Monoclonal antibodies targeting HSP70 and their therapeutic use

Abstract

This invention provides an active agent that targets HSP70. [Solution] Active agents targeting HSP70, such as antibodies and chimeric antigen receptors, are provided herein. A method for treating cancer is provided, comprising the step of administering an effective amount of an HSP70-targeting active agent to a patient in need. HSP70-specific antibodies can enhance the uptake of HSP70 by antigen-presenting cells.

Description

[Technical Field]

[0001] Reference to related applications This application claims priority under U.S. Provisional Application No. 63 / 001,011, filed on 27 March 2020, the entire contents of which are incorporated herein by reference.

[0002] Sequence listing reference This application includes a sequence listing submitted in ASCII format via EFS-Web, the entire listing of which is incorporated herein by reference. The ASCII copy, created on March 25, 2021, is named UTFCP1469WO_ST25.txt and has a size of 220 kilobytes.

[0003] 1. Field This invention generally relates to the fields of medicine, immunology, and cancer biology. More specifically, it relates to an antibody targeting HSP70 and a method of using the same. [Background technology]

[0004] 2. Description of related technology fields The development of an immune response against cancer cells is thought to depend on a series of strengthening events called the cancer immune cycle (Chen & Mellman, 2013), which begins with the release of cancer cell antigens during cancer cell death. Due to their ability to capture, process, and then present these tumor antigens to T cells via presentation through histocompatibility complex (MHC) class I and II molecules, dendritic cells (DCs) are considered key initial components of this response, which then lead to the priming and activation of effector CD4+ and CD8+ T cell responses. The crucial role of DCs is demonstrated, for one thing, by the many mechanisms utilized by tumors to suppress DC activity, including, among others, hypoxia, adenosine, lactate, low pH, and the expression of interleukin (IL)-10 and PD-L1 (Veglia & Gabrilovich, 2017).

[0005] Heat shock proteins (HSPs) in general, and HSP70 in particular, are thought to play a crucial role in this process due to their ability to link innate and adaptive immune responses (Shevtsov & Multhoff, 2016). For example, extracellular HSP70 binds to tumor antigens and acts as a chaperone, then targets antigen-presenting cells, including dendritic cells (DCs), through binding to various cell surface receptors, particularly CD91, oxidized low-density lipoprotein receptor 1 (OLR1), and scavenger receptor (SREC)-1 expressed by endothelial cells (McNulty et al., 2013), thereby delivering the bound antigen to the DCs for processing. Furthermore, extracellular HSP70 secreted from tumor cells induces inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α from macrophages (Vega et al., 2008), thereby enabling cross-presentation and T cell activation, respectively. Therefore, due to its crucial intracellular role as a cytoprotective anti-apoptotic factor that promotes the survival of cancer cells when faced with various stressors, including both radiation and various chemotherapy agents (Boudesco et al., 2018), HSP70 is considered an attractive target for cancer therapy. Furthermore, HSP70 is also considered an attractive target for cancer therapy due to its ability to stimulate immune responses not only through DCs but also possibly through macrophages, NK cells, and T cells (Shvetsov & Multhoff, 2016; Zininga et al., 2018).

[0006] Approaches that enhance the uptake of HSP70-tumor antigen complexes by dendritic cells (DCs) are expected to enhance antitumor immunity and disrupt resistance. Several pharmacological inhibitors have been developed that directly target intracellular HSP70 or, in some cases, target cochaperones of intracellular HSP70, which may act as sensitizers to radiotherapy or chemotherapy (Boudesco et al., 2018). Furthermore, membrane-bound HSP70, which is usually absent or found only at low levels in normal cells, often shows enhanced expression on the surface of tumor cells and is associated with a more invasive phenotype and poor prognosis in some malignancies (Boudesco et al., 2018; Chatterjee & Burns, 2017). - / - Tumors have been shown to be less immunogenic and more invasive (Dodd et al., 2015). This has led to the development and testing of various approaches whose activity depends on the cell surface expression of HSP70, including ferromagnetic and gold nanoparticle-based therapies, vaccine strategies (Shvetsov & Multhoff, 2016), and monoclonal antibodies such as cmHSP70.1 (Stangl et al., 2011).

[0007] In recent years, immune checkpoint inhibitors (ICIs), including monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) and its ligand PD-L1, have revolutionized immunotherapy through their ability to induce sustained remission even in advanced malignancies. Generally, tumors that respond to ICIs are thought to tend to have higher immune cell infiltration and / or interferon gene signatures, or higher mutational burden (TMB), and are sometimes referred to as "hot" tumors (Maleki Vareki, 2018). In contrast, so-called "cold" tumors with low immune cell infiltration or low TMB tend not to respond to ICIs and include pancreatic and prostate cancers (Maleki Vareki, 2018). Despite advances in treating a variety of malignancies, there is still a need for new approaches that can transform cold tumors into more immunogenic tumors and provide alternative approaches for treating these tumors. [Overview of the Initiative]

[0008] overview This invention is in part based on the discovery of anti-HSP70 monoclonal antibodies or antibody fragments. In certain circumstances, anti-HSP70 monoclonal antibodies or antibody fragments may, for example, target extracellular or soluble HSP70 associated with tumor-derived antigens using immune cells (e.g., dendritic cells), thereby treating cancer and / or enhancing the effectiveness of cancer therapies (e.g., cancer immunotherapy).

[0009] In one embodiment, the monoclonal antibody or antibody fragment is the 77A antibody described herein. For example, in several aspects, the antibody or antibody fragment includes a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6.

[0010] In some aspects, the antibody or antibody fragment includes a heavy chain variable sequence having at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% identity with SEQ ID NO:7 and a light chain variable sequence having at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% identity with SEQ ID NO:8. In some aspects, the antibody or antibody fragment includes a heavy chain variable sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:7 and a light chain variable sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:8. In some aspects, the antibody or antibody fragment includes a heavy chain variable sequence having the sequence described in SEQ ID NO:7 and a light chain variable sequence having the sequence described in SEQ ID NO:8.

[0011] In some aspects, the antibody or antibody fragment is encoded by a heavy chain variable sequence having at least 70%, at least 75%, at least 80%, at least 85% or at least 90% identity to SEQ ID NO:9 and a light chain variable sequence having at least 70%, at least 75%, at least 80%, at least 85% or at least 90% identity to SEQ ID NO:10. In some aspects, the antibody or antibody fragment is encoded by a heavy chain variable sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO:9 and a light chain variable sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO:10. In some aspects, the antibody or antibody fragment is encoded by the heavy chain variable sequence set forth in SEQ ID NO:9 and the light chain variable sequence set forth in SEQ ID NO:10.

[0012] In another aspect, a humanized variant of the 77A antibody is provided. For example, in some aspects, the monoclonal antibody or antibody fragment is a heavy chain variable sequence having the sequence of TIFF2026086489000002.tif19159, wherein X1 is Q or E, X2 is I or V, X3 is V or Q, X4 is Q or E, X5 is A, P or G, X6 is E or G, X7 is V or L, X8 is V or K, X9 is A, E, G or S, X 10 is V or L, X 11 is K or R, X 12 is V, L or I, X 13 is A or T, X 14 is K or Q, X 15 is E or K, X 16 is M or V, X 17is F or V, X 18 is F, M, or I, X 19 is T or S, X 20 is T, R, or A, X 21 is T, D, or E, X 22 is T, A, or K, and X 23 is S or N, X 24 is L or A, X 25 It is M or L, X 26 is E or Q, X 27 It is L or M, X 28 is R, S, T, or N, and X 29 is S or G, X 30 is R, K, or M, X 31 is S or T, X 32 It is either D or E, and X 33 The heavy chain variable sequence is L, S, or T. and / or A light strand variable sequence having the sequence TIFF2026086489000003.tif19159, wherein X1 is E or D, X2 is I or V, X3 is V or Q, X4 is L or M, X5 is D or S, X6 is A or S, X7 is V or A, X8 is L or V, X9 is E or D, X 10 is A or V, X 11 is N or T, X 12 is A or P, X 13 is Q or K, and X 14 is S, V, or P, X 15 is either K or R, and X 16 is D or S, X 17 is S, D, or N, X 18 is S or T, X 19 is A or P, X 20 is V or T, X 21 is Q or G, X 22 The light chain variable arrangement is L or V. Includes.

[0013] In a particular context, the antibody or antibody fragment includes a heavy chain variable sequence having a sequence selected from the group consisting of SEQ ID NO: 12 to 16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with any one of SEQ ID NO: 12 to 19; and / or a light chain variable sequence having a sequence selected from the group consisting of SEQ ID NO: 19 to 23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with any one of SEQ ID NO: 19 to 23.

[0014] Furthermore, optimized humanized variants of the 77A antibody are provided. For example, in some aspects, the monoclonal antibody or antibody fragment includes a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of GYX1FTX2YG (SEQ ID NO:214) where X1 is T, S, or I and X2 is N or K, the VHCDR2 amino acid sequence of INTYTGEX1 (SEQ ID NO:215) where X1 is P, S, T, or A, and the VHCDR3 amino acid sequence of X1RYDHX2MDY (SEQ ID NO:216) where X1 is A, T, V, or G and X2 is A, R, F, T, P, V, S, D, N, H, L, Y, or G; and / or the VLCDR1 amino acid sequence of QSLX1NSGTRKNY (SEQ ID NO:212) where X1 is L, F, or V, and SEQ ID The monoclonal antibody or antibody fragment includes a light chain variable region (VL) comprising the VLCDR2 amino acid sequence of NO:5 and the VLCDR3 amino acid sequence of KQSYX1LYT (SEQ ID NO:213) where X1 is T, N, or S. In some aspects, the monoclonal antibody or antibody fragment includes a light chain variable region (VL) comprising the VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO:1 and 164-166, the VHCDR2 amino acid sequence selected from the group consisting of SEQ ID NO:2 and 167-169, and the VHCDR3 amino acid sequence selected from the group consisting of SEQ ID NO:3 and 170-185; and / or the VLCDR1 amino acid sequence selected from the group consisting of SEQ ID NO:4 and 159-161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence selected from the group consisting of SEQ ID NO:6, 162, and 163.

[0015] In some aspects, the monoclonal antibody or antibody fragment is A heavy-chain variable sequence having the sequence TIFF2026086489000004.tif19159, where X1 is Q or H, X2 is A, D, T, V, S or P, X3 is T, S or I, X4 is N or K, X5 is P, S, T or A, X6 is T, R, K or I, X7 is A, T, V, S or G, X8 is S, R or T, X9 is A, V or G, X 10 is E or D, X 11 is L or V, X 12 is A, T, V or G, and X 13 is A, R, F, T, P, V, S, D, N, H, L, Y or G, and X 14 is T or S, the heavy chain variable arrangement, and / or A light chain variable sequence having the sequence TIFF2026086489000005.tif19159, where X1 is A, T or S, X2 is N or K, X3 is L, F or V, X4 is A, S or T, X5 is Q or K, X6 is A, P or S, X7 is K or N, X8 is L, V or I, X9 is G or A, X 10 is T or S, X 11 is S or R, X 12 is A or T, and X 13 is V, I, or L, and X 14 The variable light chain arrangement is T, N, or S. Includes.

[0016] In some aspects, the antibody or antibody fragment includes a heavy chain variable sequence having a sequence selected from the group consisting of SEQ ID NO: 17 and 26-103, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with any one of SEQ ID NO: 17 and 26-103; and / or a light chain variable sequence having a sequence selected from the group consisting of SEQ ID NO: 24 and 105-157, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with any one of SEQ ID NO: 24 and 105-157.

[0017] In some aspects, the antibody binds to or can bind to HSP70. In some aspects, the antibody, as determined by Octet Biolayer Interferometry (BLI) analysis, has a K content of less than approximately 10 nM, less than approximately 9 nM, less than approximately 8 nM, less than approximately 7 nM, less than approximately 6 nM, less than approximately 5 nM, less than approximately 4 nM, less than approximately 3 nM, less than approximately 2 nM, less than approximately 1 nM, less than approximately 0.9 nM, less than approximately 0.85 nM, less than approximately 0.8 nM, less than approximately 0.75 nM, less than approximately 0.7 nM, less than approximately 0.6 nM, or less than approximately 0.5 nM. D It then binds to human HSP70.

[0018] Monoclonal antibodies or antibody fragments that compete for binding to the same epitope as any one of the monoclonal antibodies or antibody fragments of this embodiment are also provided herein. For example, the present invention includes an anti-HSP70 antibody that competes for binding to HSP70 with the 77A antibody as defined herein. It is possible to determine whether an antibody binds to the same epitope as the 77A antibody or competes for binding with the 77A antibody by using routine methods known in the art. For example, to determine whether a test antibody binds to the same epitope as the 77A antibody, the 77A antibody is conjugated to the HSP70 protein or peptide under saturated conditions. The ability of the test antibody to bind to the HSP70 protein or peptide is then evaluated. If the test antibody can bind to the HSP70 protein or peptide after saturated binding with the 77A antibody, it can be concluded that the test antibody binds to a different epitope than the 77A antibody. On the other hand, if the test antibody cannot bind to the HSP70 protein or peptide after saturated binding with the 77A antibody, the test antibody may bind to the same epitope as the one conjugated by the 77A antibody.

[0019] In one embodiment, a monoclonal antibody or antibody fragment that binds to or can bind to an epitope on HSP70 recognized by any one antibody or antibody fragment of this embodiment is provided herein.

[0020] In one embodiment, a monoclonal antibody or antibody fragment is provided herein that binds to an epitope of HSP70 defined by a peptide corresponding to K573-Q601 of SEQ ID NO:11. In a particular context, when bound to HSP70, the monoclonal antibody or antibody fragment binds to one or two of the following residues: H594, K595, and Q601 of SEQ ID NO:11. In some contexts, when bound to HSP70, the monoclonal antibody or antibody fragment binds to all of the following residues: H594, K595, and Q601 of SEQ ID NO:11. In some contexts, when bound to HSP70, the monoclonal antibody or antibody fragment further binds to at least one of the following residues: K573, E576, W580, R596, and E598 of SEQ ID NO:11. In some cases, when bound to HSP70, the monoclonal antibody or antibody fragment further binds to at least two, three, four, or five of the following residues: K573, E576, W580, R596, and E598 of SEQ ID NO: 11. In some cases, when bound to HSP70, the monoclonal antibody or antibody fragment binds to all of the following residues: K573, E576, W580, H594, K595, R596, E598, and Q601 of SEQ ID NO: 11.

[0021] Monoclonal antibodies or antibody fragments that, in several aspects, enhance the uptake of tumor-derived ADP-HSP70-peptide antigen complexes by immune effector cells when bound to HSP70 are provided herein.

[0022] In some aspect of any of these embodiments, the antibody binds to or can bind to HSP70. In some aspect of any of these embodiments, the antibody binds to or can bind to HSP70 in an ADP-bound form. In some aspect of any of these embodiments, the antibody binds to or can bind to HSP70 in a peptide-bound form. In some aspect of any of these embodiments, the antibody binds to or can bind to HSP70 in both ADP-bound and peptide-bound forms. In some aspect of this embodiment, the antibody is determined by Octet Biolayer Interferometry (BLI) analysis to have a K content of less than approximately 10 nM, less than approximately 9 nM, less than approximately 8 nM, less than approximately 7 nM, less than approximately 6 nM, less than approximately 5 nM, less than approximately 4 nM, less than approximately 3 nM, less than approximately 2 nM, less than approximately 1 nM, less than approximately 0.9 nM, less than approximately 0.85 nM, less than approximately 0.8 nM, less than approximately 0.75 nM, less than approximately 0.7 nM, less than approximately 0.6 nM, or less than approximately 0.5 nM. D The antibody binds to or can bind to human HSP70. In some aspects of this embodiment, the antibody does not induce antibody-dependent cytotoxicity. In some aspects of this embodiment, the antibody does not induce complement-dependent cytotoxicity. In some aspects of this embodiment, the antibody enhances HSP70 uptake by immune effector cells, such as monocytes / macrophages and dendritic cells. In some aspects, uptake is mediated by human FcγR2A and / or human FcγR2B.

[0023] In some aspects of this embodiment, the antibody fragment is a monovalent scFv (single-chain fragment variable) antibody, a bivalent scFv, a Fab fragment, an F(ab')2 fragment, an F(ab')3 fragment, an Fv fragment, or a single-chain antibody. In some aspects of this embodiment, the antibody is a chimeric antibody, a bispecific antibody, or a BiTE. In some aspects of this embodiment, the antibody is an IgG antibody, a recombinant IgG antibody, or an antibody fragment.

[0024] In some aspects of this embodiment, the antibody is conjugated or fused with an imaging agent or a cytotoxic agent. In some aspects of this embodiment, the antibody is labeled. In some aspects, the labeling is fluorescent, enzymatic, or radioactive.

[0025] In some cases, the antibody or antibody fragment is an IgG antibody or antibody fragment. In some cases, the antibody or antibody fragment is an IgG1, IgG2, IgG3, or IgG4 antibody or antibody fragment, for example, the antibody or antibody fragment contains any one of SEQ ID NO: 217-221.

[0026] In one embodiment, isolated nucleic acids encoding the antibody heavy chain variable region and / or antibody light chain variable region of any antibody according to the present embodiment are provided herein. In some aspects, the isolated nucleic acids include nucleotide sequences that are at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% identical to SEQ ID NO: 9 and / or 10.

[0027] In one embodiment, an expression vector comprising any one nucleic acid of this embodiment is provided herein.

[0028] In one embodiment, a hybridoma or engineered cell comprising a nucleic acid encoding any one of the antibodies or antibody fragments of this embodiment is provided herein.

[0029] In one embodiment, a hybridoma or engineered cell containing any one nucleic acid of this embodiment is provided herein.

[0030] In one embodiment, a method for producing any one monoclonal antibody or antibody fragment of this embodiment is provided herein, comprising the steps of culturing any one hybridoma or engineered cell of this embodiment under conditions that enable antibody expression, and optionally comprising the steps of isolating the antibody from the culture.

[0031] In one embodiment, a pharmaceutical formulation comprising any one or more antibodies or antibody fragments of this embodiment is provided herein.

[0032] In one embodiment, a method for treating a patient having cancer is provided herein, comprising the step of administering to the patient an effective amount of any one antibody or antibody fragment of this embodiment. In some aspects, the method enhances the uptake of HSP70 by antigen-presenting cells. In some aspects, the uptake of HSP70 by antigen-presenting cells is mediated by human FcγR2A and / or human FcγR2B.

[0033] In some aspects, the method is further defined as a method for enhancing cytotoxic T cell-mediated antitumor immunity. In some aspects, the method is further defined as a method for increasing sensitivity to immunotherapy. In some aspects, the method is further defined as a method for enhancing the uptake of tumor-derived ADP-HSP70 peptide antigen complexes by immune effector cells. In some aspects, the method is further defined as a method for enhancing antigen presentation by dendritic cells. In some aspects, the method is further defined as a method for enhancing CD4+ and CD8+ T cell responses to tumor antigens.

[0034] In some contexts, cancer is an immunologically cold cancer, such as pancreatic cancer or prostate cancer.

[0035] In some aspects, the method further includes administering at least a second anti-cancer therapy, such as chemotherapy, immunotherapy, radiotherapy, gene therapy, surgery, hormone therapy, anti-angiogenic therapy, or cytokine therapy.

[0036] In one embodiment, a chimeric antigen receptor (CAR) protein comprising an antigen-binding domain that binds to human HSP70 is provided herein.

[0037] In some aspects, the antigen-binding domain includes a light chain variable region (VL) comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 1 and 164-166, a VHCDR2 amino acid sequence selected from the group consisting of SEQ ID NO: 2 and 167-169, and a VHCDR3 amino acid sequence selected from the group consisting of SEQ ID NO: 3 and 170-185; and / or a VLCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 4 and 159-161, a VLCDR2 amino acid sequence of SEQ ID NO: 5, and a VLCDR3 amino acid sequence selected from the group consisting of SEQ ID NO: 6, 162, and 163. In some aspects, the antigen-binding domain includes a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6. In some aspects, the CAR protein can bind to HSP70.

[0038] In some aspects, the antigen-binding domain includes a heavy chain variable sequence having a sequence selected from the group consisting of SEQ ID NO: 7, 12-17, and 26-103, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with any one of SEQ ID NO: 7, 12-17, and 26-103; and / or a light chain variable sequence having a sequence selected from the group consisting of SEQ ID NO: 8, 19-24, and 105-157, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with any one of SEQ ID NO: 8, 19-24, and 105-157.

[0039] In some aspects, the antigen-binding domain includes a heavy chain variable sequence having at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% identity with SEQ ID NO:7 and a light chain variable sequence having at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% identity with SEQ ID NO:8. In some aspects, the antigen-binding domain includes a heavy chain variable sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:7 and a light chain variable sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:8. In some aspects, the antigen-binding domain includes a heavy chain variable sequence having the sequence described in SEQ ID NO:7 and a light chain variable sequence having the sequence described in SEQ ID NO:8.

