anti-claudin Zotatuximab VH nt

[0584] CAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTGAGGCCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGCTACTGGATAAACTGGGTGAAGCAGAGGCCTGGACAAGGCCTTGAGTGGATCGGAAATATTTATCCTTCTGATAGTTATACTAACTACAATCAAAAGTTCAAGGACAAGGCCACATTGACTGTAGACAAATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCCGACATCTGAGGACTCTGCGGTCTATTACTGTACAAGATCGTGGAGGGGTAACTCCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA

[0585] >SEQ ID 218 Anti-claudin Zotatuximab VH aa

[0586] QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSS

[0587] >SEQ ID 219 Anti-claudin saroteximab VL nt

[0588] GACATTGTGATGACACAGTCTCCATCCTCCCTGACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAAACAGTGGAAATCAAAAGAACTACTTGACCTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAACTGTTGATCTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGAACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGAATGATTATAGTTATCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA

[0589] >SEQ ID 220 Anti-claudin saroteximab VL aa

[0590] DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTFGSGTKLEIK

[0591] >SEQ ID 221 Anti-HER2 trastuzumab VH nt

[0592] GAGGTTCAGCTGGTGGAGTCTGGCGGTGGCCTGGTGCAGCCAGGGGGCTCACTCCGTTTGTCCTGTGCAGCTTCTGGCTTCAACATTAAAGACACCTATATACACTGGGTGCGTCAGGCCCCGGGTAAGGGCCTGGAATGGGTTGCAAGGATTTATCCTACGAATGGTTATACTAGATATGCCGATAGCGTCAAGGGCCGTTTCACTATAAGCGCAGACACATCCAAAAACACAGCCTACCTGCAGATGAACAGCCTGCGTGCTGAGGACACTGCCGTCTATTATTGTTCTAGATGGGGAGGGGACGGCTTCTATGCTATGGACTACTGGGGTCAAGGAACCCTGGTCACCGTCTCCTCG

[0593] >SEQ ID 222 Anti-HER2 Trastuzumab VH aa

[0594] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS

[0595] >SEQ ID 223 Anti-HER2 Trastuzumab VL nt

[0596] GATATCCAGATGACCCAGTCCCCGAGCTCCCTGTCCGCCTCTGTGGGCGATAGGGTCACCATCACCTGCCGTGCCAGTCAGGATGTGAATACTGCTGTAGCCTGGTATCAACAGAAACCAGGAAAAGCTCCGAAACTACTGATTTACTCGGCATCCTTCCTCTACTCTGGAGTCCCTTCTCGCTTCTCTGGCTCCAGATCTGGGACGGATTTCACTCTGACCATCAGCAGTCTGCAGCCGGAAGACTTCGCAACTTATTACTGTCAGCAACATTATACTACTCCTCCCACGTTCGGACAGGGTACCAAGGTGGAGATCAAA

[0597] >SEQ ID 224 Anti-HER2 Trastuzumab VL aa

[0598] DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK

[0599] >SEQ ID 225 Anti-HER2 Pertuzumab VH nt

[0600] GAAGTGCAGCTCGTCGAAAGCGGTGGCGGACTGGTTCAGCCCGGTGGTTCTCTGCGGCTGTCTTGTGCTGCCTCGGGTTTCACGTTCACTGACTACACAATGGACTGGGTGCGTCAGGCTCCTGGAAAGGGATTGGAGTGGGTAGCCGACGTTAATCCAAACTCCGGCGGGAGCATCTACAACCAGAGGTTCAAGGGGAGGTTCACTCTGAGCGTGGATCGCTCCAAGAACACGCTGTACCTCCAGATGAACTCTCTCAGGGCCGAGGACACGGCTGTTTACTATTGCGCGAGGAACCTGGGTCCTTCCTTCTACTTCGACTACTGGGGACAGGGAACCCTGGTGACCGTCAGCTCC

[0601] >SEQ ID 226 Anti-HER2 Pertuzumab VH aa

[0602] EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS

[0603] >SEQ ID 227 Anti-HER2 Pertuzumab VL nt

[0604] GACATCCAGATGACACAATCTCCTAGCAGTCTGAGCGCAAGTGTTGGAGATCGTGTCACCATCACATGCAAGGCCAGCCAGGATGTGAGCATTGGAGTCGCCTGGTATCAGCAGAAACCCGGCAAGGCACCCAAGCTGCTGATCTACTCGGCCAGTTACAGATACACTGGCGTACCTTCGAGGTTTAGTGGTAGCGGTTCTGGAACCGATTTCACCCTCACCATTAGCTCCCTCCAACCCGAGGACTTCGCCACCTACTACTGCCAGCAATACTACATCTACCCTTACACGTTCGGCCAAGGCACTAAGGTCGAGATTAAA