[0040] In some cases, the antigen-binding domain is encoded by a heavy chain variable sequence having at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% identity with SEQ ID NO:9 and a light chain variable sequence having at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% identity with SEQ ID NO:10. In some cases, the antigen-binding domain is encoded by a heavy chain variable sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:9 and a light chain variable sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:10. In some aspects, the antigen-binding domain is encoded by the heavy chain variable sequence described in SEQ ID NO:9 and the light chain variable sequence described in SEQ ID NO:10.

[0041] In some aspects, the antigen-binding domain is a humanized antigen-binding domain. In some aspects, the CAR protein further comprises a hinge domain, a transmembrane domain, and an intracellular signaling domain. The hinge domain may be a CD8a hinge domain or an IgG4 hinge domain. The transmembrane domain may be a CD8a transmembrane domain or a CD28 transmembrane domain. The intracellular signaling domain may include a CD3z intracellular signaling domain.

[0042] In one embodiment, a nucleic acid molecule encoding any one of the CAR proteins of this embodiment is provided herein. In some aspects, the sequence encoding the CAR protein is functionally ligated to an expression regulatory sequence. In some aspects, the nucleic acid molecule is further defined as an expression vector.

[0043] In one embodiment, engineered cells comprising a nucleic acid molecule encoding a chimeric antigen receptor (CAR) protein having an antigen-binding domain that binds to or can bind to human HSP70 are provided herein. In some aspects, the nucleic acid molecule encodes any one of the CAR proteins of this embodiment.

[0044] In some aspects, the cell is a T cell or an NK cell. In some aspects, nucleic acids are incorporated into the cell's genome. In some aspects, the cell is a human cell.

[0045] In one embodiment, a pharmaceutical composition comprising a population of cells of any one of these embodiments in a pharmaceutically acceptable carrier is provided herein.

[0046] In one embodiment, a method for treating cancer in a human patient in need thereof is provided herein, comprising the step of administering to the patient an antitumor-effective amount of cell therapy comprising one or more cells according to any one of the embodiments thereof. In some aspects, the cells are allogeneic or autologous cells. In some aspects, the cells are HLA-matched to the subject. In some aspects, the cancer is pancreatic cancer or prostate cancer.

[0047] In some aspects, the method further includes administering at least a second anti-cancer therapy, such as chemotherapy, immunotherapy, radiotherapy, gene therapy, surgery, hormone therapy, anti-angiogenic therapy, or cytokine therapy.

[0048] In one embodiment, a method for detecting HSP70 in an in vitro sample is provided herein, comprising the steps of contacting the in vitro sample with any one antibody or antibody fragment of this embodiment, and detecting the binding of the antibody or antibody fragment to the sample. In some aspects, the detection step is performed by flow cytometry, mass spectrometry, Western blotting, immunohistochemistry, ELISA, or RIA.

[0049] In one embodiment, any one antibody molecule, pharmaceutical composition, cell, or pharmaceutical composition of this embodiment is provided herein for use in treating cancer in a subject.

[0050] In one embodiment, the use of any one antibody molecule, pharmaceutical composition, cell, or pharmaceutical composition of this embodiment in the manufacture of a pharmaceutical for treating cancer in a subject is provided herein.

[0051] As used herein, the term “essentially absent” with respect to a specified component is used herein to mean that none of the specified components are intentionally included in the composition and / or are present only as impurities or in trace amounts. Therefore, the total amount of the specified components resulting from unintentional contamination of the composition is less than 0.5%, less than 0.1%, or less than 0.05%, preferably less than 0.01%. Most preferably, the composition is such that the amount of the specified component is undetectable by standard analytical methods.

[0052] As used herein, “a” or “an” may mean one or more. As used in the claims, as used in conjunction with the word “comprising,” the terms “a” or “an” may mean one or more.

[0053] The use of the term “or” in the claims is used to mean “and / or” unless it is explicitly indicated that it refers only to the options, or that the options are not mutually exclusive; however, this disclosure supports the definitions of options only and “and / or” as used herein. Where used herein, “another” may mean at least a second or more.

[0054] Throughout this application, the term “approximately” is used to indicate that a value includes an inherent variation in the error relating to the apparatus, a method used to determine that value, a variation existing between the subjects of study, or a value that is within 10% of the stated value.

[0055] Other objects, features, and advantages of the present invention will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while illustrating preferred embodiments of the present invention, are given only as examples, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

[0056] The following drawings form part of this specification and are included to further illustrate certain aspects of the invention. The invention may be better understood by referring to one or more of these drawings in conjunction with the detailed description of the particular embodiments presented herein. [Brief explanation of the drawing]

[0057] [Figure 1] BALB / c mice injected with MOPC315.BM-luc cells were injected with 200 μg of the indicated HSP70 mAb (square) or its IgG2B isotype control (circle) twice weekly from weeks 1 to 3. Disease burden was monitored using whole-body in vivo imaging and confirmed by serum light chain levels. [Figure 2A] Octet analysis (A) shows the affinity of 77A for mouse HSP70 (top panel), human HSP70 produced in E. coli (middle panel), and human HSP70 produced in Sf9 insect cells (bottom panel). [Figure 2B] 77A exhibits preferential binding to the ADP-HSP70 complex (B). [Figure 2C]The binding of 77A to HSP70-GFP shows maximum affinity in the presence of ADP and peptide substrates (NRL) (C). In (C), the bars in each group represent, from left to right, buffer, ATP, ADP, ATP NRL, and ADP NRL. [Figure 3A] Figures 3A–F. Full-length (FL) HSP70 was expressed as an N-terminal GFP fusion protein in HSP70 KO 293T cells, along with deletion mutants of indicated lengths in which a progressively larger number of C-terminal amino acids were removed (A). After IP of cell extracts with 77A, the protein was detected by Western blotting (WB) with an anti-GFP antibody (B). Smaller deletions were then created for more detailed mapping (C), and the indicated IP was performed from cell lysates (CL) or culture medium supernatant (CM). Loading was confirmed using an α-light chain (LC) antibody. The putative binding domain of 77A is shown in the molecular model of HSP70 representing the relevant region of the protein (D). The exact amino acids constituting the 77A epitope were determined using alanine scanning analysis, and the results are shown in (E), with ribbon diagrams showing primary and secondary important sites shown in (F). [Figure 3B] See the explanation in Figure 3A. [Figure 3C] See the explanation in Figure 3A. [Figure 3D] See the explanation in Figure 3A. [Figure 3E] See the explanation in Figure 3A. [Figure 3F] See the explanation in Figure 3A. [Figure 4]Figures 4A-B. Luc-labeled MM1.S human myeloma cells were injected into nude mice and treated twice weekly for 2-5 weeks with either an IgG2B isotype control mAb or 77A at the indicated doses. Live imaging data of the whole animals are shown at 5 weeks (A), and the dorsal (upper panel) and ventral (lower panel) figures show significant tumor growth in IgG2B-treated mice, but not significant tumor growth in 77A-treated mice, especially at higher dose levels. Subsequently, the same experiment was performed in NSG mice, and tumor growth was measured by imaging (B) and by ELISA against human light chain. [Figure 5] As shown, immature mouse DC2.4 cells were incubated at 37°C for 6 hours with either the vehicle (two left panels) or 6x-His-tagged HSP70 (two right panels) in the presence of IgG2B or 77A. Immature mouse DC2.4 cells were then stained with either control IgG (left panel) or α-6x-His-tagged mAb (three right panels), and HSP70 uptake was determined by flow. Significant HSP70 uptake was observed only in the presence of 77A (far right panel). [Figure 6] DC2.4 cells exposed to Sf9-derived 6x-His tagged human HSP70 were stained with either Alexa Fluor 594-conjugated wheat germ agglutinin (WGA) for cell membrane staining, Alexa Fluor 488-tagged α-6x-His tagged mAb for HSP70 detection, or 4',6-diamidino-2-phenylindole (DAPI) for nucleus staining, in the presence of either an isotype control mAb or 77AmAb. Individual and integrated images were obtained. Representative fields are shown at 200x magnification. [Figure 7] Electron micrographs of DCs exposed to HSP70 and gold-labeled 77A. The magnification shown is 100,000x. [Figure 8A]Figures 8A-C. Mouse DC2.4 cells were treated for 48 hours in combination with 10 μg of IgG2B or 77A, either with PBS or 5 μg of ADP-HSP70 purified from A-375 melanoma cells, which are an excellent source of HSP70 because they express high levels of HSP70. RNA was collected and the cDNA was hybridized to the qPCR array described in the specification. Genes that were activated or repressed more than 2-fold are shown for comparison between IgG2B and PBS (A; upper panel) and 77A and PBS (A; lower panel). Data from three biological replicates are shown. Ingenuity pathway analysis was then performed to identify the biological processes that may be affected by these changes (B). Cytokines released by mature DCs were then analyzed using the BioRad Bio-Plex® Pro Mouse Cytokine Array. The bar graph (C) shows the significant changes induced in cells exposed to HSP70 and 77A compared to cells exposed to HSP70 and IgG2B. In (C), the left bar represents the IgG control and the right bar represents HSP70 stimulation. [Figure 8B] See the explanation in Figure 8A. [Figure 8C] See the explanation in Figure 8A. [Figure 9-1]Figure 9A-G. 7,500 luc-4T1 cells were injected into the fourth right mammary gland of BALB / c mice. After 12 days, when all mice had palpable and measurable tumors, 200 μg of either IgG2B (black square) or 77A (white square) was intravenously injected twice weekly for 3 weeks. Tumor volume was measured for primary tumors (A) using both calipers and whole-body animal imaging, while imaging was used to assess lung metastases (B). Peripheral blood was collected on day 32 and evaluated for CD4+ and CD8+ T cells (C), and also for dual CD11c+ / MHC class II+ cells and total MHC class II+ cells (D). 77A induces HSP70 uptake into human primary CD4+ and CD8+ T cells (E). 77A stimulates MHC-independent cytolytic CD4 T cell activity (F). 77A activity (G) against an A375 melanoma model in nude mice. [Figure 9-2] See the explanation in Figure 9-1. [Figure 9-3] See the explanation in Figure 9-1. [Figure 9-4] See the explanation in Figure 9-1. [Figure 10] HSP70 (shown in blue) bound to ATP in the nucleotide-binding domain (NBD) has an open conformation that allows interaction with the substrate-binding domain (SBD). Substrate-peptide interaction with the SBD, in coordination with the J protein and nucleotide exchange factor (NEF), stimulates HSP70 ATPase activity, leading to lid closure and thereby stabilizing the interaction of HSP70 with the substrate. (Source: Craig & Marszalek, 2017). The approximate location of the 77A binding on the HSP70 model is also shown in the right panel. [Figure 11]Figures 11A-C. Homogenates from a 10 mL pellet of 4T1 cells expressing HSP70-GFP were purified using an ADP-agarose column to isolate the ADP-HSP70-peptide complex. 10 μg of this complex was injected intraperitoneally into BALB / c mice on day -24, and a booster subcutaneous immunization was administered on day -10. Subsequently, 4T1-luc cells expressing HSP70-GFP were injected into these mice on day 0, as shown in the legend in Figures 9A-9D, and tumor growth was monitored by whole-body imaging of the animals (A). On day 37, at the time of euthanasia of the animals, spleen cells were isolated and analyzed by FACS on the same day, or cultured for 7 days in the presence of irradiated 4T1 cells expressing HSP70-GFP, followed by analysis by FACS. A comparison of CD4+ (B) and CD8+ (C) T cell content at spleen isolation (day 0) and after 7 days of culture is provided (left panel). Cytotoxic T cell activity was also tested by exposing living wild-type 4T1 cells or 4T1 cells expressing HSP70-GFP to the cell fractions indicated, followed by survival studies (right panel). [Figure 12] As detailed above in Figures 12A-B, cytokine release assays were performed on CD4+(A) and CD8+(B) T cells isolated from mouse spleens after exposure to either 4T1 cells or 4T1 cells expressing HSP70-GFP. IFNγ secretion is shown in the upper panel, and IL-2 secretion is shown in the lower panel. [Figure 13] 77A induces HSP70 uptake via FcγR2A and FcγR2B. The top row represents HSP70 knockout HEK293T cells expressing human FcγR2A. The bottom row represents HSP70 knockout HEK293T cells expressing the indicated human Fcγ receptor. [Figure 14] Figures 14A-B. The sequences of mouse and human HSP70 at the proposed binding site for 77A are highlighted (A). Amino acid differences are boxed, with potential phosphorylation sites in red and ubiquitination sites in green. Three amino acid mutations in human HSP70 to mimic the mouse version reduce the ability of 77A to recognize human HSP70 (B). [Figure 15] Figures 15A-B show the tumor target of 77A. PLD was evaluated in BALB / c mice orthotopically injected with 4T1 cells (A) and in a CT26-based immunoqualified colon cancer mode (B) with the addition of IgG2B or 77A. [Figure 16] The competition for binding to the HSP70 protein with the listed antibodies was tested using epitope binning experiments with antibody 77A. The numbers in Figure 16 reflect the percentage of maximum binding in the presence of potentially competing antibodies. [Figure 17] Binding of antibody 77A to ADP-HSP70 (top) and ATP-HSP70 (bottom), as measured by biolayer interferometry (BLI). [Figure 18] The binding of antibody 77A to ADP-HSP70 and ATP-HSP70 was measured by ELISA, where No. 1° and No. 2° represent negative controls in which the primary or secondary antibody was absent, respectively. [Figure 19] Tumor volume after treatment of mice with CT-26 tumors with the indicated antibody. The boxed dates (14, 17, 21) indicate the days the mice were treated. *P=0.0023 compared to isotype control (IgG2B) when determined by Dunnett's multiple comparison t-test. [Figure 20] Figures 20A-B show the sequence alignment of humanized variants hVH-1-hVH-5 (Figure 20A) and hVL-1-hVL-5 (Figure 20B). [Figure 21] HSP70 uptake after incubation of cells expressing the indicated human Fcγ receptor with HSP70GFP, GFP-Nanobody Alexa-488, and the indicated antibody, as measured by total MFI (left) and %GFP-positive cells (right). 253-77A=77A;HC1 LC12001=h77A-1;HC2 LC1=h77A-6;HC3 LC1=h77A-11. [Figure 22]HSP70 uptake after incubation of cells expressing the indicated human Fcγ receptor with HSP70GFP, GFP-Nanobody Alexa-488, and the indicated IgG2 antibody, as measured by total MFI (left) and %GFP-positive cells (right). 253-77A=77A;HC1 LC1=h77A-1;HC2 LC1=h77A-6;HC3 LC1=h77A-11. [Figure 23] HSP70 uptake after incubation of cells expressing the indicated mouse Fcγ receptor with HSP70GFP, GFP-Nanobody Alexa-488, and the indicated antibody, as measured by total MFI (left) and %GFP-positive cells (right). 253-77A=77A;HC1 LC1=h77A-1;HC2 LC1=h77A-6;HC3 LC1=h77A-11. [Figure 24] HSP70 uptake after incubation of cells expressing the indicated mouse Fcγ receptor with HSP70GFP, GFP-Nanobody Alexa-488, and the indicated IgG2 antibody, as measured by total MFI (left) and %GFP-positive cells (right). 253-77A=77A;HC1 LC1=h77A-1;HC2 LC1=h77A-6;HC3 LC1=h77A-11. [Figure 25] HSP70 uptake after incubation of DCs with HSP70GFP, GFP-Nanobody Alexa-488, and the antibodies shown, as measured by MFI (left) and %GFP-positive cells (right). Results are shown for all cells gated to HSP70GFP. 253-77A=77A;HC1 LC1=h77A-1;HC2 LC1=h77A-6;HC3 LC1=h77A-11. [Figure 26]HSP70 uptake after incubation of DCs with HSP70GFP, GFP-Nanobody Alexa-488, and the antibodies shown, as measured by %GFP-positive cells (left) and MFI (right). Results are shown for plasmacytoid DCs, CD303+ve, CD1C-ve cells. 253-77A=77A;HC1 LC1=h77A-1;HC2 LC1=h77A-6;HC3 LC1=h77A-11. [Figure 27] HSP70 uptake after incubation of DCs with HSP70GFP, GFP-Nanobody Alexa-488, and the antibodies shown, as measured by %GFP-positive cells (left) and MFI (right). Results are shown for type 1 DCs, CD141+ve, CD1c-ve cells. 253-77A=77A;HC1 LC1=h77A-1;HC2 LC1=h77A-6;HC3 LC1=h77A-11. [Figure 28] HSP70 uptake after incubation of DCs with HSP70GFP, GFP-Nanobody Alexa-488, and the antibodies shown, as measured by %GFP-positive cells (left) and MFI (right). Results are shown for type 2 DCs, CD1C+ve, CD303-ve cells. 253-77A=77A;HC1 LC1=h77A-1;HC2 LC1=h77A-6;HC3 LC1=h77A-11. [Figure 29A] Figures 29A-J show the sequence alignments of the humanized variants hVH-1.1-hVH-1.78 (Figures 29A-29F) and hVL-1.1-hVL-1.53 ​​(Figures 29G-29J). [Figure 29B] See the explanation in Figure 29A. [Figure 29C] See the explanation in Figure 29A. [Figure 29D] See the explanation in Figure 29A. [Figure 29E] See the explanation in Figure 29A. [Figure 29F] See the explanation in Figure 29A. [Figure 29G] See the explanation in Figure 29A. [Figure 29H] See the explanation in Figure 29A. [Figure 29I] See the explanation in Figure 29A. [Figure 29J] See the explanation in Figure 29A. [Modes for carrying out the invention]

[0058] Detailed explanation The present invention is, in part, based on the development of anti-HSP antibodies or fragments thereof that are useful in certain indications, such as the treatment of cancer. In certain circumstances, anti-HSP70 monoclonal antibodies or antibody fragments may, for example, target extracellular or soluble HSP70 associated with tumor-derived antigens using immune cells (e.g., dendritic cells), thereby treating cancer and / or enhancing the effectiveness of cancer therapy (e.g., cancer immunotherapy).

[0059] The data provided herein demonstrate that an anti-HSP70 mAb (referred to as clone 77A) exhibits activity independently of surface HSP70 expression and targets extracellular HSP70 with tumor-derived antigens to dendritic cells (DCs). This antibody can be used to better understand the role of HSP70 in immunity and as a therapeutic agent to enhance the efficacy of cancer immunotherapy. In particular, clone 77A is a high-affinity HSP70 mAb that exhibits antitumor effects in both hematological malignancy and solid tumor models in immunocompetent and nude mice, but not in immunodeficient mice with spontaneous protein kinase DNA-activated catalytic subunit (PRKDCSCID) mutations, also known as SCID mice. This antibody enhances intracellular uptake of HSP70 by DCs in in vitro assays, leading to upregulation of genes related to DC maturation. When tested against orthotopically transplanted 4T1 cells, an immunologically cold model of mouse triple-negative breast cancer unresponsive to ICI, 77A reduced primary tumor growth and inhibited the development of lung and liver metastases. When combined with pegylated liposomal doxorubicin (PLD), an agent that induces immunogenic cell death (ICD) and enhances the release of the HSP70-tumor peptide complex, 77A cured some mice in both 4T1 and colorectal cancer models. Finally, when the ADP-HSP70 complex purified from 4T1 cells was used as a vaccine with 77A, tumor growth after subsequent attack induction in live 4T1 cells was inhibited compared to mAb isotype controls, and the abundance of 4T1-specific cytolytic CD4+ and CD8+ T cell activity was enhanced. Therefore, enhancing HSP70 uptake by immune cells using the clone 77A mAb enhances antitumor immunity, both alone and in several reasonably designed combination regimens.

[0060] I. Definition As used herein, “nucleic acid,” “nucleic acid sequence,” “oligonucleotide,” “polynucleotide,” or other grammatical equivalents mean at least two nucleotides covalently linked to each other, i.e., either deoxyribonucleotides or ribonucleotides or their analogues. Polynucleotides are polymers of any length, including, for example, 20, 50, 100, 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. Polynucleotides described herein generally contain phosphodiester bonds, but in some cases include nucleic acid analogs that may have at least one different bond, e.g., phosphoramidate, phosphorothioate, phosphorodithioate, or O-methylphosphoramidite bond, as well as peptide nucleic acid backbone and bonds. Mixtures of naturally occurring polynucleotides and analogues can be prepared, or mixtures of different polynucleotide analogues, as well as mixtures of naturally occurring polynucleotides and analogues, can be prepared. The following are non-exclusive examples of polynucleotides: genes or gene fragments, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, cRNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. Polynucleotides may include modified nucleotides such as methylated nucleotides and nucleotide analogs. Modifications to the nucleotide structure, where present, may be conferred before or after the assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. Polynucleotides may be further modified after polymerization, such as by conjugation with labeling components. The term also includes both double-stranded and single-stranded molecules. Unless otherwise specified or requested, the term polynucleotide encompasses both the double-stranded form and each of the two complementary single-stranded forms known or expected to constitute the double-stranded form.When a polynucleotide is RNA, it consists of a specific sequence of four nucleotide bases: adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) in place of thymine. Therefore, the term “polynucleotide sequence” is an alphabetical representation of a polynucleotide molecule. Unless otherwise indicated, a specific polynucleotide sequence implicitly includes not only the explicitly stated sequence but also its conservatively modified variants (e.g., degenerate codon substitutions) and complementary sequences. Specifically, degenerate codon substitutions can be achieved by generating a sequence in which the third position of one or more selected (or all) codons is substituted with a mixed base and / or a deoxyinosine residue.

[0061] As used herein, the terms “peptide,” “polypeptide,” and “protein” refer to polymers of amino acid residues. These terms also apply to naturally occurring amino acid polymers, amino acid polymers containing modified residues, and amino acid polymers not found in nature, as well as amino acid polymers in which one or more amino acid residues are artificial chemical mimics of corresponding naturally occurring amino acids. In this context, the term “polypeptide” includes antibodies or fragments thereof.

[0062] Other terms used herein in the fields of recombinant nucleic acid technology, microbiology, immunology, antibody engineering, and molecular and cell biology will be generally understood by those skilled in the art.

[0063] II. Antibodies and Antibody Modifications Monoclonal antibodies having clones and paired CDRs derived from heavy and light chains, as illustrated in Tables 1, 6, 9, and 10, are provided herein. Such antibodies may be prepared using the methods described herein.

[0064] The monoclonal antibodies of the present invention have several applications, including use for detecting HSP70 and for the manufacture of diagnostic kits for treating diseases accompanied by elevated levels of HSP70. In these contexts, such antibodies may be conjugated to diagnostic or therapeutic agents, used as capture agents or competitors in competitive assays, or used individually without the attachment of additional active agents. Antibodies may be mutated or modified, as will be further discussed below. Methods for preparing and characterizing antibodies are well known in the art (see, for example, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988; U.S. Patent No. 4,196,265).

[0065] An "antibody" is an immunoglobulin molecule that can specifically bind to a target such as carbohydrates, polynucleotides, lipids, polypeptides, etc., via at least one antigen-recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only complete polyclonal or monoclonal antibodies, but also their fragments (Fab, Fab', F(ab')2, Fv, Fd, Fd', single-chain antibodies (ScFv), diabodies, linear antibodies, etc.), their variants, naturally occurring variants, fusion proteins containing an antibody portion with an antigen-recognition site of the required specificity, humanized antibodies, chimeric antibodies, and any other modified configurations of immunoglobulin molecules containing an antigen-recognition site of the required specificity.

[0066] "Isolated antibodies" are antibodies separated and / or recovered from components of their natural environment. These contaminants from the natural environment are materials that interfere with the diagnostic or therapeutic use of the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In certain cases, antibodies are purified to (1) be more than 95% by weight, most specifically more than 99% by weight, as determined by the Lowry method, or (2) to be homogeneous by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or silver staining. Isolated antibodies contain antibodies in situ within recombinant cells because they lack at least one component of the antibody's natural environment. However, isolated antibodies are typically prepared by at least one purification step.

[0067] The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. As used herein, the term “heavy chain” refers to the larger immunoglobulin subunit that associates with the immunoglobulin light chain via its amino-terminal region. The heavy chain has a variable region (V H ) and steady-state region (C H ) includes. The steady-state region is C H 1. Hinge, C H 2 and C H It further includes 3 domains. In the case of IgE, IgM, and IgY, the heavy chain is C H It contains four domains but lacks a hinge domain. Those skilled in the art will understand that heavy chains are classified as gamma, mu, alpha, delta, or epsilon (γ, μ, α, δ, ε), and that there are several subclasses within them (e.g., γ1-γ4, α1-α2). It is a property of this chain that the "class" of an antibody is determined as IgG, IgM, IgA, IgD, or IgE, respectively. Immunoglobulin subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, etc., are well-characterized and known to confer functional specialization.

[0068] As used herein, the term “light chain” refers to a smaller immunoglobulin subunit that associates with the amino-terminal region of the heavy chain. Similar to the heavy chain, the light chain has a variable region (V L ) and steady-state region (C L ) contains its constant domain (C L Based on their amino acid sequences, they are classified as either kappa or lambda (κ,λ). These pairs can associate with any pair of various heavy chains to form immunoglobulin molecules. Light chains having a lambda variable region (V-lambda) linked to a kappa constant region (C-kappa) or a kappa variable region (V-kappa) linked to a lambda constant region (C-lambda) are also included in the definition of light chains.

[0069] IgM antibodies consist of five basic heterotetrameric units, for example, along with a further polypeptide called a J chain, and thus contain 10 antigen-binding sites, whereas secreted IgA antibodies can polymerize to form a multivalent aggregate containing 2 to 5 basic quad units along with the J chain. In the case of IgG, a quad unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, and two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H chain and L chain also has intrachain disulfide crosslinks arranged regularly spaced apart. Each H chain has a variable region (V) at its N-terminus. H ) has, and then each of the alpha and gamma chains has three constant domains (C H ) followed, and for the mu and isotype there are four C H The domains continue. Each L chain has a variable region (V) at its N-terminus. L ) has a steady domain (C) at the other end. L ) has. V L is V H And line up, C L This is the first constant domain of the heavy chain (C H 1) Aligns with the specified amino acid residues. Certain amino acid residues are thought to form an interface between the light chain variable region and the heavy chain variable region. V H and V LThe pairing of these antibodies together forms a single antigen-binding site. For the structure and properties of various classes of antibodies, see, for example, Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, Conn., 1994, page 71, and Chapter 6.

[0070] The “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The term “variable” refers to the fact that the sequence of a particular segment of the variable region differs significantly between antibodies. L ) and heavy chain portion (V H Both variable regions of the heavy and light chains mediate antigen binding and determine the specificity of a particular antibody to that particular antigen. However, variability is not evenly distributed throughout the variable region. Instead, the variable region consists of a series of relatively invariant regions called framework regions (FRs) separated by shorter regions of extreme variability called complementarity-determining regions (CDRs) or hypervariable regions. The variable regions of the natural heavy and light chains each contain four FRs, which primarily adopt a beta-sheet structure, and these four FRs are connected by three CDRs that form loops connecting the beta-sheet structure, and in some cases, loops that form part of the beta-sheet structure. The CDRs complement the shape of the antigen and determine the affinity and specificity of the antibody to the antigen. L and V H Both chains contain six CDRs. The CDRs in each chain are brought together in close proximity by FRs and, together with the CDRs in the other chain, contribute to the formation of the antibody's antigen-binding site (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0071] As used herein, the term “hypervariable region” refers to amino acid residues of an antibody involved in antigen binding. The hypervariable region is generally defined as amino acid residues from the “complementarity-determining region” or “CDR” (for example, if numbered according to the Kabat numbering system, V L Approximately residues 24-34 (L1), 50-56 (L2), and 89-97 (L3), as well as V H Approximately 31-35 (H1), 50-65 (H2), and 95-102 (H3) within the sequence; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)); and / or residues from the "hypervariable loop" (e.g., if numbered according to the Chothia numbering system, V L The residues within are 24-34 (L1), 50-56 (L2), and 89-97 (L3), as well as V H 26-32 (H1), 52-56 (H2), and 95-101 (H3) within; Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987); and / or residues from the "hypervariable loop" / CDR (e.g., if numbered according to the IMGT numbering system, V L The residues within are 27-38 (L1), 56-65 (L2), and 105-120 (L3), as well as V H This includes 27-38 (H1), 56-65 (H2), and 105-120 (H3); Lefranc, M. et al. Nucl. Acids Res. 27:209-212 (1999), Ruiz, M. et al. Nucl. Acids Res. 28:219-221 (2000). Optionally, antibodies are numbered according to AHo, V L The following points within are 28, 36 (L1), 63, 74-75 (L2) and 123 (L3), and V Hhaving symmetric insertions to one or more of 28, 36 (H1), 63, 74-75 (H2), and 123 (H3) therein; (Honneger, A. and Plunkthun, A. J. Mol. Biol. 309:657-670 (2001)). As used herein, CDR can refer to CDRs defined by any of these numbering approaches, or a combination of approaches, or other desirable approaches. Further, new definitions of highly conserved core, boundary, and hypervariable regions can be used.

[0072] The "constant region" of an antibody refers to the constant region of an antibody light chain or the constant region of an antibody heavy chain, either alone or in combination. The light chain (C L ) and the heavy chain (in the case of IgM and IgE, C H 1, C H 2 or C H 3 or C H 4) constant regions confer important biological properties such as secretion, transplacental transfer, Fc receptor binding, complement binding, etc. By convention, the numbering of constant region domains increases as the constant region domain becomes more distal from the antigen-binding site or amino terminus of the antibody. The constant region is not directly involved in the binding of the antibody to the antigen, but exhibits various effector functions such as the involvement of the antibody in antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP), and antibody-dependent complement deposition (ADCD).

[0073] An antibody can be an antibody fragment. An "antibody fragment" contains only a part of a complete antibody and generally contains the antigen-binding site of the complete antibody and thus retains the ability to bind to an antigen. Examples of antibody fragments included by this definition are (i) a Fab fragment having V L , C L , V H and C H1 domains; (ii) a Fab' fragment, which is a Fab fragment having one or more cysteine residues at the C-terminus of the C H1 domain; (iii) V H and C HAn Fd fragment having 1 domain; (iv) V H and C H 1 domain and C H An Fd' fragment having one or more cysteine residues at the C-terminus of 1 domain; (v) V of a single antibody L and V H An Fv fragment having domains; (vi) V H A dAb fragment consisting of a domain; (vii) An isolated CDR region; (viii) An F(ab')2 fragment which is a bivalent fragment containing two Fab' fragments linked by a disulfide bridge in a hinge region; (ix) A single-chain antibody molecule (e.g., single-chain Fv; scFv); (x) A heavy-chain variable domain (V L ) linked to a light-chain variable domain (V H ) in the same polypeptide chain, a "diabody" having two antigen-binding sites; (xi) A tandem Fd segment (V H -C H 1-V H -C H 1) pairs, including a "linear antibody".

[0074] Antibodies can be chimeric antibodies. A "chimeric antibody" refers to an antibody in which one portion of the amino acid sequence of the heavy chain and light chain is homologous to a corresponding sequence in an antibody from a particular species or belonging to a particular class of antibodies, but the remaining segments of the chain are homologous to a corresponding sequence in another antibody. For example, a chimeric antibody may be an antibody containing an antigen-binding sequence from a non-human donor transplanted into a heterogeneous non-human, human, or humanized sequence (e.g., framework and / or constant domain sequence). Typically, in these chimeric antibodies, the variable regions of both the light and heavy chains mimic the variable regions of an antibody from one species of mammal, but the constant region is homologous to a sequence in an antibody from another species. For example, methods have been developed to replace the light chain constant domain and heavy chain constant domain of a monoclonal antibody with human-derived analogous domains while preserving the variable region of the exogenous antibody. Alternatively, "fully human" monoclonal antibodies are produced in mice that have been genetically modified for human immunoglobulin genes. Methods have also been developed to make the variable domain of monoclonal antibodies more human-like by recombinantly constructing antibody variable domains that have amino acid sequences from both rodents, e.g., mice and humans. In “humanized” monoclonal antibodies, only the hypervariable CDR is derived from the mouse monoclonal antibody, while the framework and constant region are derived from the human amino acid sequence (see U.S. Patents 5,091,513 and 6,881,557 incorporated herein by reference). By replacing the amino acid sequence in the rodent-specific antibody with the amino acid sequence found at the corresponding position in the human antibody, the possibility of adverse immune responses during therapeutic use is thought to be reduced. Antibody-producing hybridomas or other cells may also undergo genetic mutations or other changes that may or may not alter the binding specificity of the antibodies produced by the hybridomas.

[0075] A. Monoclonal antibodies As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies; that is, the individual antibodies constituting the population are identical except for naturally occurring variations that may be present in small amounts. Monoclonal antibodies are highly specific and are produced against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which contain different antibodies produced against different determinants (epitopes), each monoclonal antibody is produced against a single determinant on an antigen. In addition to the specificity of monoclonal antibodies, they have the advantage of being able to be synthesized without contamination by other antibodies. The modifier “monoclonal” should not be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies useful in this disclosure may be prepared by the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or by recombinant DNA methods in bacterial, eukaryotic animal, or plant cells (e.g., U.S. Patent No. 4,816,567) after single-cell sorting of antigen-specific B cells, antigen-specific plasmablasts responding to infection or immunization, or capture of ligated heavy and light chains from single cells in bulk sorted antigen-specific collectibles. Monoclonal antibodies may also be isolated from phage antibody libraries using techniques described, for example, Clackson et al., Nature 352:624-628 (1991) and Marks et al., J.Mol.Biol. 222:581-597 (1991).

[0076] Methods for producing various types of monoclonal antibodies, including humanized, chimeric, and fully human, are well known and highly predictable in the art. For example, the following U.S. patents and patent applications provide a viable description of such methods: U.S. Patent Applications Nos. 2004 / 0126828 and 2002 / 0172677; and U.S. Patents Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,196,265; 4,275,149; 4,277,437; and 4,3 No. 66,241; No. 4,469,797; No. 4,472,509; No. 4,606,855; No. 4,703,003; No. 4,742,159; No. 4,767,720; No. 4,8 No. 16,567; No. 4,867,973; No. 4,938,948; No. 4,946,778; No. 5,021,236; No. 5,164,296; No. 5,196,066; No. 5,22 No. 3,409; No. 5,403,484; No. 5,420,253; No. 5,565,332; No. 5,571,698; No. 5,627,052; No. 5,656,434; No. 5,77 No. 0,376; No. 5,789,208; No. 5,821,337; No. 5,844,091; No. 5,858,657; No. 5,861,155; No. 5,871,907; No. 5,969 Nos. 108; Nos. 6,054,297; Nos. 6,165,464; Nos. 6,365,157; ​​Nos. 6,406,867; Nos. 6,709,659; Nos. 6,709,873; Nos. 6,753,407; Nos. 6,814,965; Nos. 6,849,259; Nos. 6,861,572; Nos. 6,875,434; and Nos. 6,891,024 are incorporated herein by reference.

[0077] B. Single chain antibody Single-chain variable fragments (scFvs) are fusions of the variable regions of the heavy and light chains of immunoglobulins linked together by a short linker. This chimeric molecule retains the specificity of the original immunoglobulin despite the removal of the constant region and the introduction of a linker peptide. This modification typically preserves the specificity. scFvs can be prepared directly from subcloned heavy and light chains derived from hybridomas or B cells. Single-chain variable fragments lack the constant Fc region found in complete antibody molecules and therefore lack the common binding site (e.g., protein A / G) used to purify the antibody. Since protein L interacts with the variable region of the kappa light chain, these fragments can often be purified / immobilized using protein L.

[0078] Flexible linkers are generally composed of helical and turn-promoting amino acid residues such as alanine, serine, and glycine. However, other residues can function similarly. For example, linkers are V H It has a proline residue two residues after the C-terminus and may have abundant arginine and proline at other positions.

[0079] Single-chain antibodies can also be produced by linking receptor light and heavy chains using non-peptide linkers or chemical units. Generally, the light and heavy chains are produced and purified in separate cells and then linked together in an appropriate manner (i.e., the N-terminus of the heavy chain is attached to the C-terminus of the light chain via an appropriate chemical crosslink).

[0080] Crosslinking reagents are used to form molecular crosslinks that link the functional groups of two different molecules, for example, a stabilizer and a coagulant. However, it is thought that heteromeric complexes can be created that consist of dimers or polymers of the same analog or different analogs. To link two different compounds stepwise, heterobifunctional crosslinking agents can be used to eliminate undesirable homopolymer formation.

[0081] An example of a heterobifunctional crosslinking agent contains two reactive groups, one of which reacts with a primary amine group (e.g., N-hydroxysuccinimide) and the other with a thiol group (e.g., pyridyl disulfide, maleimide, halogen, etc.). Via the primary amine reactive group, the crosslinking agent may react with a lysine residue of one protein (e.g., a selected antibody or fragment), and if the crosslinking agent is already bound to the first protein, it may react via the thiol reactive group with a cysteine ​​residue (free sulfhydryl group) of another protein (e.g., a selector).

[0082] It is preferable to use a crosslinking agent that has reasonable stability in the blood. Many types of disulfide bond-containing linkers are known that can be successfully used to conjugate targeting agents and therapeutic / preventive agents. Linkers containing sterically obstructed disulfide bonds may be found to provide greater stability in vivo and prevent the release of targeted peptides before they reach the site of action. Therefore, these linkers constitute one group of linkers.

[0083] For example, SMPT is a bifunctional crosslinking agent containing a disulfide bond that is "sterically hindered" by adjacent benzene rings and methyl groups. The steric interference of the disulfide bond is thought to serve to protect the bond from attack by thiolate anions, such as glutathione, which may be present in tissues and blood, thereby helping to prevent the separation of the conjugate before the conjugated active ingredient can be delivered to the target site. Like many other known crosslinking agents, SMPT crosslinking agents confer the ability to crosslink functional groups such as the SH of cysteine ​​or primary amines (e.g., the ε-amino group of lysine). Another possible type of crosslinking agent is a heterobifunctional photoreactive phenyl azide containing a cleavable disulfide bond, such as sulfosuccinimidyl-2-(p-azidosalicylamide)ethyl-1,3'-dithiopropionate. The N-hydroxy-succinimidyl group reacts with primary amino groups, and the phenyl azide (in photodegradation) reacts non-selectively with any amino acid residue.

[0084] In addition to interfered crosslinking agents, uninterrupted linkers can also be used according to this specification. Other useful crosslinking agents that are not thought to contain or generate protected disulfides include SATA, SPDP, and 2-iminothiolane. The use of such crosslinking agents is well understood in the art. Flexible linkers can also be used.

[0085] U.S. Patent No. 4,680,338 describes a bifunctional linker useful for generating ligand conjugates with amine-containing polymers and / or proteins, particularly for forming antibody conjugates with chelators, drugs, enzymes, detectable labels, etc. U.S. Patents Nos. 5,141,648 and 5,563,250 disclose cleavable conjugates containing unstable bonds that can be cleaved under a variety of mild conditions. This linker is particularly useful in that the active substance of interest can be directly bound to the linker, and cleavage results in the release of the active substance. Specific applications include adding free amino or free sulfhydryl groups to proteins or drugs such as antibodies.

[0086] U.S. Patent No. 5,856,456 provides a peptide linker for use in linking polypeptide components to produce fusion proteins, such as single-chain antibodies. The linker is up to approximately 50 amino acids long and contains at least one proline following a charged amino acid (preferably arginine or lysine), characterized by greater stability and reduced aggregation. U.S. Patent No. 5,880,270 discloses an aminooxy-containing linker useful in various immunodiagnostic and separation techniques.

[0087] C. Bispecific and multispecific antibodies Antibodies can be bispecific or multispecific. A “bispecific antibody” is an antibody that has binding specificity to at least two different epitopes. An exemplary bispecific antibody may bind to two different epitopes of a single antigen. Other such antibodies may combine a first antigen-binding site with a binding site for a second antigen. Alternatively, to concentrate and localize cellular defense mechanisms on infected cells, the antigen-specific arm may be combined with an arm that binds to a trigger molecule on leukocytes, such as a T cell receptor molecule (e.g., CD3), or to an Fc receptor for IgG (FcγR), such as FcγRI(CD64), FcγRII(CD32), and FcγRIII(CD16). Bispecific antibodies can also be used to localize cytotoxic agents to infected cells. These antibodies have an antigen-binding arm and an arm that binds to a cytotoxic agent (e.g., saporins, anti-interferon-α, vinca alkaloids, lysine A chain, methotrexate, or radioisotope haptens). Bispecific antibodies can be prepared as full-length antibodies or antibody fragments (e.g., F(ab')2 bispecific antibodies). Taki et al. (2015) describe a bispecific anti-HSP70 / anti-CD3 antibody.

[0088] Methods for producing bispecific antibodies are known in the art. Traditional production of full-length bispecific antibodies is based on the co-expression of two immunoglobulin heavy-light chain pairs, where the two chains have different specificities. Due to random combinations of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Purification of the correct molecule, usually performed by affinity chromatography, is quite cumbersome and results in low product yields.