[0605] >SEQ ID 228 Anti-HER2 Pertuzumab VL aa

[0606] DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIK

[0607] >SEQ ID 229 Anti-Mesothelin Amatuximab VH nt

[0608] CAGGTACAACTGCAGCAGTCTGGGCCTGAGCTGGAGAAGCCTGGCGCTTCAGTGAAGATATCCTGCAAGGCTTCTGGTTACTCATTCACTGGCTACACCATGAACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGACTTATTACTCCTTACAATGGTGCTTCTAGCTACAACCAGAAGTTCAGGGGCAAGGCCACATTAACTGTAGACAAGTCATCCAGCACAGCCTACATGGACCTCCTCAGTCTGACATCTGAAGACTCTGCAGTCTATTTCTGTGCAAGGGGGGGTTACGACGGGAGGGGTTTTGACTACTGGGGATCTGGGACCCCGGTCACCGTCTCCTCA

[0609] >SEQ ID 230 Anti-Mesothelin Amatuximab VH aa

[0610] QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASSYNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGSGTPVTVSS

[0611] >SEQ ID 231 Anti-mesothelin Amatuximab VL nt

[0612] GACATCGAGCTCACTCAGTCTCCAGCAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTGCCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGTCAGGCACCTCCCCCAAAAGATGGATTTATGACACATCCAAACTGGCTTCTGGAGTCCCAGGTCGCTTCAGTGGCAGTGGGTCTGGAAACTCTTACTCTCTCACAATCAGCAGCGTGGAGGCTGAAGATGATGCAACTTATTACTGCCAGCAGTGGAGTAAGCACCCTCTCACGTTCGGATCCGGGACCAAGGTGGAAATCAAA

[0613] >SEQ ID 232 Anti-mesothelin Amatuximab VL aa

[0614] DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGNSYSLTISSVEAEDDATYYCQQWSKHPLTFGSGTKVEIK

[0615] >SEQ ID 233 Anti-GD2 Dinutuximab VH nt

[0616] GAGGTCCAACTGCTGCAGTCTGGACCTGAGCTGGAGAAGCCTGGCGCTTCAGTGATGATATCCTGCAAGGCTTCTGGTTCCTCATTCACTGGCTACAACATGAACTGGGTGAGGCAGAACATTGGAAAGAGCCTTGAATGGATTGGAGCTATTGATCCTTACTATGGTGGAACTAGCTACAACCAGAAGTTCAAGGGCAGGGCCACATTGACTGTAGACAAATCGTCCAGCACAGCCTACATGCACCTCAAGAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGTAAGCGGAATGGAGTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA

[0617] >SEQ ID 234 Anti-GD2 Dinutuximab VH aa

[0618] EVQLLQSGPELEKPGASVMISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRATLTVDKSSSTAYMHLKSLTSEDSAVYYCVSGMEYWGQGTSVTVSS

[0619] >SEQ ID 235 Anti-GD2 Dinutuximab VL nt

[0620] GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGATCTAGTCAGAGTCTTGTACACCGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATTCACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGTTCTCAAAGTACACATGTTCCTCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA

[0621] >SEQ ID 236 Anti-GD2 Dinutuximab VL aa

[0622] EIVMTQSPATLSVSPGERATLSCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELK

[0623] >SEQ ID 237 anti-CD20 Rituximab VH nt

[0624] CAGGTGCAGCTGCAGCAGCCCGGCGCCGAGCTGGTGAAGCCCGGCGCCAGCGTGAAGATGAGCTGCAAGGCCAGCGGCTACACCTTCACCAGCTACAACATGCACTGGGTGAAGCAGACCCCCGGCCGGGGCCTGGAGTGGATCGGCGCCATCTACCCCGGCAACGGCGACACCAGCTACAACCAGAAGTTCAAGGGCAAGGCCACCCTGACCGCCGACAAGAGCAGCAGCACCGCCTACATGCAGCTGAGCAGCCTGACCAGCGAGGACAGCGCCGTGTACTACTGCGCCCGGAGCACCTACTACGGCGGCGACTGGTACTTCAACGTGTGGGGCGCCGGCACCACCGTGACCGTGAGCGCC

[0625] >SEQ ID 238 anti-CD20 Rituximab VH aa

[0626] QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA

[0627] >SEQ ID 239 anti-CD20 Rituximab VL nt

[0628] CAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGGTGGAAACACAGACTATAATACACCTTTCACATCCAGACTGAGCATCAACAAGGACAATTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAATCTAATGACACAGCCATATATTACTGTGCCAGAGCCCTCACCTACTATGATTACGAGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTAGC

[0629] >SEQ ID 240 Anti-CD20 Rituximab VL aa

[0630] QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK

[0631] >SEQ ID 241 Anti-EGFR Cetuximab VH nt

[0632] CAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGGTGGAAACACAGACTATAATACACCTTTCACATCCAGACTGAGCATCAACAAGGACAATTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAATCTAATGACACAGCCATATATTACTGTGCCAGAGCCCTCACCTACTATGATTACGAGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTAGC

[0633] >SEQ ID 242 Anti-EGFR Cetuximab VH aa

[0634] QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSS

[0635] >SEQ ID 243 anti-EGFR cetuximab VL nt

[0636] GACATCTTGCTGACTCAGTCTCCAGTCATCCTGTCTGTGAGTCCAGGAGAAAGAGTCAGTTTCTCCTGCAGGGCCAGTCAGAGTATTGGCACAAACATACACTGGTATCAGCAAAGAACAAATGGTTCTCCAAGGCTTCTCATAAAGTATGCTTCTGAGTCTATCTCTGGGATTCCTTCCAGGTTTAGTGGCAGTGGATCAGGGACAGATTTTACTCTTAGCATCAACAGTGTGGAGTCTGAAGATATTGCAGATTATTACTGTCAACAAAATAATAACTGGCCAACCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA

[0637] >SEQ ID 244 anti-EGFR cetuximab VL aa

[0638] DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK

[0639] >SEQ ID 245 anti-EGFR panitumumab VH nt

[0640] CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCGTCAGCAGTGGTGATTACTACTGGACCTGGATCCGGCAGTCCCCAGGGAAGGGACTGGAGTGGATTGGACACATCTATTACAGTGGGAACACCAATTATAACCCCTCCCTCAAGAGCCGACTCACCATATCAATTGACACGTCCAAGACTCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCTGCGGACACGGCCATTTATTACTGTGTGCGAGATCGAGTGACTGGTGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCGAGC

[0641] >SEQ ID 246 Anti-EGFR panitumumab VH aa

[0642] QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS

[0643] >SEQ ID 247 Anti-EGFR panitumumab VL nt

[0644] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATCAGCAACTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTTCTGTCAACACTTTGATCATCTCCCGCTCGCTTTCGGCGGAGGGACCAAGGTGGAAATTAAA

[0645] >SEQ ID 248 Anti-EGFR panitumumab VL aa

[0646] DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIK

[0647] >SEQ ID 249 Anti-EGFR nectinumumab VH nt

[0648] CAGGTGCAGCTGCAGCAGAGCGGCGCCGAGGTGAAGAAGCCCGGCAGCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCACCAACTACTACATCTACTGGGTGCGGCAGGCCCCCGGCCAGGGCCTGGAGTGGATCGGCGGCATCAACCCCACCAGCGGCGGCAGCAACTTCAACGAGAAGTTCAAGACCCGGGTGACCATCACCGCCGACGAGAGCAGCACCACCGCCTACATGGAGCTGAGCAGCCTGCGGAGCGAGGACACCGCCTTCTACTTCTGCACCCGGCAGGGCCTGTGGTTCGACAGCGACGGCCGGGGCTTCGACTTCTGGGGCCAGGGCACCACCGTGACCGTGAGCAGC

[0649] >SEQ ID 250 Anti-EGFR nectinumumab VH aa

[0650] QVQLQQSGAEVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWIGGINPTSGGSNFNEKFKTRVTITADESSTTAYMELSSLRSEDTAFYFCTRQGLWFDSDGRGFDFWGQGTTVTVSS

[0651] >SEQ ID 251 Anti-EGFR nectinumumab VL nt

[0652] GATATTCAAATGACTCAATCTCCTTCTTCTCTTTCTGCTTCTGTTGGTGATCGTGTTACTATTACTTGTCGTTCTTCTCAAAATATTGTTCATTCTAATGGTAATACTTATCTTGATTGGTATCAACAAACTCCTGGTAAAGCTCCTAAACTTCTTATTTATAAAGTTTCTAATCGTTTTTCTGGTGTTCCTTCTCGTTTTTCTGGTTCTGGTTCTGGTACTGATTTTACTTTTACTATTTCTTCTCTTCAACCTGAAGATATTGCTACTTATTATTGTTTTCAATATTCTCATGTTCCTTGGACTTTTGGTCAAGGTACTAAACTTCAAATTACT

[0653] >SEQ ID 252 Anti-EGFR Nectinumab VL aa

[0654] DIQMTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQYSHVPWTFGQGTKLQIT

[0655] >SEQ ID 253 Anti-CD22 Ontuxizumab VH nt

[0656] GAGGTGCAATTGGTCCAGTCAGGAGCAGAGGTTAAGAAGCCTGGTGCTTCCGTCAAAGTTTCGTGTAAGGCCAGCGGCTACAGGTTCACAAATTATTGGATTCATTGGGTCAGGCAGGCTCCGGGACAAGGCCTGGAATGGATCGGTGGCATTAATCCCGGGAATAACTACGCTACATATAGGAGAAAATTCCAGGGCAGAGTTACGATGACCGCGGACACCTCCACAAGCACTGTCTACATGGAGCTGTCATCTCTGAGATCCGAGGACACCGCAGTGTACTATTGTACTAGAGAAGGCTACGGTAATTACGGAGCCTGGTTCGCCTACTGGGGCCAGGGTACCCTAGTCACAGTCTCCTCA

[0657] >SEQ ID 254 Anti-CD22 Inotuzumab ozogamicin VH aa

[0658] EVQLVQSGAEVKKPGASVKVSCKASGYRFTNYWIHWVRQAPGQGLEWIGGINPGNNYATYRRKFQGRVTMTADTSTSTVYMELSSLRSEDTAVYYCTREGYGNYGAWFAYWGQGTLVTVSS