[0089] According to a different approach, an antibody variable region (antibody-antigen binding site) with desired binding specificity is fused to the immunoglobulin constant domain sequence. Preferably, the fusion is performed using a hinge, C H2 and C H3This is a fusion with an Ig heavy chain constant domain that includes at least a portion of the region. At least one of the fusion products contains a first heavy chain constant region (C) that contains the site necessary for light chain binding. H1 It is preferable to have the immunoglobulin heavy chain fusion and, if desired, the DNA encoding the immunoglobulin light chain, which are inserted into separate expression vectors and simultaneously translocated into suitable host cells. This provides greater flexibility in adjusting the relative proportions of the three polypeptide chains when unequal ratios of the three polypeptide chains used in construction yield the optimal yield of the desired bispecific antibody. However, if the expression of at least two polypeptide chains in equal ratios yields a high yield, or if the ratio does not significantly affect the yield of the desired chain combination, it is possible to insert the coding sequences of two or all three polypeptide chains into a single expression vector.

[0090] A bispecific antibody may consist of a hybrid immunoglobulin heavy chain having a primary binding specificity in one arm and a hybrid immunoglobulin heavy-light chain pair (giving a secondary binding specificity) in the other arm. This asymmetric structure facilitates the separation of a desired bispecific compound from undesirable immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only half of the bispecific molecule provides an easy separation method. This approach is disclosed in International Publication No. 94 / 04690. For further details on the preparation of bispecific antibodies, see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).

[0091] According to another approach described in U.S. Patent No. 5,731,168, the interface between pairs of antibody molecules can be manipulated to maximize the proportion of heterodimers recovered from recombinant cell culture. A preferred interface is C H3This method involves at least a portion of the domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). By replacing the larger amino acid side chain with a smaller amino acid side chain (e.g., alanine or threonine), a compensatory "cavity" of the same or similar size as the larger side chain is created on the interface of the second antibody molecule. This provides a mechanism that increases the yield of heterodimers compared to other undesirable end products such as homodimers.

[0092] Bispecific antibodies include crosslinked antibodies or "heteroconjugate" antibodies. For example, one end of an antibody in a heteroconjugate can be conjugated to avidin and the other to biotin. Such antibodies are intended, for example, to direct immune system cells towards undesirable cells (U.S. Patent No. 4,676,980). Heteroconjugate antibodies can be produced using any convenient crosslinking method. Suitable crosslinking agents are well known in the art and are disclosed in U.S. Patent No. 4,676,980 along with several crosslinking techniques.

[0093] Techniques for producing bispecific antibodies from antibody fragments are also described in the literature. For example, bispecific antibodies can be prepared using chemical bonding. Brennan et al., Science, 229:81 (1985) describe a procedure for generating F(ab')2 fragments by proteolytically cleaving a complete antibody. To stabilize adjacent dithiols and prevent intermolecular disulfide formation, these fragments are reduced in the presence of sodium arsenite, a dithiol complexing agent. The resulting Fab' fragments are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to a Fab'-thiol by reduction with mercaptoethylamine and mixed with an equimolar amount of the other Fab'-TNB derivative to form a bispecific antibody. The produced bispecific antibody can be used as a working agent for selective enzyme immobilization.

[0094] Techniques exist to facilitate the direct recovery of Fab'-SH fragments from E. coli that can be chemically bound to form bispecific antibodies. Shalaby et al., J.Exp. Med., 175:217-225 (1992) describe the production of the humanized bispecific antibody F(ab')2 molecule. Each Fab' fragment was secreted separately from E. coli and subjected to targeted chemical binding in vitro to form bispecific antibodies. The bispecific antibodies thus formed could bind to cells overexpressing the ErbB2 receptor and normal human T cells, and could also trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

[0095] Various techniques for directly producing and isolating bispecific antibody fragments from recombinant cell cultures have also been described (Merchant et al., Nat. Biotechnol. 16, 677-681 (1998)). For example, bispecific antibodies have been produced using leucine zippers (Kostelny et al., J. Immunol., 148(5):1547-1553, 1992). By gene fusion, leucine zipper peptides derived from Fos and Jun proteins were linked to the Fab' portion of two different antibodies. The antibody homodimer was reduced at the hinge region to form monomers, and then reoxidized to form an antibody heterodimer. This method can also be used to produce antibody homodimers. The "diabody" technique described by Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993) provided an alternative mechanism for producing bispecific antibody fragments. This fragment is V, which is due to a linker that is too short to allow pairing between two domains on the same chain. L V connected H It includes V of one fragment. H and V L The domain is a complementary V of another fragment. L and V HThe domain is paired with another, thereby forming two antigen-binding sites. Another strategy for producing bispecific antibody fragments using single-chain Fv(sFv) dimers has also been reported. See Gruber et al., J.Immunol., 152:5368 (1994).

[0096] Bispecific or multispecific antibodies can be formed as DOCK-AND-LOCK® (DNL®) complexes (see, for example, U.S. Patents No. 7,521,056; No. 7,527,787; No. 7,534,866; No. 7,550,143 and No. 7,666,400). Generally, this technique utilizes the specific and high-affinity binding interaction that occurs between the dimerization and docking domain (DDD) sequence of the regulatory® subunit of cAMP-dependent protein kinase (PKA) and the anchor domain (AD) sequence derived from any of the various AKAP proteins (Baillie et al., FEBS Letters. 2005;579:3264; Wong and Scott, Nat. Rev. Mol. Cell Biol. 2004;5:959). The DDD and AD peptides can bind to any protein, peptide or other molecule. Since the DDD sequence spontaneously dimerizes and binds to the AD sequence, this technique enables the formation of complexes between any selected molecules that can bind to either the DDD or AD sequence.

[0097] Antibodies with more than two binding titers are intended. For example, triplicate antibodies can be prepared (Tutt et al., J.Immunol. 147:60,1991; Xu et al., Science,358(6359):85-90,2017). These antibodies may also contain sequences or moieties that enable receptor dimerization or multimerization. Such sequences include IgA-derived sequences that enable multimerization together with the J chain. Another multimerizing domain is the Gal4 dimerizing domain.

[0098] Polyvalent antibodies may be translocated (and / or catabolized) more quickly than bivalent antibodies by cells expressing the antigen to which the antibody binds. The antibodies of this disclosure may be polyvalent antibodies having three or more antigen-binding sites (e.g., tetravalent antibodies) which can be readily produced by recombinant expression of the nucleic acid encoding the polypeptide chain of the antibody. The polyvalent antibody may include a dimerization domain and three or more antigen-binding sites. A preferred dimerization domain includes (or consists of) an Fc region or a hinge region. In this scenario, the antibody includes an Fc region and three or more antigen-binding sites at the amino terminus relative to the Fc region. The polyvalent antibody may include (or consist of) three to about eight, e.g., four, antigen-binding sites. The polyvalent antibody includes at least one polypeptide chain (preferably two polypeptide chains), and the polypeptide chain includes two or more variable regions. For example, the polypeptide chain may be VD1-(X1) n -VD2-(X2) n -May include Fc, where VD1 is the first variable region, VD2 is the second variable region, Fc is one polypeptide chain of the Fc region, X1 and X2 represent amino acids or polypeptides, and n is 0 or 1. For example, the polypeptide chain may include a VH-CH1-flexible linker-VH-CH1-Fc region chain or a VH-CH1-VH-CH1-Fc region chain. The polyvalent antibody described herein may further include at least two (preferably four) light chain variable region polypeptides. The polyvalent antibody described herein may, for example, include about 2 to about 8 light chain variable region polypeptides. The light chain variable region polypeptide described herein includes a light chain variable region and optionally C L Includes domains as well.

[0099] Charge modification is particularly useful in the context of multispecific antibodies, and amino acid substitutions in Fab molecules reduce mispairing of the light chain with the mismatched heavy chain (Bence-Jones type byproduct) that can occur in the construction of Fab-based dual / multispecific antigen-binding molecules involving VH / VL exchange in one of the binding arms of the Fab-based dual / multispecific antigen-binding molecule (more than one in the case of molecules containing more than two antigen-binding Fab molecules) (see also International Publication 2015 / 150447, which is incorporated in its entirety herein by reference, and in particular the examples therein).

[0100] D. BiTES Bispecific T-cell inducers (BiTE®) are artificial bispecific monoclonal antibodies that induce cytotoxic activity of the host immune system, more specifically T cells, to target affected cells. BiTE is a fusion protein consisting of two single-chain variable fragments (scFv) of different antibodies on a single peptide chain of approximately 55 kilodaltons, i.e., amino acid sequences from four different genes. One scFv binds to T cells via the CD3 receptor, while the other binds to infected cells via a specific molecule.

[0101] Like other bispecific antibodies, and unlike typical monoclonal antibodies, BiTE forms a linkage between T cells and target cells. This allows T cells to exert cytotoxic activity against target cells by producing proteins such as perforin and granzyme, regardless of the presence of MHCI or costimulatory molecules. These proteins enter the target cells and initiate apoptosis. This action mimics the physiological processes observed during T cell attack on infected cells.

[0102] E. Antibody conjugates The antibodies of this disclosure may be conjugated to at least one active substance to form an antibody conjugate. The conjugate may be, for example, an antibody conjugated to another proteinaceous molecule, carbohydrate molecule, lipid molecule, or mixed partial molecule. Such antibody conjugates include, but are not limited to, modifications that involve conjugating the antibody to one or more polymers. For example, an antibody may be conjugated to one or more water-soluble polymers. Conjugation to a water-soluble polymer reduces the likelihood of the antibody precipitating in an aqueous environment, such as a physiological environment. Those skilled in the art can select an appropriate water-soluble polymer based on considerations including, but not limited to, whether the polymer / antibody conjugate will be used in patient treatment, and if so, the pharmacological profile of the antibody (e.g., half-life, dose, activity, antigenicity, and / or other factors).

[0103] To increase the effectiveness of antibody molecules as diagnostic or therapeutic agents, it has been conventional practice to ligate, covalently bond, or complex them with at least one desired molecule or part. Such molecules or parts may, but are not limited to, at least one effector or reporter molecule. Effector molecules include molecules having a desired activity, e.g., cytotoxic activity. Non-limiting examples of effector molecules that have been conjugated to antibodies include toxins, antitumor agents, therapeutic enzymes, radionuclides, antivirals, chelating agents, cytokines, growth factors, and oligo or polynucleotides. In contrast, a reporter molecule is defined as any part that can be detected using an assay. Non-limiting examples of reporter molecules that have been conjugated to antibodies include enzymes, radiolabels, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, photoaffinity molecules, colored particles or ligands, enzymes (e.g., catalyzing colorimetric or fluorescent quantitative reactions), substrates, solid matrices, e.g., biotin. Antibodies may contain one, two, or more of these labels.

[0104] Antibody conjugates can be used to deliver cytotoxic agents to target cells. This type of cytotoxic agent may include components such as cytokines, radioisotopes, chemotherapeutic agents (including prodrugs), bacterial toxins (e.g., Pseudomonas exotoxin, diphtheria toxin, etc.), plant toxins (e.g., lysine, geronin, etc.), chemical conjugates (e.g., maytansinoid toxins, auristatin, α-amanitin, anthracyclines, calicheamicin, etc.), radioconjugates, and enzyme conjugates (e.g., RNase conjugates, granzyme antibody-targeted enzyme / prodrug therapy).

[0105] Antibody conjugates are also used as diagnostic agents. Antibody diagnostics generally belong to two classes: those for use in in vitro diagnostics such as various immunoassays, and those for use in in vivo diagnostic protocols commonly known as “antibody-directed imaging.” Many suitable imaging agents are known in the art, as are methods for conjugating imaging agents to antibodies (see, for example, U.S. Patents 5,021,236, 4,938,948, and 4,472,509). The imaging portions used may be paramagnetic ions, radioisotopes, fluorescent dyes, NMR-detectable substances, and X-ray imaging agents.

[0106] Paramagnetic ions intended for use as conjugates include chromium(III), manganese(II), iron(III), iron(II), cobalt(II), nickel(II), copper(II), neodymium(III), samarium(III), ytterbium(III), gadolinium(III), vanadium(II), terbium(III), dysprosium(III), holmium(III), and / or erbium(III), with gadolinium being particularly preferred. Ions useful in other situations such as X-ray imaging include, but are not limited to, lanthanum(III), gold(III), lead(II), and bismuth(III).

[0107] Astatine is one of the radioactive isotopes that is expected to be used as a conjugate. 211 , 14 carbon, 51 chromium, 36 chlorine, 57 cobalt, 58 Cobalt, copper 67 , 152 EU, Gallium 67 , 3 Hydrogen, iodine 123 iodine 125 iodine 131 ,indium 111 , 59 iron, 32 Phosphorus, Rhenium 186 ,rhenium 188 , 75 selenium, 35 Sulfur, technetium 99m and / or yttrium 90 These are some examples. 125 I is often preferred. Technetium 99m and / or indium 111 However, because of its low energy and suitability for long-range detection, it is often preferred. The radiolabeled monoclonal antibodies of this disclosure can be prepared according to methods well known in the art. For example, monoclonal antibodies can be iodized by contact with a chemical oxidizing agent such as sodium iodide and / or potassium iodide and sodium hypochlorite, or an enzymatic oxidizing agent such as lactoperoxidase. The monoclonal antibodies of this disclosure can be prepared by ligand exchange by, for example, reducing pertechnate with a tin solution, chelating the reduced technetium onto a Sephadex column, and applying the antibody to this column. 99m It can be labeled with a methyl group. Alternatively, direct labeling techniques can be used, for example, by incubating the antibody with a reducing agent such as pertecnate or SNCl2, a buffer such as sodium potassium phthalate solution, etc. Intermediate functional groups often used to bind radioisotopes, which exist as metal ions, to antibodies are diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA).

[0108] Fluorescent labels intended for use as conjugates include Alexa 350, Alexa 430, AMCA, BODIPY 630 / 650, BODIPY 650 / 665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, Cascade Blue, Cy3, Cy5,6-FAM, fluorescein isothiocyanate, HEX, 6-JOE, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, REG, Rhodamine Green, Rhodamine Red, Renographin, ROX, TAMRA, TET, tetramethylrhodamine, and / or Texas Red.

[0109] Further types of antibodies envisioned in this disclosure are antibodies primarily intended for in vitro use, and the antibodies are linked to a secondary ligand and / or an enzyme (enzyme tag) that produces a colored product upon contact with a chromogenic substrate. Examples of preferred enzymes include urease, alkaline phosphatase, (horseradish) hydrogen peroxidase, or glucose oxidase. Preferred secondary ligands are biotin and avidin and streptavidin compounds.

[0110] Several methods for conjugating or binding an antibody to its conjugate portion are known in the art. Some conjugation methods include, for example, the use of metal chelate complexes using organic chelating agents such as diethylenetriaminepentaacetic anhydride (DTPA); ethylenetriaminetetraacetic acid; N-chloro-p-toluenesulfonamide; and / or tetrachloro-3α-6α-diphenylglycouryl-3 (U.S. Patents 4,472,509 and 4,938,948) conjugated to the antibody. Monoclonal antibodies can also be reacted with enzymes in the presence of coupling agents such as glutaraldehyde or periodates. Conjugates with fluorescein markers are prepared in the presence of these coupling agents or by reaction with isothiocyanates. In U.S. Patent No. 4,938,948, imaging of breast tumors is achieved using a monoclonal antibody, and the detectable imaging portion is conjugated to the antibody using a linker such as methyl-p-hydroxybenzimidate or N-succinimidyl-3-(4-hydroxyphenyl)propionate.

[0111] Another known method for site-specific binding of molecules to antibodies involves the reaction of antibodies with hapten-based affinity labels. Essentially, hapten-based affinity labels react with amino acids in the antigen-binding site, thereby disrupting this site and blocking the specific antigen reaction. However, this can be unfavorable because it results in the loss of antigen binding by the antibody conjugate.

[0112] Molecules containing azide groups can also be used to form covalent bonds with proteins via reactive nitrene intermediates generated by low-intensity ultraviolet light. In particular, 2- and 8-azide analogs of purine nucleotides have been used as site-specific optical probes for identifying nucleotide-binding proteins in crude cell extracts. 2- and 8-azide nucleotides have also been used to map nucleotide-binding domains of purified proteins and can be used as antibody conjugates.

[0113] Derivatization of immunoglobulins by selectively introducing sulfhydryl groups into the Fc region of immunoglobulins using reaction conditions that do not alter the antibody binding site is also envisioned. Antibody conjugates produced according to this methodology have been disclosed to exhibit improved lifetime, specificity, and sensitivity (U.S. Patent No. 5,196,066, incorporated herein by reference). Site-specific binding of effector or reporter molecules, in which the reporter or effector molecule is conjugated to a carbohydrate residue in the Fc region, has also been disclosed in the literature. This approach has been reported to produce diagnostic and therapeutically promising antibodies currently undergoing clinical evaluation.

[0114] F. Antibody-drug conjugates Antibody-drug conjugates, or ADCs, are a new class of highly potent biopharmaceuticals designed as targeted therapies to treat people with disease. ADCs are complex molecules consisting of an antibody (whole mAb or antibody fragment such as scFv) conjugated to a biologically active cytotoxic / antiviral payload or drug via a stable chemical linker with an unstable binding linkage. Antibody-drug conjugates are examples of bioconjugates and immunoconjugates.

[0115] By combining the unique targeting capabilities of monoclonal antibodies with the cancer-killing abilities of cytotoxic drugs, antibody-drug conjugates enable highly sensitive differentiation between healthy and affected tissue. This means that, in contrast to conventional systemic approaches, antibody-drug conjugates target and attack affected cells in a way that minimizes the impact on healthy cells.

[0116] In the development of ADC-based antitumor therapies, an anticancer drug (e.g., cytotoxin) is bound to an antibody that specifically targets a particular cellular marker (e.g., a protein found only in or on affected cells). The antibody tracks these proteins in the body and attaches to the surface of affected cells. A biochemical reaction between the antibody and the target protein (antigen) triggers a signal in the targeted cell, which then absorbs the antibody along with the cytotoxin or allows it to move into the cell. After the ADC has moved into the cell, the cytotoxic drug is released, killing the cell or impairing cell replication. Due to this targeting, ideally, the drug has fewer side effects than other agents and offers a broader therapeutic range.

[0117] Stable linking between antibodies and cytotoxic agents is a crucial aspect of ADCs. Linkers, based on chemical motifs including disulfides, hydrazones, or peptides (cleavable) or thioethers (non-cleavable), control the distribution and delivery of cytotoxic agents to target cells. Both cleavable and non-cleavable linkers have been proven safe in preclinical and clinical trials. Brentuximab vedotin contains an enzyme-sensitive cleavable linker that delivers the synthetic antineoplastic agent monomethyl auristatin E or MMAE, a potent and highly toxic antimicrotubule agent, to human-specific CD30-positive malignant cells. Due to its high toxicity, MMAE, which inhibits cell division by blocking tubulin polymerization, cannot be used as a monotherapy agent. However, combinations of MMAE linked to anti-CD30 monoclonal antibodies (cAC10, tumor necrosis factor, or TNF receptor cell membrane proteins) have been proven stable in extracellular fluid, cleavable by cathepsin, and safe for treatment. Another approved ADC, trastuzumab emtansine, is a combination of the microtubule formation inhibitor meltansine (DM-1), a derivative of maytansine, and the antibody trastuzumab (Herceptin® / Genentech / Roche), which is conjugated by a stable, non-cleavable linker.

[0118] The availability of superior and more stable linkers has altered the function of chemical bonds. The type of linker—cleavable or non-cleavable—confers specific properties to cytotoxic (e.g., anticancer) drugs. For example, non-cleavable linkers retain the drug within the cell. As a result, the entire antibody, linker, and cytotoxic agent enter the targeted cell, where the antibody is broken down to the amino acid level. The resulting complex—amino acids, linker, and cytotoxic agent—becomes the active drug at this point. In contrast, cleavable linkers are catalyzed by enzymes in the host cell, thereby releasing the cytotoxic agent.

[0119] Another type of cleavable linker adds an additional molecule between the cytotoxic drug and the cleavage site. This linker technology allows researchers to create more flexible ADCs without worrying about altering cleavage kinetics. Researchers are also developing new methods of peptide cleavage based on Edman degradation. Future directions in ADC development also include the development of site-directed conjugations (TDCs) as well as alpha-releasing immunoconjugates and antibody-conjugated nanoparticles to further improve stability and therapeutic index.

[0120] G. Intrabody In certain embodiments, antibodies are recombinant antibodies adapted for action inside cells, and such antibodies are known as “intrabodies.” These antibodies can disrupt target functions through a variety of mechanisms, such as altering intracellular protein transport, interfering with enzyme function, and blocking protein-protein or protein-DNA interactions. In many respects, the structure of these antibodies mimics or is similar to that of the single-chain and single-domain antibodies discussed above. Indeed, single transcript / single chain is a key feature that enables intracellular expression in target cells and also makes transmembrane protein transport more feasible. However, further features are needed. A further feature that intrabodies may require is a signal for intracellular targeting. Vectors have been designed and are commercially available (Invitrogen Corp.) that can direct intracellular regions such as the cytoplasm, nucleus, mitochondria, and ER to intracellular regions.

[0121] Two major issues affecting the execution of intrabody therapies are delivery, including cell / tissue targeting, and stability. Regarding delivery, various approaches have been employed, including tissue-directed delivery, the use of cell-type-specific promoters, virus-based delivery, the use of cell-permeable / membrane transfer peptides, and delivery using exosomes. One means of delivery involves the use of lipid-based nanoparticles or exosomes, as taught in U.S. Patent Application Publication 2018 / 0177727, which is incorporated herein by reference in its entirety. Regarding stability, this approach generally involves either brute-force screening, such as methods including phage display and potentially including sequence maturation or development of consensus sequences, or more targeted modifications such as insertion-stabilizing sequences (e.g., Fc regions, chaperone protein sequences, leucine zippers) and disulfide substitutions / modifications.

[0122] H. Antibody preparation and purification Methods for producing monoclonal antibodies generally begin in the same way as methods for preparing polyclonal antibodies. The first step in both of these methods is immunization of a suitable host. As is well known in the art, the immunogenicity of a given composition for immunization can vary. Therefore, it is often necessary to enhance the host immune system, which can be achieved by conjugating a peptide or polypeptide immunogen to a carrier. Exemplary and preferred carriers are keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA). Other albumins such as ovalbumin, mouse serum albumin, or rabbit serum albumin can also be used as carriers. Means for conjugating polypeptides to carrier proteins are well known in the art and include glutaraldehyde, m-maleimidebencyl-N-hydroxysuccinimide ester, carbodiimide, and bis-biazoted benzidine. Also, as is well known in the art, the immunogenicity of a particular immunogen composition can be enhanced by the use of nonspecific stimulants of the immune response, known as adjuvants. Exemplary and preferred adjuvants in animals include complete Freund's adjuvant (a nonspecific stimulant of the immune response containing dead Mycobacterium tuberculosis), incomplete Freund's adjuvant, and aluminum hydroxide adjuvant, while in humans, examples include alum, CpG, MFP59, and combinations of immunostimulatory molecules ("adjuvant systems" such as AS01 or AS03). Further experimental forms of inoculation for inducing antigen-specific B cells are possible, such as nanoparticle vaccines or antigens encoded by genes delivered as DNA or RNA genes in physical delivery systems (e.g., on lipid nanoparticles or gold microparticle gun beads), delivered using needles, gene guns, or percutaneous electroporation devices. Antigen genes may also be delivered encoded by viral vectors, either replication-capable or replication-deficient, such as adenoviruses, adeno-associated viruses, poxviruses, herpesviruses, or alphavirus replicons, or virus-like particles.

[0123] Methods for creating hybrids of antibody-producing cells and myeloma cells typically involve mixing somatic cells with myeloma cells in a 2:1 ratio in the presence of one or more activating factors (chemical or electrical) that promote cell membrane fusion, although this ratio can vary from approximately 20:1 to approximately 1:1. In some cases, transformation of human B cells with Epstein-Barr virus (EBV) as a first step increases the size of the B cells and enhances fusion with relatively larger myeloma cells. The efficiency of EBV transformation is enhanced by using CpG and Chk2 inhibitors in the transformation medium. Alternatively, human B cells can be activated by co-culturing transfected cell lines expressing CD40 ligand (CD154) in a medium containing further soluble factors such as IL-21 and human B cell activator (BAFF), a type II member of the TNF superfamily. Fusion methods using Sendai virus or polyethylene glycol (PEG) are also known. The use of electrically induced fusion methods is also appropriate. Fusion procedures typically involve approximately 1 × 10⁻⁶ fusions. -6 ~Approx. 1×10 -8While this method produces live hybrids at a low frequency, optimized procedures can achieve fusion efficiencies of nearly 1 in 200. However, the relatively low efficiency of fusion does not pose a problem, as the live fused hybrids differentiate from the injected parent cells (particularly injected myeloma cells, which typically continue to divide indefinitely) by culturing them in selective media. Selective media generally contain agents that block the de novo synthesis of nucleotides in tissue culture media. Exemplary and preferred agents are aminopterin, methotrexate, and azaserin. Aminopterin and methotrexate block the de novo synthesis of both purines and pyrimidines, while azaserin blocks only purine synthesis. When aminopterin or methotrexate is used, the medium is supplemented with hypoxanthine and thymidine as sources of nucleotides (HAT medium). When azaserin is used, the medium is supplemented with hypoxanthine. If the B cell source is a human B cell line transformed with EBV, ouabain is added to eliminate EBV-transformed cells that have not fused to myeloma.

[0124] The preferred selective medium is HAT or HAT containing ouabain. Only cells capable of activating the nucleotide salvage pathway can survive in HAT medium. Myeloma cells lack key enzymes in the salvage pathway, such as hypoxanthine phosphoribosyltransferase (HPRT), and therefore cannot survive. B cells can activate this pathway, but their lifespan in culture is limited, and they generally die within about two weeks. Therefore, the only cells that can survive in selective medium are hybrids formed from myeloma and B cells. If the source of B cells used for fusion is an EBV-transformed B cell line, as here, then ouabain can also be used for drug selection of the hybrid, since EBV-transformed B cells are sensitive to drug killing, while the myeloma partner used is selected to be ouabain-resistant.

[0125] Culture provides a population of hybridomas from which specific hybridomas are selected. Typically, hybridoma selection is performed by culturing cells by single-clonal dilution in microtiter plates, and then (after about 2-3 weeks) testing the individual clonal supernatant for the desired reactivity. The assay should be highly sensitive, simple, and rapid, such as radioimmunoassays, enzyme immunoassays, cytotoxicity assays, plaque assays, and dot immunoconjugation assays. The selected hybridomas are then serially diluted or sorted into single cells by flow cytometry and cloned into individual antibody-producing cell lines, which can then be grown indefinitely to provide monoclonal antibodies. Cell lines can be utilized for monoclonal antibody production in two basic ways. Samples of hybridomas can be injected into animals (e.g., mice) (often intraperitoneally). Optionally, the animals are stimulated with oils such as hydrocarbons, particularly pristane (tetramethylpentadecane), before injection. When human hybridomas are used in this way, it is best to inject them into immunocompromised mice, such as SCID mice, to prevent tumor rejection. The injected animals develop tumors that secrete specific monoclonal antibodies produced by the fusion cell hybrid. Then, to provide high concentrations of monoclonal antibodies, animal fluids such as serum or ascites can be extracted. Individual cell lines can also be cultured in vitro, and the monoclonal antibodies are spontaneously secreted into the culture medium and can be easily obtained from the culture medium in high concentrations. Alternatively, human hybridoma cell lines can be used in vitro to produce immunoglobulins in the cell supernatant. To optimize the ability to recover high-purity human monoclonal immunoglobulins, the cell lines can be adapted for growth in serum-free medium.

[0126] Hybridomas can be cultured, then the cells can be lysed, and total RNA can be extracted. A cDNA copy of the RNA can be generated using a random hexamer with RT, and then PCR can be performed using a multiplex mixture of PCR primers expected to amplify all human variable gene sequences. The PCR product can be cloned into a pGEM-T Easy vector and then sequenced by automated DNA sequencing using standard vector primers. Binding and neutralization assays can be performed using antibodies collected from the hybridoma supernatant and purified by FPLC using a Protein G column.

[0127] Recombinant full-length IgG antibodies can be produced by subcloning heavy and light chain FvDNA from a cloning vector into an IgG plasmid vector and translocating it into 293 (e.g., Freestyle) or CHO cells, and the antibodies can be collected and purified from the 293 or CHO cell supernatant. Other suitable host cell lines include bacteria such as E. coli, insect cells (S2, Sf9, Sf29, High Five), plant cells (e.g., tobacco, with or without manipulation for human-like glycans), algae, or various non-human transgenic situations such as mice, rats, goats, or cattle.

[0128] The expression of antibody-coding nucleic acids is also intended for both the purpose of subsequent antibody purification and host immunization. The antibody-coding sequence can be RNA, such as native RNA or modified RNA. Modified RNA is intended to have certain chemical modifications that confer increased stability and lower immunogenicity to mRNA, thereby promoting the expression of therapeutically important proteins. For example, N1-methyl-psoidouridine (N1mΨ) is superior to several other nucleoside modifications and their combinations in terms of translational ability. In addition to halting the immune / eIF2α phosphorylation-dependent inhibition of translation, incorporated N1mΨ nucleotides dramatically alter the dynamics of the translation process by increasing ribosome rest and density on mRNA. Modified mRNA is more readily initiated by preferring either ribosome recycling or denovulatory ribosome recruitment on the same mRNA, due to the increased loading of modified mRNA onto ribosomes. Such modifications can be used to enhance antibody expression in vivo after RNA inoculation. RNA, whether natural or modified, can be delivered as naked RNA or encapsulated in a delivery vehicle such as lipid nanoparticles.

[0129] Alternatively, DNA encoding antibodies can be used for the same purpose. The DNA is contained within an expression cassette that includes an active promoter in a host cell to which the expression cassette is designed. The expression cassette is advantageously contained within a replicable vector such as a conventional plasmid or minivector. The vectors include viral vectors, such as poxviruses, adenoviruses, herpesviruses, adeno-associated viruses, and lentiviruses. Replicons encoding antibody genes, such as alphavirus replicons based on VEE virus or Sindbisvirus, are also conceivable. Such vectors can be delivered by needle via intramuscular, subcutaneous, or intradermal routes, or by percutaneous electroporation if in vivo expression is desired.

[0130] Alternatively, molecular cloning approaches may be used to produce monoclonal antibodies. Single B cells labeled with the antigen of interest can be physically sorted using paramagnetic bead selection or flow cytometry sorting, and RNA can then be isolated from the single cells and antibody genes amplified by RT-PCR. Alternatively, matched heavy-chain and light-chain variable genes can be recovered from single cells by separating a bulk-sorted antigen-specific cell population into microvesicles and physically linking the heavy-chain and light-chain amplicons, or by common barcoding of the heavy-chain and light-chain genes from the vesicles. Matched heavy-chain and light-chain genes from single cells can also be obtained from a population of antigen-specific B cells by treating the cells with cell-permeable nanoparticles having barcodes and RT-PCR primers for marking the transcript with one barcode per cell. Antibody variable genes can also be isolated by RNA extraction of hybridoma strains, and the antibody genes can be obtained by RT-PCR and cloned into immunoglobulin expression vectors. Alternatively, combinatorial immunoglobulin phagemide libraries are prepared from RNA isolated from cell lines, and phagemides expressing the appropriate antibodies are selected by panning using viral antigens. The advantages of this approach over conventional hybridoma technology are approximately 10 4 The advantages include the ability to produce and screen twice as many antibodies in a single round, and the generation of new specificities through the combination of H and L chains, which further increases the likelihood of finding the appropriate antibody.

[0131] Other U.S. patents incorporating herein by reference that teach the production of antibodies useful in this disclosure include U.S. Patent No. 5,565,332 describing the production of chimeric antibodies using a combinatorial approach; U.S. Patent No. 4,816,567 describing recombinant immunoglobulin preparations; and U.S. Patent No. 4,867,973 describing antibody-therapeutic conjugates.

[0132] Monoclonal antibodies prepared by any means may be purified, if desired, by filtration, centrifugation, and various chromatographic methods such as FPLC or affinity chromatography. Monoclonal antibody fragments of this disclosure can be obtained from purified monoclonal antibodies by methods including digestion with enzymes such as pepsin or papain, and / or by cleavage of disulfide bonds by chemical reduction. Alternatively, monoclonal antibody fragments encompassed by this disclosure can be synthesized using an automated peptide synthesizer.

[0133] The antibodies of this disclosure may be purified. As used herein, the term “purified” is intended to mean a composition that can be isolated from other components, and a protein is purified to any degree compared to its naturally occurring state. Thus, a purified protein also means a protein that has been removed from the environment in which it could naturally exist. Where the term “substantially purified” is used, this notation means a composition in which a protein or peptide forms the main component of the composition, such as constituting about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more of the protein in the composition.

[0134] Protein purification techniques are well known to those skilled in the art. These techniques, at one level, involve the crude fractionation of the cellular environment into polypeptide and non-polypeptide fractions. After separating polypeptides from other proteins, chromatography and electrophoresis techniques may be used to further purify the polypeptide of interest to achieve partial or complete purification (or purification to homogeneity). Analytical methods particularly suitable for the preparation of pure peptides are ion-exchange chromatography, exclusion chromatography; polyacrylamide gel electrophoresis; and isoelectric focusing. Other methods for protein purification include centrifugation after precipitation or thermal denaturation with ammonium sulfate, PEG, antibodies, etc.; gel filtration, reverse-phase, hydroxyapatite, and affinity chromatography; and combinations of such techniques with other techniques.

[0135] When purifying the antibodies of this disclosure, it may be desirable to express the polypeptide in a prokaryotic or eukaryotic expression system and extract the protein using denaturing conditions. The polypeptide may be purified from other cellular components using an affinity column that binds to the tagged portion of the polypeptide. As is generally known in the art, the order in which various purification steps are performed may be changed, or certain steps may be omitted, which is still considered to result in a suitable method for preparing substantially purified proteins or peptides.

[0136] Generally, complete antibodies are fractionated using an active agent (i.e., protein A) that binds to the Fc portion of the antibody. Alternatively, an antigen may be used to simultaneously purify and select the appropriate antibody. Such methods often utilize a selector conjugated to a support such as a column, filter, or beads. The antibody is bound to the support, impurities are removed (e.g., by washing), and the antibody is released by applying conditions (e.g., salt, heat).

[0137] Various methods for quantifying the degree of purification of a protein or peptide will be known to those skilled in the art in light of this disclosure. These include, for example, determining the specific activity of an active fraction or assessing the amount of polypeptide in a fraction by SDS / PAGE analysis. Another method for assessing the purity of a fraction is to calculate the specific activity of the fraction and compare the specific activity of the fraction with the specific activity of the initial extract to calculate the purity. The actual units used to express the amount of activity will, of course, depend on the specific assay technique chosen to follow the purification and whether the expressed protein or peptide exhibits detectable activity.

[0138] Polypeptide migration is known to vary significantly, sometimes considerably, under different SDS / PAGE conditions. Therefore, it should be understood that the apparent molecular weight of purified or partially purified expression products may change under different electrophoretic conditions.

[0139] I. Modification of Antibodies Antibody sequences can be modified for a variety of reasons, such as improved expression, improved cross-reactivity, or reduced off-target binding. Modified antibodies can be produced by any technique known to those skilled in the art, including expression through standard molecular biological techniques or chemical synthesis of polypeptides.

[0140] For example, it may be desirable to modify antibody molecules by introducing conservative changes. When making such changes, hydroxylometric indicators of amino acids may be considered. The importance of hydroxylometric amino acid indicators in conferring interactive biological functions to proteins is generally understood in this art (Kyte and Doolittle, 1982). It is recognized that the relative hydroxylometric properties of amino acids contribute to the secondary structure of the resulting protein, which in turn dictates the protein's interactions with other molecules, such as enzymes, substrates, receptors, DNA, antibodies, and antigens.

[0141] Substitutions of similar amino acids can be effectively carried out based on hydrophilicity. U.S. Patent No. 4,554,101, incorporated herein by reference, states that the maximum local mean hydrophilicity of a protein, governed by the hydrophilicity of its adjacent amino acids, correlates with the biological properties of the protein. As detailed in U.S. Patent No. 4,554,101, the following hydrophilicity values ​​are assigned to amino acid residues: Basic amino acids: Arginine (+3.0), Lysine (+3.0), and Histidine (-0.5); Acidic amino acids: Aspartic acid (+3.0±1), Glutamic acid (+3.0±1), Asparagine (+0.2), and Glutamine (+0.2); Hydrophilic nonionic amino acids: Serine (+0.3), Asparagine (+0.2) ), glutamine (+0.2) and threonine (-0.4), sulfur-containing amino acids: cysteine ​​(-1.0) and methionine (-1.3); hydrophobic non-aromatic amino acids: valine (-1.5), leucine (-1.8), isoleucine (-1.8), proline (-0.5±1), alanine (-0.5) and glycine (0); hydrophobic aromatic amino acids: tryptophan (-3.4), phenylalanine (-2.5) and tyrosine (-2.3).

[0142] Amino acids can be substituted with other amino acids having similar hydrophilicity, thereby producing biologically or immunologically modified proteins. In such changes, substitutions of amino acids with a hydrophilicity value of ±2 are preferred, substitutions of an amino acid with a value of ±1 are particularly preferred, and substitutions of an amino acid with a value of ±0.5 are even more particularly preferred.

[0143] Amino acid substitutions are generally based on the relative similarities of amino acid side-chain substituents, such as their hydrophobicity, hydrophilicity, charge, and size. Exemplary substitutions taking various aforementioned characteristics into account are well known to those skilled in the art, including arginine and lysine; glutamic acid and aspartic acid; serine and threonine; glutamine and asparagine; valine, leucine, and isoleucine.

[0144] This disclosure also envisions isotype modification. Different functionalities can be achieved by modifying the Fc region to have different isotypes. For example, modification to IgG1 can increase antibody-dependent cytotoxicity, switching to class A can improve tissue distribution, and switching to class M can improve binding titer.

[0145] For example, by modifying C1q binding and / or FcγR binding, thereby altering CDC activity and / or ADCC activity, the Fc region of an antibody can be designed to have altered effector function. “Effector function” refers to a role in activating or attenuating biological activity (e.g., in a target). Examples of effector functions include, but are not limited to, C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and downregulation of cell surface receptors (e.g., B cell receptors; BCRs). Such effector functions may require the Fc region to be combined with a binding domain (e.g., an antibody-variable domain) and can be evaluated using various assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.).

[0146] For example, variant Fc regions of antibodies can be created that have improved C1q binding and improved FcγRIII binding (e.g., both improved ADCC activity and improved CDC activity). Alternatively, if it is desired to reduce or eliminate effector function, the variant Fc region can be manipulated to have reduced CDC activity and / or reduced ADCC activity. In other embodiments, only one of these activities may be increased (e.g., to create Fc region variants that have improved ADCC activity but reduced CDC activity, or vice versa), and optionally, the other activity may also be decreased.

[0147] The isolated monoclonal antibody or its antigen-binding fragment may contain a substantially homogeneous glycan free of sialic acid, galactose, or fucose. This substantially homogeneous glycan may be covalently bound to the heavy chain constant region.

[0148] Monoclonal antibodies may possess novel Fc glycosylation patterns. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked glycosylation refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for the enzymatic attachment of the carbohydrate moiety to the asparagine side-chain peptide sequence are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline. Therefore, the presence of either of these peptide sequences in the polypeptide creates a potential glycosylation site.

[0149] The glycosylation pattern can be altered, for example, by deleting one or more glycosylation sites found in the polypeptide, and / or by adding one or more glycosylation sites that are not present in the polypeptide. Addition of glycosylation sites to the Fc region of an antibody is conveniently achieved by modifying the amino acid sequence to contain one or more of the above tripeptide sequences (in the case of N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution at the heavy chain residue Asn297. Modifications can also be carried out by adding or substituting one or more serine or threonine residues into the original polypeptide sequence (in the case of O-linked glycosylation sites). Furthermore, the change of Asn297 to Ala can remove one of the glycosylation sites.

[0150] Isolated monoclonal antibodies or their antigen-binding fragments may exist in a substantially homogeneous composition represented by GNGN or G1 / G2 glycoforms, and show increased binding affinity to FcγRI and FcγRIII compared to the same antibodies that do not have a substantially homogeneous GNGN glycoform but have glycoforms containing G0, G1F, G2F, GNF, GNGNF, or GNGNFX. Fc glycosylation plays a crucial role in the antiviral and anticancer properties of therapeutic mAbs. Removal of core fucose dramatically improves the ADCC activity of mAbs mediated by natural killer (NK) cells, but appears to have the opposite effect on ADCC activity in polymorphonuclear cells (PMNs).

[0151] The isolated monoclonal antibody or its antigen-binding fragment can be expressed in cells expressing β(1,4)-N-acetylglucosaminyltransferase III (GnTIII), such that GnTIII adds GlcNAc to the antibody. Methods for producing antibodies in this manner are provided in International Publication No. 9954342 and International Publication No. 03011878. Cell lines can be modified to enhance, reduce, or eliminate certain post-translational modifications, such as glycosylation, using genome editing techniques such as clustering and regularly arranged short palindromic sequence repeats (CRISPR). For example, CRISPR technology can be used to eliminate genes encoding glycosylation enzymes in 293 cells or CHO cells used to express monoclonal antibodies.