[0659] >SEQ ID 255 Anti-CD22 Inotuzumab ozogamicin VL nt

[0660] GACGTTCAAGTGACCCAGAGCCCATCCAGCCTGAGCGCATCTGTAGGAGACCGGGTCACCATCACTTGTAGATCCAGTCAGAGTCTTGCAAACAGTTATGGGAACACCTTTTTGTCTTGGTATCTGCACAAACCAGGTAAAGCCCCACAATTGCTCATCTACGGAATCTCTAACAGATTTAGTGGTGTACCAGACAGGTTCAGCGGTTCCGGAAGTGGTACTGATTTCACCCTCACGATCTCGTCTCTCCAGCCAGAAGATTTCGCCACTTATTACTGTTTACAAGGTACACATCAGCCGTACACATTCGGTCAGGGTACTAAAGTAGAAATCAAA

[0661] >SEQ ID 256 Anti-CD22 Inotuzumab ozogamicin VL aa

[0662] DVQVTQSPSSLSASVGDRVTITCRSSQSLANSYGNTFLSWYLHKPGKAPQLLIYGISNRFSGVPDRFSGSGSGTDFTLTISSLQPEDFATYYCLQGTHQPYTFGQGTKVEIK

[0663] >SEQ ID 257 Anti-CD30 Brentuximab vedotin VH nt

[0664] CAGATCCAGCTGCAGCAGTCTGGACCTGAGGTGGTGAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGGCTTCTGGCTACACCTTCACTGACTACTATATAACCTGGGTGAAGCAGAAGCCTGGACAGGGACTTGAGTGGATTGGATGGATTTATCCTGGAAGCGGTAATACTAAGTACAATGAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACACATCCTCCAGCACAGCCTTCATGCAGCTCAGCAGCCTGACATCTGAGGACACTGCTGTCTATTTCTGTGCGAACTATGGTAACTACTGGTTTGCTTACTGGGGCCAAGGGACTCAGGTCACTGTCTCTGCA

[0665] >SEQ ID 258 Anti-CD30 Brentuximab VH aa

[0666] QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSA

[0667] >SEQ ID 259 Anti-CD30 Brentuximab VL nt

[0668] GACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCACCATCTCCTGCAAGGCCAGCCAAAGTGTTGATTTTGATGGTGATAGTTATATGAACTGGTACCAACAGAAACCAGGACAGCCACCCAAAGTCCTCATCTATGCTGCATCCAATCTAGAATCTGGGATCCCAGCCAGGTTTAGTGGCAGTGGGTCTGGGACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATTACTGTCAGCAAAGTAATGAGGATCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA

[0669] >SEQ ID 260 Anti-CD30 Brentuximab VL aa

[0670] DIVLTQSPASLAVSLGQRATISCKASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIK

[0671] >SEQ ID 261 Anti-HER3 MM-111 VH nt

[0672] CAGGTGCAATTGCAGGAGTCGGGGGGAGGCCTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAGTTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAACCGCGATGGAAGTGCGAGTTACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACGACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGTGGGGTGGGCTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACCGTCTCGAGC

[0673] >SEQ ID 262 Anti-HER3 MM-111 VH aa

[0674] QVQLQESGGGLVKPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCARDRGVGYFDLWGRGTLVTVSS

[0675] >SEQ ID 263 Anti-HER3 MM-111 VL nt

[0676] CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTTTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCATGATCTATGATGTCAGTGATCGGCCCTCAGGGGTGTCTGATCGCTTCTCCGGCTCCAAGTCTGGCAACACGGCCTCCCTGATCATCTCTGGCCTCCAGGCTGACGACGAGGCTGATTATTACTGCAGCTCATATGGGAGCAGCAGCACTCATGTGATTTTCGGCGGAGGGACCAAGGTGACCGTCCTA

[0677] >SEQ ID 264 Anti-HER3 MM-111 VL aa

[0678] QSALTQPASVSGSPGQSITISCTGTSSDVGGYNFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLIISGLQADDEADYYCSSYGSSSTHVIFGGGTKVTVL

[0679] >SEQ ID 265 Anti-EGFRvIII ABT-806 VH nt

[0680] GATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA

[0681] >SEQ ID 266 Anti-EGFRvIII ABT-806 VH aa

[0682] DVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSA

[0683] >SEQ ID 267 Anti-EGFRvIII ABT-806 VL nt

[0684] GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA

[0685] >SEQ ID 268 Anti-EGFRvIII ABT-806 VL aa

[0686] DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIK

[0687] >SEQ ID 269 Anti-CD19 21D4 VH nt

[0688] GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA

[0689] >SEQ ID 270 Anti-CD19 21D4 VH aa

[0690] EVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSS

[0691] >SEQ ID 271 Anti-CD19 21D4 VL nt

[0692] GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA

[0693] >SEQ ID 272 Anti-CD19 21D4 VL aa

[0694] AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK

[0695] >SEQ ID 273 Anti-CD33 Gemtuzumab VH nt

[0696] GAGGTCCAATTGGTACAATCCGGCGCTGAGGTTAAGAAACCGGGTTCCTCAGTCAAAGTTAGTTGTAAGGCATCAGGTTACACGATCACTGATAGTAACATACATTGGGTGAGACAGGCTCCTGGGCAGTCCCTTGAGTGGATTGGATACATTTATCCATATAATGGCGGCACGGATTACAACCAGAAATTTAAGAATAGAGCGACACTGACCGTTGACAACCCCACCAATACCGCGTATATGGAATTGTCAAGCCTGAGGTCTGAGGACACGGCCTTCTACTATTGCGTAAACGGTAACCCGTGGCTGGCCTACTGGGGGCAGGGGACACTCGTAACCGTCTCTTCT