[0152] It is possible to enhance the manufacturability and safety of antibody variable gene sequences obtained from human B cells by manipulating them. Potential protein sequence liabilities can be identified by searching for sequence motifs containing the following: 1) Unpaired Cys residues, 2) N-linked glycosylation, 3) Asn deamidation, 4) Asp isomerization, 5) SYE cutting, 6) Met oxidation, 7) Trp oxidation, 8) N-terminal glutamate, 9) Integrin bond, 10) CD11c / CD18 binding, or 11) Fragmentation Such motifs can be eliminated by modifying synthetic genes, including the cDNA encoding the antibody.

[0153] Antibodies can be manipulated to increase their solubility. For example, some hydrophilic residues, such as aspartic acid, glutamic acid, and serine, contribute significantly more favorably to protein solubility than other hydrophilic residues, such as asparagine, glutamine, threonine, lysine, and arginine.

[0154] Deep sequencing of the B cell repertoire of human B cells derived from blood donors has been extensively performed. Sequence information on significant portions of the human antibody repertoire facilitates the statistical evaluation of common antibody sequence characteristics in healthy humans. Using knowledge of antibody sequence characteristics in the Human Recombinant Antibody Variable Gene Reference Database, the degree of position-specificity of "human similarity" (HL) of antibody sequences can be estimated. HL has been shown to be useful in the development of antibodies for clinical use, such as therapeutic antibodies or vaccines. The ultimate goal is to increase the human similarity of antibodies to reduce potential adverse effects and anti-antibody immune responses that could result in significantly reduced efficacy of antibody drugs or induce serious health effects. We were able to evaluate the antibody properties of a combined antibody repertoire from three healthy human blood donors totaling approximately 400 million sequences, and created a novel "relative human similarity" (rHL) score that focuses on the hypervariable regions of antibodies. The rHL score allows for easy distinction between human sequences (positive score) and non-human sequences (negative score). Antibodies can be engineered to eliminate residues that are not common in the human repertoire.

[0155] Methods for reducing or eliminating the antigenicity of antibodies and antibody fragments are known in the art. When antibodies are administered to humans, they are preferably “humanized” to reduce or eliminate their antigenicity in humans. Preferably, each humanized antibody has the same or substantially the same affinity for the antigen as the non-humanized mouse antibody from which each humanized antibody is derived.

[0156] One humanization approach involves creating chimeric proteins in which the mouse immunoglobulin constant region is replaced with a human immunoglobulin constant region. See, for example, Morrison et al., 1984, PROC.NAT.ACAD.SCI. 81:6851-6855, Neuberger et al., 1984, Nature 312:604-608; U.S. Patent No. 6,893,625 (Robinson); No. 5,500,362 (Robinson); and No. 4,816,567 (Cabilly).

[0157] In an approach known as CDR transplantation, CDRs of the light chain variable region and heavy chain variable region are transplanted into a framework derived from another species. For example, mouse CDRs can be transplanted into human FRs. In some embodiments, CDRs of the light chain variable region and heavy chain variable region of an antibody are transplanted into human FRs or consensus human FRs. To create a consensus human FR, FRs from several human heavy or light chain amino acid sequences are aligned to identify a consensus amino acid sequence. CDR porting is applicable to U.S. Patent Nos. 7,022,500 (Queen); 6,982,321 (Winter); 6,180,370 (Queen); 6,054,297 (Carter); ; 5,859,205 (Adair); 5,693,761 (Queen); 5,565,332 (Hoogenboom); 5,585,089 (Queen); 5,530,101 (Queen); Jones et al.(1986)Nature 321:522-525;Riechmann et al.(1988)Nature 332:323-327;Verhoeyen et al.(1988)Science This is described in 239:1534-1536 and Winter (1998) Febs Lett 430:92-94.

[0158] In an approach called "SUPERHUMANIZATION™," human CDR sequences are selected from human germline genes based on their structural similarity to the CDRs of the mouse antibody being humanized. See, for example, U.S. Patent No. 6,881,557 (Foote) and Tan et al., 2002, J.Immunol. 169:1119-1125.

[0159] Other methods for reducing immunogenicity include "remodeling," "hyperchimerization," and "veniering / resurfacing." See, for example, Vaswami et al., 1998, Annals Of Allergy, Asthma, &Immunol. 81:105; Roguska et al., 1996, Prot. Engineer 9:895-904 and U.S. Patent No. 6,072,035 (Hardman). In the veneering / resurfacing approach, amino acid residues accessible on the surface of a mouse antibody are replaced with amino acid residues more frequently found at the same position in a human antibody. This type of antibody resurfacing is described, for example, in U.S. Patent No. 5,639,641 (Pedersen).

[0160] Another approach to converting mouse antibodies into a form suitable for medical use in humans is known as the ACTIVMAB® technology (Vaccinex, Inc., Rochester, NY), which includes a vaccinia virus-based vector for expressing antibodies in mammalian cells. This can generate a high level of diversity in IgG heavy and light chain combinations. See, for example, U.S. Patent No. 6,706,477 (Zauderer); No. 6,800,442 (Zauderer); and No. 6,872,518 (Zauderer). Another approach to converting mouse antibodies into a form suitable for human use is a technology commercially implemented by KaloBios Pharmaceuticals, Inc. (Palo Alto, CA). This technology involves the use of a proprietary human "acceptor" library to create an "epitope-focused" library for antibody selection. Another approach to modifying mouse antibodies into a form suitable for medical use in humans is the HUMAN ENGINEERING® technology, which is commercially implemented by XOMA(US) LLC. See, for example, International Publication No. 93 / 11794 and U.S. Patents No. 5,766,886 (Studnicka); No. 5,770,196 (Studnicka); No. 5,821,123 (Studnicka); and No. 5,869,619 (Studnicka).

[0161] Any appropriate approach, including any of the approaches described above, can be used to reduce or eliminate the human immunogenicity of the antibody.

[0162] J. Determination of Antibody Properties The antibodies described herein may, in the first example, be defined by their binding specificity. A person skilled in the art can determine whether such an antibody falls within the scope of the claims by evaluating the binding specificity / affinity of a given antibody using techniques well known to those skilled in the art. For example, the epitope to which a given antibody binds may consist of a single continuous sequence of three or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) amino acids located within the antigen molecule (e.g., a linear epitope in a domain). Alternatively, the epitope may consist of a plurality of discontinuous amino acids (or amino acid sequences) located within the antigen molecule (e.g., a structural epitope).

[0163] Various techniques known to those skilled in the art can be used to determine whether an antibody "interacts with one or more amino acids" within a polypeptide or protein. Exemplary techniques include routine cross-blocking assays, such as those described in Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harbor, NY). Cross-blocking can be measured by various binding assays, such as ELISA, biolayer interferometry, or surface plasmon resonance. Other methods include alanine scanning mutation analysis, peptide blot analysis (Reineke (2004) Methods Mol. Biol. 248:443-63), peptide cleavage analysis, high-resolution electron microscopy techniques using single-particle reconstruction, cryoEM, or tomography, crystallographic studies, and NMR analysis. Furthermore, methods such as epitope excision, epitope extraction, and antigen chemical modification can be used (Tomer (2000) Prot. Sci. 9:487-496). Another method that can be used to identify amino acids within polypeptides that antibodies interact with is hydrogen / deuterium exchange, detected by mass spectrometry. Generally speaking, the hydrogen / deuterium exchange method involves deuterizing the protein of interest and then conjugating the antibody to the deuterized protein. The protein / antibody complex is then transferred to water, and the exchangeable protons in the amino acids protected by the antibody complex undergo reverse exchange from deuterium to hydrogen at a slower rate than the exchangeable protons in the amino acids that are not part of the interface. As a result, the amino acids that form part of the protein / antibody interface may retain deuterium and therefore may exhibit a relatively higher mass compared to amino acids not included in the interface. After antibody dissociation, the target protein is subjected to protease cleavage and mass spectrometry to reveal the deuterium-labeled residues corresponding to the specific amino acids that the antibody interacts with. See, for example, Ehring (1999) Analytical Biochemistry 267:252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.

[0164] The term "epitope" refers to a site on an antigen to which B cells and / or T cells respond. B cell epitopes can be formed from both consecutive amino acids or discontinuous amino acids juxtaposed by tertiary folding of proteins. Epitopes formed from adjacent amino acids are typically retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents. Epitopes typically contain at least three, more commonly at least five or eight to ten, amino acids in a distinctive spatial structure.

[0165] Modification-assisted profiling (MAP), also known as antigen-based antibody profiling (ASAP), is a method for classifying a large number of monoclonal antibodies produced against the same antigen according to the similarity of the binding profiles of each antibody to a chemically or enzymatically modified antigen surface (see U.S. Patent Application Publication 2004 / 0101920, which is incorporated specifically herein by reference in its entirety). Each category may reflect a unique epitope that is distinctly different from or partially overlaps with the epitopes represented by another category. This technique enables rapid filtering of genetically identical antibodies, allowing characterization to focus on genetically distinct antibodies. When applied to hybridoma screening, MAP can facilitate the identification of rare hybridoma clones that produce monoclonal antibodies with desired characteristics. MAP can be used to sort the antibodies of this disclosure into groups of antibodies that bind to different epitopes.

[0166] This disclosure includes antibodies that can bind to the same epitope or a portion of the same epitope. By using routine methods known in the art, it is readily possible to determine whether an antibody binds to the same epitope as a reference antibody or whether it competes for binding with the reference antibody. For example, to determine whether a test antibody binds to the same epitope as a reference antibody, the reference antibody is bound to the target molecule under saturated conditions. The ability of the test antibody to bind to the target molecule is then evaluated. If the test antibody can bind to the target molecule after saturated binding with the reference antibody, it can be concluded that the test antibody binds to a different epitope than the reference antibody. On the other hand, if the test antibody cannot bind to the target molecule after saturated binding with the reference antibody, the test antibody may bind to the same epitope as the one bound by the reference antibody.

[0167] To determine whether an antibody competes for binding with, for example, the 77A antibody, the above binding methodology is performed in two directions: In the first direction, the 77A antibody is bound to the HSP70 protein under saturated conditions, and then the binding of the test antibody to the HSP70 protein is evaluated. In the second direction, the test antibody is bound to the HSP70 protein under saturated conditions, and then the binding of the 77A antibody to the HSP70 protein is evaluated. In both directions, if only the first (saturated) antibody can bind to the HSP70 molecule, it can be concluded that the test antibody and the 77A antibody compete for binding to HSP70. As will be understood by those skilled in the art, an antibody that competes for binding with a reference antibody does not necessarily bind to the same epitope as the reference antibody, but can sterically block the binding of the reference antibody by binding to an overlapping or adjacent epitope.

[0168] If each antibody competitively inhibits (blocks) the binding of the other to the antigen, the two antibodies will bind to the same or overlapping epitopes. That is, as measured in a competitive binding assay, a 1x, 5x, 10x, 20x, or 100x excess of one antibody will inhibit the binding of the other by at least 50%, but preferably 75%, 90%, or even 99% (see, for example, Junghans et al., Cancer Res. 1990 50:1495-1502). Alternatively, if essentially all amino acid mutations in the antigen that reduce or eliminate the binding of one antibody reduce or eliminate the binding of the other, the two antibodies will have the same epitope. If several amino acid mutations that reduce or eliminate the binding of one antibody reduce or eliminate the binding of the other, the two antibodies will have overlapping epitopes.

[0169] Next, further routine experiments (e.g., peptide mutation and binding analysis) can be performed to confirm whether the observed lack of binding of the test antibody is actually due to binding to the same epitope as the reference antibody, or whether steric blockage (or another phenomenon) is the cause of the observed lack of binding. These types of experiments can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art.

[0170] In another context, antibodies can be defined by the variable sequence of the antibody, which includes additional “framework” regions. These are provided in Tables 2, 3, 6, 9, and 10, which represent the complete variable regions. Furthermore, antibody sequences can differ from these sequences by any means, which are discussed in more detail below. For example, a nucleic acid sequence can be differentiated by (a) the variable region being separated from the constant domains of the light and heavy chains, (b) the nucleic acid being altered from the nucleic acid without affecting the residues it encodes, (c) the nucleic acid being altered from the nucleic acid with a given percentage of homology, e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or (d) the nucleic acid being supplied by approximately 0.02 M to approximately 0.15 M NaCl at a temperature of approximately 50°C to approximately 70°C. (e) an amino acid may be altered from the nucleic acid for the ability to hybridize under high stringency conditions, such as those exemplified by low-salt and / or high-temperature conditions, with a given percentage of homology, e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or (f) an amino acid may be altered from the nucleic acid sequence in that it may differ from the amino acid by allowing conservative substitutions.

[0171] When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if, when aligned to obtain the greatest possible match, the sequences of nucleotides or amino acids in the two sequences are the same, as described below. Comparison between two sequences is typically performed by comparing the sequences across a comparison window to identify and compare local regions of sequence similarity. As used herein, a “comparison window” refers to at least about 20 consecutive positions, typically 30 to about 75 or 40 to about 50 segments, where the two sequences can be compared to a reference sequence at the same number of consecutive positions after the two sequences have been optimally aligned.

[0172] Optimal alignment of sequences for comparison can be performed using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, Wis.) with initial setting parameters. Alternatively, optimal alignment of sequences for comparison can be performed by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, the similarity search method of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, Wis.), or by testing.

[0173] One specific example of an algorithm suitable for determining percent sequence identity and sequence similarity is the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nucl. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. BLAST and BLAST 2.0 can be used with, for example, the parameters described herein to determine percent sequence identity for the polynucleotides and polypeptides of the present disclosure. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. Due to the rearranged nature of antibody sequences and the variable length of each gene, multiple BLAST searches are required for a single antibody sequence. Also, manual assembly of different genes is difficult and error-prone. The sequence analysis tool IgBLAST (world wide web ncbi.nlm.nih.gov / igblast / ) identifies matches to germline V, D, and J genes, details at the rearranged junctions, and depicts IgV domain framework regions and complementarity-determining regions. IgBLAST can analyze nucleotide or protein sequences, process sequences in batch, and simultaneously search germline gene databases and other sequence databases, minimizing the possibility of missing the most likely matching germline V gene.

[0174] In one approach, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window of at least 20 positions, where the portion of the polynucleotide or polypeptide sequence in the comparison window may include additions or deletions of 20% or less, usually 5 - 15%, or 10 - 12% (i.e., gaps) as compared to the reference sequence for optimal alignment of the two sequences (without additions or deletions). The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues are present in both sequences to obtain the number of matching positions, dividing the number of matching positions by the total number of positions in the reference sequence (i.e., window size), and multiplying the result by 100 to obtain the percentage of sequence identity.

[0175] Yet another way to define an antibody is as a "derivative" of any of the antibodies and their antigen-binding fragments provided herein. Derivative antibodies or antibody fragments can be modified by chemical modifications using techniques known to those of skill in the art, including, but not limited to, specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicamycin, etc. In one aspect, an antibody derivative has a function similar or identical to that of the parental antibody. In another aspect, an antibody derivative exhibits a changed activity as compared to the parental antibody. For example, a derivative antibody (or fragment thereof) may be able to bind more tightly to its epitope than the parental antibody or may be more resistant to proteolysis.

[0176] The term “derivative” refers to an antibody or its antigen-binding fragment that binds immunospecifically to an antigen but contains one, two, three, four, five or more amino acid substitutions, additions, deletions, or modifications compared to the “parent” (or wild-type) molecule. Such amino acid substitutions or additions may introduce naturally occurring amino acid residues (i.e., those encoded by DNA) or amino acid residues that are not naturally occurring. The term “derivative” also includes variants having altered CH1, hinge, CH2, CH3, or CH4 regions to form, for example, an antibody having an enhanced or impaired effector or binding property variant Fc region. The term “derivative” further includes amino acids that are non-amino acid modified, such as glycosylation (e.g., having altered mannose, 2-N-acetylglucosamine, galactose, fucose, glucose, sialic acid, 5-N-acetylneuraminic acid, 5-glycolneuraminic acid, etc.), acetylation, pegylation, phosphorylation, amidation, derivatization by known protective / blocking groups, proteolytic cleavage, or linkage to cellular ligands or other proteins. In some embodiments, altered carbohydrate modifications regulate one or more of the following: antibody solubilization, enhancement of intracellular transport and secretion of antibodies, enhancement of antibody construction, conformational integrity, and antibody-mediated effector function. In certain embodiments, altered carbohydrate modifications enhance antibody-mediated effector function compared to antibodies lacking carbohydrate modifications. Carbohydrate modifications that result in altered antibody-mediated effector function are well known in the art.

[0177] The biophysical properties of antibodies can be determined. High temperatures can be used to unfold the antibody and determine its relative stability using its average apparent melting temperature. Differential scanning calorimetry (DSC) can determine the molecular heat capacity C as a function of temperature. p (The heat required to warm a molecule per degree Celsius) is measured. DSC can be used to study the thermal stability of antibodies. DSC data for mAbs decomposes the unfolding of individual domains within the mAb structure and is reflected in the thermogram (Fab, C H2 and C HIt is particularly interesting because it can produce up to three peaks (from the unfolding of three domains). Typically, the unfolding of the Fab domain yields the strongest peak. The DSC profile and relative stability of the Fc portion show characteristic differences for human IgG1, IgG2, IgG3, and IgG4 subclasses (Garber and Demarest, Biochem.Biophys.Res.Commun. 355,751-757, 2007). The mean apparent melting temperature can also be determined using circular dichroism (CD) performed with a CD spectrometer. Far-UV CD spectra are measured in 0.5 nm increments in the range of 200 nm to 260 nm for the antibody. The final spectrum can be determined as the average of 20 cumulative values. The residual ellipticity value can be calculated after background subtraction. Thermal unfolding of the antibody (0.1 mg / mL) can be monitored at 25–95°C and a heating rate of 1°C / min, at 235 nm. Dynamic light scattering (DLS) can be used to assess the tendency towards aggregation. DLS is used to characterize the sizes of various particles, including proteins. If the size of the system is not dispersed, the mean effective diameter of the particles can be determined. This measurement depends on the size of the particle core, the size of the surface structure, and the particle concentration. Since DLS essentially measures the variation in scattered light intensity by the particles, the diffusion coefficient of the particles can be determined. DLS software in commercially available DLS instruments shows particle populations of different diameters. Stability studies can be conveniently performed using DLS. DLS measurements of a sample can indicate whether particles aggregate over time or with temperature variations by determining whether the hydrodynamic radius of the particles increases. If particles aggregate, a larger population of particles with larger radii can be seen. Temperature-dependent stability can be analyzed by controlling the temperature in situ. Capillary electrophoresis (CE) techniques include proven methodologies for characterizing antibody stability.The iCE approach can be used to separate antibody-protein charge variants resulting from deamidation, C-terminal lysine, sialylation, oxidation, glycosylation, and any other changes to the protein that may lead to changes in the protein's pI. Each expressed antibody protein can be evaluated by high-throughput free-solution isoelectric focusing (IEF) (cIEF) in a capillary column using a Protein Simple Maurice instrument. For real-time monitoring of molecules concentrated at the isoelectric point (pI), whole-column UV absorption detection can be performed every 30 seconds. This approach eliminates the need for transfer steps while combining the high resolution of conventional gel IEF with the quantification and automation advantages found in column-based separations. This technique results in reproducible quantitative analysis of the identity, purity, and heterogeneity profiles of expressed antibodies. The results identify charge heterogeneity and molecular size on the antibody in both absorbance and intrinsic fluorescence detection modes, and with detection sensitivities down to 0.7 μg / mL.

[0178] The intrinsic solubility score of an antibody sequence can be determined. This intrinsic solubility score can be calculated using CamSol Intrinsic (Sormanni et al., J Mol Biol 427,478-490,2015). The amino acid sequence of residues 95-102 (Kabat numbering) in HCDR3 of each antibody fragment, such as scFv, can be evaluated via an online program to calculate the solubility score. Solubility can also be determined using laboratory techniques. Various techniques exist, including adding lyophilized protein to a solution until the solution is saturated and reaches its solubility limit, or concentration by ultrafiltration in a microconcentrator with an appropriate molecular weight cutoff. The simplest method is the induction of amorphous precipitation, which involves measuring protein solubility using a method that includes protein precipitation using ammonium sulfate (Trevino et al., J Mol Biol, 366:449-460,2007). Ammonium sulfate precipitation provides rapid and accurate information regarding relative solubility values. Ammonium sulfate precipitation produces a precipitate solution with clearly separated aqueous and solid phases and requires relatively small amounts of protein. Solubility measurements performed using amorphous precipitation induction with ammonium sulfate can also be easily carried out at different pH values. Protein solubility is highly pH-dependent, and pH is considered the most important exogenous factor influencing solubility.

[0179] Generally, autoreactive clones are thought to be eliminated during ontogeny by negative selection; however, many human native antibodies with autoreactive properties persist in the adult maturation repertoire, and it has become clear that autoreactivity can enhance the antiviral function of many antibodies against pathogens. It has been noted that HCDR3 loops in antibodies during early B cell development are often positively charged and exhibit autoreactive patterns (Wardemann et al., Science 301, 1374-1377, 2003). A given antibody can be tested for autoreactivity by evaluating its binding level to human-derived cells using microscopy (using adherent HeLa or HEp-2 epithelial cells) and flow cytometry cell surface staining (using suspended Jurkat T cells and 293S human embryonic kidney cells). Autoreactivity can also be investigated using evaluation of binding to tissues in tissue arrays.