[0697] >SEQ ID 274 Anti-CD33 Gemtuzumab VH aa

[0698] EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGGTDYNQKFKNRATLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQGTLVTVSS

[0699] >SEQ ID 275 Anti-CD33 Gemtuzumab VL nt

[0700] GATATACAACTTACGCAGTCTCCCTCCACTCTGTCAGCGTCCGTAGGGGACAGAGTAACGATAACATGCAGGGCCTCAGAAAGTCTTGACAACTACGGCATAAGGTTCCTCACATGGTTTCAACAGAAGCCGGGTAAAGCACCAAAACTCCTGATGTATGCTGCGTCTAACCAGGGGTCCGGTGTTCCTAGTCGGTTTTCAGGCAGCGGTAGCGGTACCGAGTTCACTCTCACAATTTCCAGTCTTCAGCCTGACGATTTCGCAACGTATTATTGCCAACAAACTAAGGAAGTGCCTTGGAGCTTTGGGCAAGGCACCAAGGTCGAGGTGAAG

[0701] >SEQ ID 276 Anti-CD33 Gemtuzumab VL aa

[0702] DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAASNQGSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVK

[0703] >SEQ ID 277 Anti-CD3 284A10 VH nt

[0704] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACA

[0705] >SEQ ID 278 Anti-CD3 284A10 VH aa

[0706] EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVST

[0707] >SEQ ID 279 Anti-CD3 284A10 VL nt

[0708] GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA

[0709] >SEQ ID 280 Anti-CD3 284A10 VL aa

[0710] DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK

[0711] >SEQ ID 281 Anti-PD-L1 PL221G5 VH nt

[0712] GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC

[0713] >SEQ ID 282 Anti-PD-L1 PL221G5 VH aa

[0714] EVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSS

[0715] >SEQ ID 283 Anti-PD-L1 PL221G5 VL nt

[0716] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA

[0717] >SEQ ID 284 Anti-PD-L1 PL221G5 VL aa

[0718] DIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK

[0719] >SEQ ID 285 Anti-4-1BB 466F6 VH nt

[0720] CGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA

[0721] >SEQ ID 286 Anti-4-1BB 466F6 VH aa

[0722] RSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSS

[0723] >SEQ ID 287 Anti-4-1BB 466F6 VL nt

[0724] GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA

[0725] >SEQ ID 288 Anti-4-1BB 466F6 VL aa

[0726] DVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK

[0727] >SEQ ID 289 Anti-CD19 SI-BU12 VH nt

[0728] CAGGTCACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGCCTCACCTGTGCCTTCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAAAGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAAAGTCGGCTGACCATTAGTAAGGATACCTCAAAAAATCAAGTGTACTTGCAAATGAATAGCCTTGACGCCGAGGATACGGCTGTATATTATTGCGCTCGGATGGAACTCTGGTCTTACTACTTTGATTATTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGT

[0729] >SEQ ID 290 Anti-CD 19 SI-BU12 VH aa

[0730] QVTLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSS

[0731] >SEQ ID 291 Anti-CD 19 SI-BU12 VL nt

[0732] GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCACTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCCCAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCCGGCTCAGGCAACGATCACACCCTTACGATTTCCAGTATGGAACCCGAAGATTTTGCAACTTATTATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACCGTCCTA

[0733] >SEQ ID 292 Anti-CD 19 SI-BU12 VL aa

[0734] ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWIYDTSKLASGVPSRFSGSGSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVL

[0735] >SEQ ID 293 NKG2D nt

[0736] TTTCTTAATTCCCTTTTCAACCAAGAGGTTCAGATCCCCTTGACTGAAAGCTATTGCGGCCCTTGTCCGAAAAACTGGATATGTTACAAGAATAATTGTTACCAATTCTTCGACGAAAGCAAGAACTGGTATGAGAGTCAGGCGTCTTGTATGAGTCAGAATGCCAGCCTGCTTAAGGTTTATTCAAAAGAAGACCAGGATCTGCTTAAGTTGGTAAAGAGCTACCACTGGATGGGGCTGGTACATATCCCAACGAATGGGTCATGGCAGTGGGAGGACGGTTCTATTCTGAGTCCAAATCTCCTGACGATCATCGAAATGCAGAAAGGGGACTGTGCCCTGTATGCATCATCCTTCAAGGGGTACATCGAGAACTGCAGTACCCCAAATACCTACATTTGTATGCAAAGAACGGTT

[0737] >SEQ ID 294 NKG2D aa

[0738] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0739] >SEQ ID 295 4-1BB ligand nt

[0740]

[0741] >SEQ ID 296 4-1BB ligand aa

[0742] REGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGSTGSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGL

[0743] >SEQ ID 301 SI-55P9 chain A nt

[0744]