[0180] K. Specific aspects In one embodiment, the heavy chain variable region (VH) includes the VHCDR1 amino acid sequence of GYX1FTX2YG (SEQ ID NO:214) where X1 is T, S, or I, and X2 is N or K; the VHCDR2 amino acid sequence of INTYTGEX1 (SEQ ID NO:215) where X1 is P, S, T, or A; and the VHCDR3 amino acid sequence of X1RYDHX2MDY (SEQ ID NO:216) where X1 is A, T, V, or G, and X2 is A, R, F, T, P, V, S, D, N, H, L, Y, or G; and / or the VLCDR1 amino acid sequence of QSLX1NSGTRKNY (SEQ ID NO:212) where X1 is L, F, or V, and SEQ ID This specification provides a monoclonal antibody or antibody fragment comprising a light chain variable region (VL) including the VLCDR2 amino acid sequence of NO:5 and the VLCDR3 amino acid sequence of KQSYX1LYT (SEQ ID NO:213), wherein X1 is T, N, or S.

[0181] In one embodiment, a monoclonal antibody or antibody fragment is provided herein, comprising a heavy chain variable region (VH) including a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 1 and 164-166, a VHCDR2 amino acid sequence selected from the group consisting of SEQ ID NO: 2 and 167-169, and a VHCDR3 amino acid sequence selected from the group consisting of SEQ ID NO: 3 and 170-185; and / or a light chain variable region (VL) including a VLCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 4 and 159-161, a VLCDR2 amino acid sequence of SEQ ID NO: 5, and a VLCDR3 amino acid sequence selected from the group consisting of SEQ ID NO: 6, 162, and 163.

[0182] In one embodiment, a monoclonal antibody or antibody fragment is provided herein, the antibody or antibody fragment comprising: (i) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (ii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (iii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (iv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (v) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (vi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:172; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (vii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (viii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:173; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (ix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (x) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:175; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (xii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:176; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:177; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:178; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:179; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:179; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:180; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xx) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:181; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (xxi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:182; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:181; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:185; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:169, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:160, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxx) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:175; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:169, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxix)A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xl)A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:178; and / or a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (xli)A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and / or a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (xlii)A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and / or a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xliii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xliv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; or (xlvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6.

[0183] In one embodiment, a monoclonal antibody or antibody fragment is provided herein, comprising a heavy chain variable region (VH) including a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 192-195, a VHCDR2 amino acid sequence selected from the group consisting of SEQ ID NO: 196-211, and a VHCDR3 amino acid sequence selected from the group consisting of SEQ ID NO: 3 and 170-185, and / or a light chain variable region (VL) including a VLCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 186-190, a VLCDR2 amino acid sequence of SEQ ID NO: 191, and a VLCDR3 amino acid sequence selected from the group consisting of SEQ ID NO: 6, 162, and 163.

[0184] In one embodiment, a monoclonal antibody or antibody fragment is provided herein, the antibody or antibody fragment comprising: (i) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:192, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (ii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:197, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (iii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (iv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:198, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (v) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (vi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (vii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (viii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:172; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (ix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:187, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (x) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:173; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:199, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:192, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:175; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:200, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:201, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:201, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:187, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:188, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (xviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:189, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:176; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xx) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:187, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:173; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:197, and the VHCDR3 amino acid sequence of SEQ ID NO:177; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:192, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:178; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:179; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:179; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:187, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:192, the VHCDR2 amino acid sequence of SEQ ID NO:202, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:180; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:201, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (xxix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:181; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (xxx) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:182; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (xxxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:181; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:203, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:194, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:185; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:189, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:195, the VHCDR2 amino acid sequence of SEQ ID NO:197, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:204, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:192, the VHCDR2 amino acid sequence of SEQ ID NO:205, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:206, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xl) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:194, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xli) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:207, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:190, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xliii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:206, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xliv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:175; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:189, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:202, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:207, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:195, the VHCDR2 amino acid sequence of SEQ ID NO:202, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:208, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (l) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:195, the VHCDR2 amino acid sequence of SEQ ID NO:209, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (i) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:209, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:187, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (lii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:195, the VHCDR2 amino acid sequence of SEQ ID NO:206, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (liii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:210, and the VHCDR3 amino acid sequence of SEQ ID NO:178; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (liv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 192, the VHCDR2 amino acid sequence of SEQ ID NO: 197, and the VHCDR3 amino acid sequence of SEQ ID NO: 170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 186, the VLCDR2 amino acid sequence of SEQ ID NO: 191, and the VLCDR3 amino acid sequence of SEQ ID NO: 162; (lv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 193, the VHCDR2 amino acid sequence of SEQ ID NO: 210, and the VHCDR3 amino acid sequence of SEQ ID NO: 174; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 188, the VLCDR2 amino acid sequence of SEQ ID NO: 191, and the VLCDR3 amino acid sequence of SEQ ID NO: 6; (lvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 195, the VHCDR2 amino acid sequence of SEQ ID NO: 196, and the VHCDR3 amino acid sequence of SEQ ID NO: 183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 187, the VLCDR2 amino acid sequence of SEQ ID NO: 191, and the VLCDR3 amino acid sequence of SEQ ID NO: 6; (lvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:209, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (lviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:188, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (lix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:194, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (lx) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 195, the VHCDR2 amino acid sequence of SEQ ID NO: 196, and the VHCDR3 amino acid sequence of SEQ ID NO: 183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 188, the VLCDR2 amino acid sequence of SEQ ID NO: 191, and the VLCDR3 amino acid sequence of SEQ ID NO: 6; (lxi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 192, the VHCDR2 amino acid sequence of SEQ ID NO: 211, and the VHCDR3 amino acid sequence of SEQ ID NO: 170; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 186, the VLCDR2 amino acid sequence of SEQ ID NO: 191, and the VLCDR3 amino acid sequence of SEQ ID NO: 6; (lxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:210, and the VHCDR3 amino acid sequence of SEQ ID NO:172; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:189, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (lxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:195, the VHCDR2 amino acid sequence of SEQ ID NO:196, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:187, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (lxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:194, the VHCDR2 amino acid sequence of SEQ ID NO:206, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:187, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (lxv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 193, the VHCDR2 amino acid sequence of SEQ ID NO: 208, and the VHCDR3 amino acid sequence of SEQ ID NO: 183; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 186, the VLCDR2 amino acid sequence of SEQ ID NO: 191, and the VLCDR3 amino acid sequence of SEQ ID NO: 6; (lxvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:199, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:187, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6; or (lxvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:193, the VHCDR2 amino acid sequence of SEQ ID NO:199, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and / or light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:186, the VLCDR2 amino acid sequence of SEQ ID NO:191, and the VLCDR3 amino acid sequence of SEQ ID NO:6.

[0185] In some aspects, the antibody or antibody fragment is A heavy-chain variable sequence having the sequence TIFF2026086489000006.tif19159, where X1 is Q or E, X2 is I or V, X3 is V or Q, X4 is Q or E, X5 is A, P or G, X6 is E or G, X7 is V or L, X8 is V or K, X9 is A, E, G or S, X 10 is V or L, X 11 is either K or R, and X 12 is V, L, or I, and X 13 is A or T, and X 14 is K or Q, and X 15 is E or K, X 16 is M or V, X 17 is F or V, X 18 is F, M, or I, X 19 is T or S, X 20 is T, R, or A, X 21 is T, D, or E, X 22 is T, A, or K, and X 23 is S or N, X 24 is L or A, X 25 It is M or L, X 26 is E or Q, X 27 It is L or M, X 28 is R, S, T, or N, and X 29 is S or G, X 30 is R, K, or M, X31 is S or T, X 32 It is either D or E, and X 33 The heavy chain variable sequence is L, S, or T. and / or A light chain variable sequence having the sequence TIFF2026086489000007.tif19159, wherein X1 is E or D, X2 is I or V, X3 is V or Q, X4 is L or M, X5 is D or S, X6 is A or S, X7 is V or A, X8 is L or V, X9 is E or D, X 10 is A or V, X 11 is N or T, X 12 is A or P, X 13 is Q or K, and X 14 is S, V, or P, X 15 is either K or R, and X 16 is D or S, X 17 is S, D, or N, X 18 is S or T, X 19 is A or P, X 20 is V or T, X 21 is Q or G, X 22 The light chain variable arrangement is L or V. Includes.

[0186] In some aspects, the antibody or antibody fragment is A heavy-chain variable sequence having the sequence TIFF2026086489000008.tif28159, where X1 is Q or H, X2 is A, D, T, V, S or P, X3 is T, S or I, X4 is N or K, X5 is P, S, T or A, X6 is T, R, K or I, X7 is A, T, V, S or G, X8 is S, R or T, X9 is A, V or G, X 10 is E or D, X 11 is L or V, X 12 is A, T, V or G, and X 13is A, R, F, T, P, V, S, D, N, H, L, Y or G, and X 14 is T or S, the heavy chain variable arrangement, and / or A light chain variable sequence having the sequence TIFF2026086489000009.tif21159, where X1 is A, T, or S, X2 is N or K, X3 is L, F, or V, X4 is A, S, or T, X5 is Q or K, X6 is A, P, or S, X7 is K or N, X8 is L, V, or I, X9 is G or A, X 10 is T or S, X 11 is S or R, X 12 is A or T, and X 13 is V, I, or L, and X 14 The variable light chain arrangement is T, N, or S. Includes.

[0187] In some aspects, the antibody or antibody fragment is a heavy chain variable sequence having a sequence selected from the group consisting of SEQ ID NO: 7, 12-17, 26-103 and 225-229, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with any one of SEQ ID NO: 7, 12-17, 26-103, and 225-229; and / or a light chain variable sequence having a sequence selected from the group consisting of SEQ ID NO: 8, 19-24, 105-157, and 230-234, or SEQ ID It includes a light chain variable sequence that has at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with any one of NO:8, 19-24, 105-157, and 230-234.

[0188] In some aspects, the antibody or antibody fragment includes the following: (i) A heavy chain variable sequence having the sequence described in SEQ ID NO:7, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:7; and / or a light chain variable sequence having the sequence described in SEQ ID NO:8, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:8; (ii) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and / or a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (iii) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and / or a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (iv) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and / or a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (v) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and / or a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (vi) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and / or a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (vii) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and / or a light chain variable sequence having the sequence described in SEQ ID NO:24, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:24; (viii) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and / or a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (ix) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and / or a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (x) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and / or a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (xi) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and / or a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (xii) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and / or a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (xiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and / or a light chain variable sequence having the sequence described in SEQ ID NO:24, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:24; (xiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and / or a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (xv) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and / or a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (xvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and / or a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (xvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and / or a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (xviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and / or a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (xix) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and / or a light chain variable sequence having the sequence described in SEQ ID NO:24, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:24; (xx) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and / or a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (xxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and / or a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (xxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and / or a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (xxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and / or a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (xxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and / or a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (xxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and / or a light chain variable sequence having the sequence described in SEQ ID NO:24, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:24; (xxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and / or a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (xxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and / or a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (xxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and / or a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (xxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and / or a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; A heavy chain variable sequence having the sequence described in (xxx)SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and / or a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (xxxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and / or a light chain variable sequence having the sequence described in SEQ ID NO:24, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:24; (xxxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:17, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:17; and / or a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (xxxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:17, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:17; and / or a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (xxxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:17, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:17; and / or a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (xxxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:17, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:17; and / or a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (xxxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:17, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:17; and / or a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (xxxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:17, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:17; and / or a light chain variable sequence having the sequence described in SEQ ID NO:24, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:24; (xxxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:26, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:26; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xxxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:27, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:27; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xl) A heavy chain variable sequence having the sequence described in SEQ ID NO:28, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:28; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xli) A heavy chain variable sequence having the sequence described in SEQ ID NO:29, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:29; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xlii) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and / or a light chain variable sequence having the sequence described in SEQ ID NO:106, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:106; (xliii) A heavy chain variable sequence having the sequence described in SEQ ID NO:31, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:31; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; A heavy chain variable sequence having the sequence described in (xliv)SEQ ID NO:32, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:32; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xlv) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and / or a light chain variable sequence having the sequence described in SEQ ID NO:107, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:107; (xlvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:33, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:33; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xlvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:34, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:34; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xlviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and / or a light chain variable sequence having the sequence described in SEQ ID NO:108, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:108; (xlix) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and / or a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (l) A heavy chain variable sequence having the sequence described in SEQ ID NO:35, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:35; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (i) A heavy chain variable sequence having the sequence described in SEQ ID NO:36, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:36; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lii) A heavy chain variable sequence having the sequence described in SEQ ID NO:37, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:37; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (liii) A heavy chain variable sequence having the sequence described in SEQ ID NO:26, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:26; and / or a light chain variable sequence having the sequence described in SEQ ID NO:107, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:107; (liv) A heavy chain variable sequence having the sequence described in SEQ ID NO:38, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:38; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lv) A heavy chain variable sequence having the sequence described in SEQ ID NO:31, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:31; and / or a light chain variable sequence having the sequence described in SEQ ID NO:110, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:110; (lvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:39, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:39; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:40, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:40; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:34, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:34; and / or a light chain variable sequence having the sequence described in SEQ ID NO:111, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:111; (lix) A heavy chain variable sequence having the sequence described in SEQ ID NO:41, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:41; and / or a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (lx) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and / or a light chain variable sequence having the sequence described in SEQ ID NO:112, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:112; (lxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:28, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:28; and / or a light chain variable sequence having the sequence described in SEQ ID NO:113, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:113; or (lxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:32, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:32; and / or a light chain variable sequence having the sequence described in SEQ ID NO:114, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:114; (lxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:42, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:42; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:36, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:36; and / or a light chain variable sequence having the sequence described in SEQ ID NO:115, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:115; (lxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:43, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:43; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:32, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:32; and / or a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (lxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:44, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:44; and / or a light chain variable sequence having the sequence described in SEQ ID NO:116, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:116; (lxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:35, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:35; and / or a light chain variable sequence having the sequence described in SEQ ID NO:117, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:117; (lxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:45, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:45; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; A heavy chain variable sequence having the sequence described in (lxx)SEQ ID NO:46, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:46; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; A heavy chain variable sequence having the sequence described in (lxxi)SEQ ID NO:36, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:36; and / or a light chain variable sequence having the sequence described in SEQ ID NO:118, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:118; (lxxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:47, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:47; and / or a light chain variable sequence having the sequence described in SEQ ID NO:115, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:115; (lxxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:48, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:48; and / or a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (lxxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:49, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:49; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lxxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:50, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:50; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lxxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:51, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:51; and / or a light chain variable sequence having the sequence described in SEQ ID NO:106, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:106; (lxxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:52, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:52; and / or a light chain variable sequence having the sequence described in SEQ ID NO:119, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:119; (lxxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:53, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:53; and / or a light chain variable sequence having the sequence described in SEQ ID NO:108, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:108; (lxxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:54, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:54; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; A heavy chain variable sequence having the sequence described in (lxxx)SEQ ID NO:55, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:55; and / or a light chain variable sequence having the sequence described in SEQ ID NO:116, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:116; (lxxxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:56, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:56; and / or a light chain variable sequence having the sequence described in SEQ ID NO:116, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:116; (lxxxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:57, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:57; and / or a light chain variable sequence having the sequence described in SEQ ID NO:120, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:120; (lxxxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:58, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:58; and / or a light chain variable sequence having the sequence described in SEQ ID NO:121, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:121; (lxxxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:59, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:59; and / or a light chain variable sequence having the sequence described in SEQ ID NO:122, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:122; A heavy chain variable sequence having the sequence described in (lxxxv)SEQ ID NO:60, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:60; and / or a light chain variable sequence having the sequence described in SEQ ID NO:108, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:108; (lxxxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:61, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:61; and / or a light chain variable sequence having the sequence described in SEQ ID NO:123, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:123; (lxxxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:62, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:62; and / or a light chain variable sequence having the sequence described in SEQ ID NO:114, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:114; (lxxxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:63, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:63; and / or a light chain variable sequence having the sequence described in SEQ ID NO:124, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:124; (lxxxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:64, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:64; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xc) A heavy chain variable sequence having the sequence described in SEQ ID NO:65, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:65; and / or a light chain variable sequence having the sequence described in SEQ ID NO:125, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:125; (xci) A heavy chain variable sequence having the sequence described in SEQ ID NO:66, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:66; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xcii) A heavy chain variable sequence having the sequence described in SEQ ID NO:67, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:67; and / or a light chain variable sequence having the sequence described in SEQ ID NO:125, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:125; (xciii) A heavy chain variable sequence having the sequence described in SEQ ID NO:68, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:68; and / or a light chain variable sequence having the sequence described in SEQ ID NO:126, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:126; A heavy chain variable sequence having the sequence described in (xciv)SEQ ID NO:69, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:69; and / or a light chain variable sequence having the sequence described in SEQ ID NO:127, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:127; A heavy chain variable sequence having the sequence described in (xcv)SEQ ID NO:70, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:70; and / or a light chain variable sequence having the sequence described in SEQ ID NO:128, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:128; (xcvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:71, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:71; and / or a light chain variable sequence having the sequence described in SEQ ID NO:117, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:117; (xcvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:72, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:72; and / or a light chain variable sequence having the sequence described in SEQ ID NO:129, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:129; (xcviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:73, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:73; and / or a light chain variable sequence having the sequence described in SEQ ID NO:130, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:130; A heavy chain variable sequence having the sequence described in (xcix)SEQ ID NO:74, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:74; and / or a light chain variable sequence having the sequence described in SEQ ID NO:131, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:131; (c) A heavy chain variable sequence having the sequence described in SEQ ID NO:73, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:73; and / or a light chain variable sequence having the sequence described in SEQ ID NO:132, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:132; (ci) A heavy chain variable sequence having the sequence described in SEQ ID NO:75, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:75; and / or a light chain variable sequence having the sequence described in SEQ ID NO:133, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:133; (cii) A heavy chain variable sequence having the sequence described in SEQ ID NO:76, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:76; and / or a light chain variable sequence having the sequence described in SEQ ID NO:134, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:134; (ciii) A heavy chain variable sequence having the sequence described in SEQ ID NO:77, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:77; and / or a light chain variable sequence having the sequence described in SEQ ID NO:107, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:107; A heavy chain variable sequence having the sequence described in (civ)SEQ ID NO:78, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:78; and / or a light chain variable sequence having the sequence described in SEQ ID NO:135, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:135; (cv) A heavy chain variable sequence having the sequence described in SEQ ID NO:79, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:79; and / or a light chain variable sequence having the sequence described in SEQ ID NO:136, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:136; (cvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:80, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:80; and / or a light chain variable sequence having the sequence described in SEQ ID NO:137, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:137; (cvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:41, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:41; and / or a light chain variable sequence having the sequence described in SEQ ID NO:138, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:138; (cviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:81, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:31; and / or a light chain variable sequence having the sequence described in SEQ ID NO:139, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:139; (cix) A heavy chain variable sequence having the sequence described in SEQ ID NO:82, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:82; and / or a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (cx) A heavy chain variable sequence having the sequence described in SEQ ID NO:83, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:83; and / or a light chain variable sequence having the sequence described in SEQ ID NO:126, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:126; (cxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:84, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:84; and / or a light chain variable sequence having the sequence described in SEQ ID NO:140, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:140; (cxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:85, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:85; and / or a light chain variable sequence having the sequence described in SEQ ID NO:141, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:141; (cxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:86, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:86; and / or a light chain variable sequence having the sequence described in SEQ ID NO:141, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:141; (cxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:87, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:87; and / or a light chain variable sequence having the sequence described in SEQ ID NO:117, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:117; (cxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:88, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:88; and / or a light chain variable sequence having the sequence described in SEQ ID NO:142, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:142; (cxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:89, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:89; and / or a light chain variable sequence having the sequence described in SEQ ID NO:143, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:143; (cxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:90, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:90; and / or a light chain variable sequence having the sequence described in SEQ ID NO:144, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:144; (cxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:91, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:91; and / or a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (cxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:92, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:92; and / or a light chain variable sequence having the sequence described in SEQ ID NO:145, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:145; A heavy chain variable sequence having the sequence described in (cxx)SEQ ID NO:93, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:93; and / or a light chain variable sequence having the sequence described in SEQ ID NO:146, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:146; A heavy chain variable sequence having the sequence described in (cxxi)SEQ ID NO:94, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:94; and / or a light chain variable sequence having the sequence described in SEQ ID NO:147, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:147; (cxxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:95, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:95; and / or a light chain variable sequence having the sequence described in SEQ ID NO:148, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:148; (cxxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:96, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:96; and / or a light chain variable sequence having the sequence described in SEQ ID NO:149, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:149; (cxxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:97, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:97; and / or a light chain variable sequence having the sequence described in SEQ ID NO:150, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:150; A heavy chain variable sequence having the sequence described in (cxxv)SEQ ID NO:98, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:98; and / or a light chain variable sequence having the sequence described in SEQ ID NO:151, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:151; (cxxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:99, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:99; and / or a light chain variable sequence having the sequence described in SEQ ID NO:152, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:152; (cxxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:100, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:100; and / or a light chain variable sequence having the sequence described in SEQ ID NO:136, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:136; (cxxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:91, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:91; and / or a light chain variable sequence having the sequence described in SEQ ID NO:153, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:153; (cxxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:101, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:101; and / or a light chain variable sequence having the sequence described in SEQ ID NO:154, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:154; A heavy chain variable sequence having the sequence described in (cxxx)SEQ ID NO:102, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:102; and / or a light chain variable sequence having the sequence described in SEQ ID NO:155, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:155; (cxxxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:36, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:36; and / or a light chain variable sequence having the sequence described in SEQ ID NO:156, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:156; or (cxxxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:103, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:103; and / or a light chain variable sequence having the sequence described in SEQ ID NO:157, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:157.