[0745] >SEQ ID 302 SI-55P9 chain A aa

[0746]

[0747] >SEQ ID 303 SI-55P9 chain B nt

[0748]

[0749] >SEQ ID 304 SI-55P9 chain B aa

[0750] ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWIYDTSKLASGVPSRFSGSGSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQVTLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0751] >SEQ ID 305 SI-55P10 chain A nt

[0752]

[0753] >SEQ ID 306 SI-55P10 chain A aa

[0754]

[0755] >SEQ ID 307 SI-55P10 chain B nt

[0756]

[0757] >SEQ ID 308 SI-55P10 chain B aa

[0758] ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWIYDTSKLASGVPSRFSGSGSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQVTLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0759] >SEQ ID 309 NKG2D dimer nt

[0760] TTTCTTAATTCCCTTTTCAACCAAGAGGTTCAGATCCCCTTGACTGAAAGCTATTGCGGCCCTTGTCCGAAAAACTGGATATGTTACAAGAATAATTGTTACCAATTCTTCGACGAAAGCAAGAACTGGTATGAGAGTCAGGCGTCTTGTATGAGTCAGAATGCCAGCCTGCTTAAGGTTTATTCAAAAGAAGACCAGGATCTGCTTAAGTTGGTAAAGAGCTACCACTGGATGGGGCTGGTACATATCCCAACGAATGGGTCATGGCAGTGGGAGGACGGTTCTATTCTGAGTCCAAATCTCCTGACGATCATCGAAATGCAGAAAGGGGACTGTGCCCTGTATGCATCATCCTTCAAGGGGTACATCGAGAACTGCAGTACCCCAAATACCTACATTTGTATGCAAAGAACGGTTGGAGGCGGTGGCTCAGGCGGAGGCGGCTCAGGAGGTGGCGGTTCAGGAGGCGGCGGATCTTTCCTAAACTCATTATTCAACCAAGAAGTTCAAATTCCCTTGACCGAAAGTTACTGTGGCCCATGTCCTAAAAACTGGATATGTTACAAAAATAACTGCTACCAATTTTTTGATGAGAGTAAAAACTGGTATGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATACAGCAAAGAGGACCAGGATTTACTTAAACTGGTGAAGTCATATCATTGGATGGGACTAGTACACATTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAATAATTGAAATGCAGAAGGGAGACTGTGCACTCTATGCCTCGAGCTTTAAAGGCTATATAGAAAACTGTTCAACTCCAAATACGTACATCTGCATGCAAAGGACTGTG

[0761] >SEQ ID 310 NKG2D dimer aa

[0762] FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV

[0763] >SEQ ID 311 Anti-FITC 4-4-20 VH nt

[0764] GAGGTGAAGCTGGATGAGACTGGAGGAGGCTTGGTGCAACCTGGGAGGCCCATGAAACTCTCCTGTGTTGCCTCTGGATTCACTTTTAGTGACTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAAGGACTGGAGTGGGTAGCACAAATTAGAAACAAACCTTATAATTATGAAACATATTATTCAGATTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGTAGTGTCTACCTGCAAATGAACAACTTAAGAGTTGAAGACATGGGTATCTATTACTGTACGGGTTCTTACTATGGTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA

[0765] >SEQ ID 312 Anti-FITC 4-4-20 VH aa

[0766] EVKLDETGGGLVQPGRPMKLSCVASGFTFSDYWMNWVRQSPEKGLEWVAQIRNKPYNYETYYSDSVKGRFTISRDDSKSSVYLQMNNLRVEDMGIYYCTGSYYGMDYWGQGTSVTVSS

[0767] >SEQ ID 313 Anti-FITC 4-4-20 VL nt

[0768] GATGTCGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACGTTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGGTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA

[0769] >SEQ ID 314 Anti-FITC 4-4-20 VL aa

[0770] DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLRWYLQKPGQSPKVLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK

[0771] >SEQ ID 315 Anti-CD3 284A10 FR 1 VH nt

[0772] GAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCAGCCTGAGGCTGAGCTGCACCGCCAGCGGCTTCACCATCAGCACCAACGCCATGAGCTGGGTGAGGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTGGGCGTGATCACCGGCAGGGACATCACCTACTACGCCAGCTGGGCCAAGGGCAGGTTCACCATCAGCAGGGACACCAGCAAGAACACCGTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGGGACGGCGGCAGCAGCGCCATCACCAGCAACAACATCTGGGGCCAGGGCACCCTGGTGACCGTGAGCAGC

[0773] >SEQ ID 316 Anti-CD3 284A10 FR 1 VH aa

[0774] EVQLVESGGGLVQPGGSLRLSCTASGFTISTNAMSWVRQAPGKGLEWVGVITGRDITYYASWAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSS

[0775] >SEQ ID 317 Anti-CD3 284A10 FR 1 VL nt

[0776] GAGATCGTGATGACCCAGAGCCCCAGCACCCTGAGCGCCAGCGTGGGCGACAGGGTGATCATCACCTGCCAGGCCAGCGAGAGCATCAGCAGCTGGCTGGCCTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACGAGGCCAGCAAGCTGGCCAGCGGCGTGCCCAGCAGGTTCAGCGGCAGCGGCAGCGGCGCCGAGTTCACCCTGACCATCAGCAGCCTGCAGCCCGACGACTTCGCCACCTACTACTGCCAGGGCTACTTCTACTTCATCAGCAGGACCTACGTGAACAGCTTCGGCCAGGGCACCAAGCTGACCGTGCTG

[0777] >SEQ ID 318 Anti-CD3 284A10 FR 1 VL aa

[0778] EIVMTQSPSTLSASVGDRVIITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGQGTKLTVL

[0779] >SEQ ID 319 Anti-EGFR H7 VH nt

[0780] CAAGTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTGAGACGCTTAGTATAACGTGTACTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGATTCGGCAGGCACCCGGCAAAGGTTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGACTATAACACCCCCTTTACAAGTCGGTTCACAATTACGAAAGATAATTCCAAAAATCAAGTTTATTTCAAGTTGAGATCCGTCCGCGCGGACGACACTGCGATCTACTATTGTGCGAGGGCACTGACCTACTACGATTACGAATTTGCGTATTGGGGGCAAGGGACTCTTGTAACAGTCTCGAGC

[0781] >SEQ ID 320 Anti-EGFR H7 VH aa

[0782] QVQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFTSRFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSS

[0783] >SEQ ID 321 Anti-EGFR H7 VL nt

[0784] GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCTCTTGCAGGGCAAGTCAATCCATAGGGACTAATATACATTGGTATCAACAAAAGCCAGGTAAACCACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGATCAGGCAGTGGCACAGAGTTCACACTCACCATATCTAGTGTGCAATCAGAGGACTTCGCCGTGTATTACTGCCAACAGAATAATAACTGGCCGACTACCTTCGGACCCGGTACAAAGCTGACCGTTTTA

[0785] >SEQ ID 322 Anti-EGFR H7 VL aa

[0786] EIVLTQSPSTLSVSPGERATFSCRASQSIGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSGSGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLTVL

[0787] >SEQ ID 323 SI-77H4 Chain A nt

[0788]

[0789] >SEQ ID 324 SI-77H4 chain A aa

[0790]

[0791] >SEQ ID 325 SI-77H4 chain B nt

[0792]

[0793] >SEQ ID 326 SI-77H4 chain B aa

[0794] ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWIYDTSKLASGVPSRFSGSGSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQVTLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSEIVLTQSPSTLSVSPGERATFSCRASQSIGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSGSGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGCGTKLTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLIISGLQADDEADYYCSSYGSSSTHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLSLSCAASGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCARDRGVGYFDLWGRGTLVTVSS

[0795] >SEQ ID 327 SI-77H5 chain A nt

[0796]

[0797] >SEQ ID 328 SI-77H5 chain A aa

[0798]

[0799] >SEQ ID 329 SI-77H5 chain B nt

[0800]

[0801] >SEQ ID 330 SI-77H5 chain B aa

[0802] ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWIYDTSKLASGVPSRFSGSGSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQVTLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGCGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLIISGLQADDEADYYCSSYGSSSTHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLSLSCAASGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCARDRGVGYFDLWGRGTLVTVSS

[0803] >SEQ ID 331 SI-55H12 chain A nt

[0804]

[0805] >SEQ ID 332 SI-55H12 chain A aa

[0806]

[0807] >SEQ ID 333 SI-55H12 chain B nt

[0808]

[0809] >SEQ ID 334 SI-55H12 chain B aa

[0810] ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWIYDTSKLASGVPSRFSGSGSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQVTLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLIISGLQADDEADYYCSSYGSSSTHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLSLSCAASGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCARDRGVGYFDLWGRGTLVTVS

Claims

1. A hexa-specific antibody protein having an N-terminus and a C-terminus, comprising in this order from the N-terminus to the C-terminus: a first binding domain (D1) at the N-terminus, a Fab region comprising a light chain and a heavy chain as a second binding domain (D2), a Fc region, a third binding domain (D3) having binding affinity to PD-L1, and a fourth binding domain (D4) at the C-terminus having binding affinity to 4-1BB, wherein in D2, the light chain comprises a fifth binding domain (D5) covalently linked to the C-terminus, a sixth binding domain (D6) covalently linked to the N-terminus, and D1 is connected to the N-terminus of the heavy chain, and the Fc region is connected to the C-terminus of the heavy chain, the D1, D3, D4, D5, and D6 are independently scFv domains, and the hexa-specific antibody protein comprises: D1 having binding affinity to EGFR, D2 having binding affinity to CD3, D3 having binding affinity to PD-L1, D4 having binding affinity to 4-1BB, D5 having binding affinity to CD19, and D6 having binding affinity to HER3, wherein: D1 is a scFv domain having binding affinity to EGFR, D2 is a scFv domain having binding affinity to CD3, D3 is a scFv domain having binding affinity to PD-L1, D4 is a scFv domain having binding affinity to 4-1BB, D5 is a scFv domain having binding affinity to CD19, and D6 is a scFv domain having binding affinity to HER3, wherein: D1 is a scFv domain having binding affinity to EGFR, D2 is a scFv domain having binding affinity to CD3, D3 is a scFv domain having binding affinity to PD-L1, D4 is a scFv domain having binding affinity to 4-1BB, D5 is a scFv domain having binding affinity to CD19, and D6 is a scFv domain having binding affinity to HER3, wherein: D1 is a scFv domain having binding affinity to EGFR, D2 is a scFv domain having binding affinity to CD3, D3 is a scFv domain having binding affinity to PD-L1, D4 is a scFv domain having binding affinity to 4-1BB, D5 is a scFv domain having binding affinity to CD19, and D6 is a scFv domain having binding affinity to HER3, wherein: D1 is a scFv domain having binding affinity to EG D1 comprises a HCDR1 as set forth in the amino acid sequence QASQDISNYLN, a HCDR2 as set forth in the amino acid sequence DASNLET, a HCDR3 as set forth in the amino acid sequence QHFDHLPLA, a LCDR1 as set forth in the amino acid sequence SGDYYWT, a LCDR2 as set forth in the amino acid sequence HIYYSGNTNYNPSLKS, and a LCDR3 as set forth in the amino acid sequence DRVTGAFDI; D2 comprises a HCDR1 as set forth in the amino acid sequence TNAMS, a HCDR2 as set forth in the amino acid sequence VITGRDITYYASWAKG, a HCDR3 as set forth in the amino acid sequence DGGSSAITSNNI, a LCDR1 as set forth in the amino acid sequence QASESISSWLA, a LCDR2 as set forth in the amino acid sequence EASKLAS, and a LCDR3 as set forth in the amino acid sequence QGYFYFISRTYVNS; D3 comprises a HCDR1 as set forth in the amino acid sequence SGYDMC, a HCDR2 as set forth in the amino acid sequence CIAAGSAGITYDANWAKG, a HCDR3 as set forth in the amino acid sequence SAFSFDYAMDL, a LCDR1 as set forth in the amino acid sequence QASQSISSHLN, a LCDR2 as set forth in the amino acid sequence KASTLAS, and a LCDR3 as set forth in the amino acid sequence QQGYSWGNVDNV; D4 comprises a HCDR1 as set forth in the amino acid sequence SYHMQ, a HCDR2 as set forth in the amino acid sequence TISSGGNVYYASSARG, a HCDR3 as set forth in the amino acid sequence DSGYSDPM, a LCDR1 as set forth in the amino acid sequence QASQNIRTYLS, a LCDR2 as set forth in the amino acid sequence AAANLA, and a LCDR3 as set forth in the amino acid sequence QSTYLGTDYVGGA; D5 comprises a HCDR1 as set forth in the amino acid sequence TSGMGVG, a HCDR2 as set forth in the amino acid sequence HIWWDDDKRYNPALKS, a HCDR3 as set forth in the amino acid sequence MELWSYYFDY, a LCDR1 as set forth in the amino acid sequence SASSSVSYMH, a LCDR2 as set forth in the amino acid sequence DTSKLAS, and a LCDR3 as set forth in the amino acid sequence FQGSVYPFT; and D6 comprises a HCDR1 as set forth in the amino acid sequence TGTSSDVGGYNFVS, a HCDR2 as set forth in the amino acid sequence DVSDRPS, a HCDR3 as set forth in the amino acid sequence SSTHVI, a LCDR1 as set forth in the amino acid sequence SYWMS, a LCDR2 as set forth in the amino acid sequence NINRDGSASYYVDSVKG, and a LCDR3 as set forth in the amino acid sequence DRGVGYFDL.

2. The hexa-specific antibody protein according to claim 1, comprising the amino acid sequences set forth in SEQ ID NOs: 176 and 178.

3. A hexa-specific antibody protein, whose amino acid sequences of chain A and chain B are respectively: the amino acid sequences set forth in SEQ ID NOs: 106 and 108; or, the amino acid sequences set forth in SEQ ID NOs: 324 and 326; or, the amino acid sequences set forth in SEQ ID NOs: 328 and 330; or, the amino acid sequences set forth in SEQ ID NOs: 332 and 334.

4. An isolated nucleic acid sequence encoding the amino acid sequence of the hexa-specific antibody protein of any one of claims 1-3.

5. An expression vector comprising the isolated nucleic acid sequence of claim 4.

6. A host cell comprising the isolated nucleic acid sequence of claim 4, wherein the host cell is a prokaryotic cell or a eukaryotic cell.

7. An immunoconjugate comprising a cytotoxic agent or an imaging agent linked to the hexa-specific antibody protein of any one of claims 1-3 via a linker, wherein the linker comprises a covalent bond.

8. The immunoconjugate of claim 7, wherein the covalent bond comprises an ester bond, an ether bond, an amide bond, a disulfide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphoester bond, a peptide bond, a hydrophobic poly(ethylene glycol) linker, or a combination thereof.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the hexa-specific antibody protein of any one of claims 1-3, the immunoconjugate of claim 7 or 8, or both.

10. A solution comprising an effective concentration of the hexa-specific antibody protein of any one of claims 1-3, wherein the solution is the plasma of a human subject.

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