[0189] In one embodiment, a monoclonal antibody or antibody fragment is provided herein that competes for binding to the same epitope on HSP70 as any one of the antibodies or antibody fragments of this embodiment. In one embodiment, a monoclonal antibody or antibody fragment is provided herein that binds to or can bind to an epitope on HSP70 recognized by any one of the antibodies or antibody fragments of this embodiment.

[0190] In one embodiment, a monoclonal antibody or antibody fragment is provided herein that binds to an epitope of HSP70 defined by a peptide corresponding to K573-Q601 of SEQ ID NO:11. In some aspects, when bound to HSP70, the monoclonal antibody or antibody fragment binds to one or two of the following residues: H594, K595, and Q601 of SEQ ID NO:11. In some aspects, when bound to HSP70, the monoclonal antibody or antibody fragment binds to all of the following residues: H594, K595, and Q601 of SEQ ID NO:11. In some aspects, when bound to HSP70, the monoclonal antibody or antibody fragment further binds to at least one of the following residues: K573, E576, W580, R596, and E598 of SEQ ID NO:11. In some cases, when bound to HSP70, the monoclonal antibody or antibody fragment further binds to at least two, three, four, or five of the following residues: K573, E576, W580, R596, and E598 of SEQ ID NO: 11. In some cases, when bound to HSP70, the monoclonal antibody or antibody fragment binds to all of the following residues: K573, E576, W580, H594, K595, R596, E598, and Q601 of SEQ ID NO: 11.

[0191] In some aspect of this embodiment, the antibody binds to or can bind to HSP70. In some aspect of this embodiment, the antibody binds to or can bind to HSP70 in an ADP-conjugated form. In some aspect of this embodiment, the antibody binds to or can bind to HSP70 in a peptide-conjugated form. In some aspect of this embodiment, the antibody binds to or can bind to HSP70 in both ADP-conjugated and peptide-conjugated forms. In some aspect of this embodiment, the antibody does not induce antibody-dependent cell-mediated cytotoxicity. In some aspect of this embodiment, the antibody does not induce complement-dependent cell-mediated cytotoxicity. In some aspect of this embodiment, the antibody enhances HSP70 uptake by immune effector cells, such as monocytes / macrophages and dendritic cells. In some aspect, uptake is mediated by human FcγR2A and / or human FcγR2B.

[0192] In some aspects, the antibody binds to or can bind to HSP70. In some aspects, the antibody, when measured by Octet Biolayer Interferometry (BLI) analysis, is approximately 20, approximately 10, approximately 9, approximately 8, approximately 7, approximately 6, approximately 5, approximately 4, approximately 3, approximately 2, approximately 1, approximately 0.9, approximately 0.85, approximately 0.8, approximately 0.75, approximately 0.7, approximately 0.6, approximately 0.5, approximately 0.1, approximately 0.05 nM or 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.85, 0.8, 0.75, 0.7, 0.6, 0.5, 0.1, or less than 0.05 pM K DIt binds to human HSP70 (e.g., HSP70 in ADP-bound and / or peptide-bound forms). In several aspects, when measured by Octet Biolayer Interferometry (BLI) analysis, antibodies were found to be approximately 20 nM to 0.05 nM, 20 nM to 0.075 nM, 20 nM to 0.1 nM, 20 nM to 0.5 nM, 20 nM to 1 nM, 10 nM to 0.05 nM, 10 nM to 0.075 nM, 10 nM to 0.1 nM, 10 nM to 0.5 nM, 10 nM to 1 nM, 5 nM to 0.05 nM, 5 nM to 0.075 nM, 5 nM to 0.1 nM, 5 nM to 0.5 nM, 5 nM to 1 nM, 3 nM to 0.05 nM, and 3 nM. ~about 0.075nM, about 3nM to about 0.1nM, about 3nM to about 0.5nM, about 3nM to about 1nM, about 3nM to about 2nM, about 2nM to about 0.05n M, about 2nM to about 0.075nM, about 2nM to about 0.1nM, about 2nM to about 0.5nM, about 2nM to about 1nM, about 1nM to about 0.05nM, about 1n M ~ about 0.075nM, about 1nM to about 0.1nM, about 1nM to about 0.5nM, about 0.5nM to about 0.05nM, about 0.5nM to about 0.075nM , about 0.5nM to about 0.1nM, about 0.1nM to about 0.05nM, about 0.1nM to about 0.075nM or about 0.075nM to about 0.05nM DIt then binds to human HSP70 (for example, HSP70 in the form of ADP-bound and / or peptide-bound HSP70). In several aspects, when measured by Octet Biolayer Interference (BLI) analysis, the antibody levels were approximately 20 pM to 0.05 pM, 20 pM to 0.075 pM, 20 pM to 0.1 pM, 20 pM to 0.5 pM, 20 pM to 1 pM, 10 pM to 0.05 pM, 10 pM to 0.075 pM, 10 pM to 0.1 pM, 10 pM to 0.5 pM, 10 pM to 1 pM, 5 pM to 0.05 pM, 5 pM to 0.075 pM, 5 pM to 0.1 pM, 5 pM to 0.5 pM, 5 pM to 1 pM, 3 pM to 0.05 pM, and 3 pM. ~about 0.075pM, about 3pM to about 0.1pM, about 3pM to about 0.5pM, about 3pM to about 1pM, about 3pM to about 2pM, about 2pM to about 0.05p M, about 2pM to about 0.075pM, about 2pM to about 0.1pM, about 2pM to about 0.5pM, about 2pM to about 1pM, about 1pM to about 0.05pM, about 1p K in the ranges of M ~ approximately 0.075 pM, approximately 1 pM ~ approximately 0.1 pM, approximately 1 pM ~ approximately 0.5 pM, approximately 0.5 pM ~ approximately 0.05 pM, approximately 0.5 pM ~ approximately 0.075 pM, approximately 0.5 pM ~ approximately 0.1 pM, approximately 0.1 pM ~ approximately 0.05 pM, approximately 0.1 pM ~ approximately 0.075 pM, or approximately 0.075 pM ~ approximately 0.05 pM D It then binds to human HSP70 (for example, HSP70 in the form of ADP-bound and / or peptide-bound HSP70).

[0193] In some aspects, it is assumed that any one VH sequence or any variant of a heavy chain variable region sequence, e.g., SEQ ID NO: 7, 12-17 and 26-103, can be covalently bound to various heavy chain constant region sequences known in the art. Similarly, it is assumed that any one VL sequence or any variant of a light chain variable region sequence, e.g., SEQ ID NO: 8, 19-24 and 105-157, can be covalently bound to various light chain constant region sequences known in the art.

[0194] For example, an antibody or antibody fragment may have a heavy chain constant region selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE, and in particular, a heavy chain constant region selected from, for example, the (e.g., human) heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In another embodiment, an antibody or antibody fragment may have a light chain constant region selected from, for example, the (e.g., human) light chain constant regions of kappa or lambda. The constant region may be altered, for example, mutated, to modify the properties of the antibody or antibody fragment (e.g., to increase or decrease one or more of the Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, and / or complement function). In one embodiment, the antibody or antibody fragment has effector function and can immobilize complement. In other embodiments, the antibody or antibody fragment does not recruit effector cells or immobilize complement. In another embodiment, the antibody or antibody fragment has reduced ability to bind to the Fc receptor or does not have the ability to bind to the Fc receptor. For example, the antibody or antibody fragment is an isotype or subtype, fragment or other variant that does not support binding to the Fc receptor, and for example, the antibody or antibody fragment has a mutagenerated or deleted Fc receptor binding region.

[0195] In some aspects, the constant region of the heavy chain of the antibody or antibody fragment is the human IgG1 isotype, and the amino acid sequence is: It has TIFF2026086489000010.tif41153.

[0196] In some cases, the constant region of human IgG1 is modified at amino acid Asn297 (boxed in SEQ ID NO:217 in the previous paragraph) to prevent antibody glycosylation (e.g., Asn297Ala(N297A)). In some cases, the constant region of the antibody is modified at amino acid Leu235 (boxed in SEQ ID NO:217 in the previous paragraph) to alter the Fc receptor interaction (e.g., Leu235Glu(L235E) or Leu235Ala(L235A)). In some cases, the constant region of the antibody is modified at amino acid Leu234 (boxed in SEQ ID NO:217 in the previous paragraph) to alter the Fc receptor interaction (e.g., Leu234Ala(L234A)). In some cases, the constant region of the antibody is modified at amino acid Glu233 (boxed in SEQ ID NO:217 in the previous paragraph) (e.g., Glu233Pro (E233P)). In some cases, the constant region of the antibody is altered at both amino acids 234 and 235, e.g., Leu234Ala and Leu235Ala (L234A / L235A). In some cases, the constant region of the antibody is altered at amino acids 233, 234, and 234, e.g., Glu233Pro, Leu234Ala, and Leu235Ala (E233P L234A / L235A) (Armour KL. et al. (1999) Eur.J.Immunol.29(8):2613-24). All residue numbers follow EU numbering (Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242).

[0197] In some aspects, the constant region of the antibody heavy chain is the human IgG1 isotype, and its amino acid sequence is: It has TIFF2026086489000011.tif41153.

[0198] In some cases, the constant region of human IgG1 is modified at amino acid Asn297 (boxed in SEQ ID NO:218 in the previous paragraph) to inhibit antibody glycosylation (e.g., Asn297Ala(N297A)). In some cases, the constant region of the antibody is modified at amino acid Leu235 (boxed in SEQ ID NO:218 in the previous paragraph) to alter the Fc receptor interaction (e.g., Leu235Glu(L235E) or Leu235Ala(L235A)). In some cases, the constant region of the antibody is modified at amino acid Leu234 (boxed in SEQ ID NO:218 in the previous paragraph) to alter the Fc receptor interaction (e.g., Leu234Ala(L234A)). In some cases, the constant region of the antibody is modified at amino acid Glu233 (boxed in SEQ ID NO:218 in the previous paragraph) (e.g., Glu233Pro (E233P)). In some cases, the constant region of the antibody is altered at both amino acids 234 and 235, e.g., Leu234Ala and Leu235Ala (L234A / L235A). In some cases, the constant region of the antibody is altered at amino acids 233, 234, and 234, e.g., Glu233Pro, Leu234Ala, and Leu235Ala (E233P L234A / L235A) (Armour KL. et al. (1999) Eur.J.Immunol.29(8):2613-24). All residue numbers follow EU numbering (Kabat, EA, et al., previously mentioned).

[0199] In some aspects, the human IgG1 constant region has been modified to include either a "knob" mutation, e.g., T366Y, or a "hole" mutation, e.g., Y407T, for heterodimerization with a second constant region (residue number according to EU numbering (Kabat, EA, et al., cited above)).

[0200] In some aspects, the constant region of the antibody heavy chain is a human IgG1 isotype, such as an allotype of a human IgG1 isotype, such as IgG1 G1m3 allotype. Exemplary human IgG1 allotypes are described in Magdelaine-Beuzelin et al., (2009) Pharmacogenet. Genomics 19(5):383-7.

[0201] In some aspects, the constant region of the antibody heavy chain is the human IgG2 isotype, and its amino acid sequence is: It has TIFF2026086489000012.tif41153.

[0202] In some aspects, the constant region of human IgG2 is modified at amino acid Asn297 (boxed in SEQ ID NO:219 in the previous paragraph) to prevent antibody glycosylation (e.g., Asn297Ala(N297A)), and the residue number follows EU numbering (Kabat, EA, et al., cited above).

[0203] In some aspects, the constant region of the antibody heavy chain is the human IgG3 isotype, and its amino acid sequence is: It has TIFF2026086489000013.tif48153.

[0204] In some cases, the human IgG3 constant region is modified at amino acid Asn297 (boxed in SEQ ID NO:220 in the previous paragraph) to prevent antibody glycosylation (e.g., Asn297Ala(N297A)). In some cases, the human IgG3 constant region is modified at amino acid Arg435 (boxed in SEQ ID NO:220 in the previous paragraph) to extend the half-life (e.g., Arg435H(R435H)). All residue numbers follow EU numbering (Kabat, EA, et al., previously mentioned).

[0205] In some aspects, the constant region of the antibody heavy chain is the human IgG4 isotype, and its amino acid sequence is: It has TIFF2026086489000014.tif41154.

[0206] In some aspects, the human IgG4 constant region is modified within the hinge region to prevent or reduce chain exchange; for example, in some aspects, the human IgG4 constant region is modified at Ser228 (boxed in SEQ ID NO:221 in the previous paragraph) (e.g., Ser228Pro (S228P)). In other aspects, the human IgG4 constant region is modified at the amino acid Leu235 (boxed in SEQ ID NO:221 in the previous paragraph) to alter the Fc receptor interaction (e.g., Leu235Glu (L235E)). In some aspects, the human IgG4 constant region is modified at both Ser228 and Leu335 (e.g., Ser228Pro and Leu235Glu (S228P / L235E)). In some aspects, the constant region of human IgG4 is modified at amino acid Asn297 (boxed in SEQ ID NO:221 in the previous paragraph) to prevent antibody glycosylation (e.g., Asn297Ala(N297A)). All residue numbers follow EU numbering (Kabat, EA, et al., cited above).

[0207] In some aspects, the constant region of human IgG is modified to enhance FcRn binding. Examples of Fc mutations that enhance FcRn binding include Met252Tyr, Ser254Thr, and Thr256Glu (M252Y, S254T, and T256E, respectively) (Dall'Acqua et al. (2006) J. Biol. Chem. 281(33):23514-23524), or Met428Leu and Asn434Ser (M428L, N434S) (Zalevsky et al. (2010) Nature Biotech. 28(2):157-159). All residue numbers follow EU numbering (Kabat, EA, et al., previously cited).

[0208] In several aspects, the constant region of human IgG has been modified to alter antibody-dependent cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), e.g., Natsume et al. (2008) Cancer Res. 68(10):3863-72; Idusogie et al. (2001) J.Immunol. 166(4):2571-5; Moore et al. (2010) mAbs 2(2):181-189; Lazar et al. (2006) Proc.Natl.Acad.Sci.USA 103(11):4005-4010; Shields et al. (2001) J.Biol.Chem. 276(9):6591-6604; Stavenhagen et al. (2007) Cancer Res. The amino acid modifications described in 67(18):8882-8890; Stavenhagen et al. (2008) Advan. Enzyme Regul. 48:152-164; and Alegre et al. (1992) J. Immunol. 148:3461-3468.

[0209] In several aspects, the constant region of human IgG is modified to induce heterodimerization. For example, a heavy chain having an amino acid modification at Thr366 within the CH3 domain, e.g., substitution with a bulkier amino acid, e.g., Tyr (T366W), can preferentially pair with a second heavy chain having a CH3 domain with amino acid modifications at positions Thr366, Leu368, and Tyr407, e.g., to less bulkier amino acids, e.g., Ser, Ala, and Val (T366S / L368A / Y407V), respectively. Heterodimerization via CH3 modification can be further stabilized by introducing disulfide bonds, for example, by changing Ser354 to Cys (S354C) and Y349 to Cys (Y349C) on the opposing CH3 domain (Carter (2001) J. Immunol. Methods 248:7-15).

[0210] In some aspects, the constant region of the antibody light chain is the human κ constant region, for example, the amino acid sequence: This is a human κ constant region containing TIFF2026086489000015.tif12157.

[0211] In some aspects, the constant region of the antibody light chain is the human κ constant region, for example, the amino acid sequence: This is a human κ-constant region containing TIFF2026086489000016.tif12158.

[0212] In some aspects, the constant region of the antibody light chain is the human λ constant region, for example, the amino acid sequence: This is a human λ constant region containing TIFF2026086489000017.tif12157.

[0213] III. Chimeric Antigen Receptors Chimeric antigen receptor (CAR) molecules are recombinant fusion proteins distinguished by both their ability to bind to antigens and their ability to transmit activation signals via an immune receptor activation motif (ITAM) present in the cytoplasmic tail of the CAR molecule, thereby activating genetically modified immune effector cells for killing, proliferating, and cytokine production. Receptor constructs that utilize the antigen-binding moiety (e.g., generated from a single-chain antibody (scFv)) offer the further advantage of being "universal" in that they bind to native antigens on the surface of target cells in an HLA-independent manner.

[0214] Embodiments of CARs described herein include nucleic acids encoding antigen-specific CAR polypeptides comprising an intracellular signaling domain, a transmembrane domain, and an extracellular domain including an antigen-binding domain. CARs may recognize epitopes consisting of spaces shared between one or more antigens. Optionally, CARs may include a hinge domain positioned between the transmembrane domain and the antigen-binding domain. CARs may further include a signal peptide that directs CAR expression toward the cell surface. For example, CARs may include a signal peptide derived from GM-CSF. To improve persistence, CARs may also be co-expressed with membrane-bound cytokines. For example, CARs may be co-expressed with membrane-bound IL-15.

[0215] Depending on the arrangement of the CAR domain and the specific sequences used within the domain, immune effector cells expressing the CAR may have different levels of activity against target cells. Different CAR sequences may be introduced into immune effector cells to generate engineered cells, engineered cells selected for elevated SRCs, and selected cells tested for activity to identify the CAR construct predicted to have the greatest therapeutic efficacy.

[0216] Chimeric antigen receptors can be prepared by any means known in the art, but are preferably prepared using recombinant DNA technology. Nucleic acid sequences encoding several regions of the chimeric antigen receptor can be prepared by standard molecular cloning techniques (e.g., genomic library screening, PCR, primer-assisted ligation, scFv libraries from yeast and bacteria, site-directed mutagenesis) and assembled into a complete coding sequence. The resulting coding region can be inserted into an expression vector and used to transform suitable expression host allogenes or autoimmune effector cells, such as T cells or NK cells.

[0217] Chimeric constructs can be introduced into immunoeffector cells as naked DNA or in a suitable vector. Methods for stably transposing cells by electroporation using naked DNA are known in the art. See, for example, U.S. Patent No. 6,410,319. Naked DNA generally refers to DNA encoding a chimeric receptor contained in a plasmid expression vector in an orientation suitable for expression. Alternatively, viral vectors (e.g., retroviral vectors, adenovirus vectors, adeno-associated virus vectors, or lentiviral vectors) can be used to introduce chimeric constructs into immunoeffector cells. Suitable vectors for use according to the methods of the present invention are non-replicating in immunoeffector cells. Numerous virus-based vectors are known, such as HIV, SV40, EBV, HSV, or BPV-based vectors, in which the number of viral copies maintained in the cell is low enough to maintain cell survival.

[0218] A. Antigen-binding domain The antigen-binding domain may include the complementarity-determining region of a monoclonal antibody, the variable region of a monoclonal antibody, and / or its antigen-binding fragment. The antigen-binding region or domain may include fragments of the VH and VL chains of a single-chain variable fragment (scFv) derived from a particular mouse monoclonal antibody, human monoclonal antibody, or humanized monoclonal antibody. The fragment may also be any number of different antigen-binding domains of an antigen-specific antibody. The fragment may be an antigen-specific scFv encoded by a sequence optimized for human codon use for expression in human cells. In certain contexts, the VH and VL domains of a CAR are separated by a linker sequence such as a Whitlow linker.

[0219] The prototype CAR encodes an scFv containing VH and VL domains derived from a single monoclonal antibody (mAb), which are bound to a transmembrane domain and one or more cytoplasmic signaling domains (e.g., a costimulatory domain and a signaling domain). Thus, the CAR may contain LCDR1-3 and HCDR1-3 sequences of an antibody that binds to HSP70. However, in a further context, two or more antibodies that bind to an antigen of interest are identified, and a CAR is constructed containing (1) the HCDR1-3 sequences of a first antibody that binds to the antigen and (2) the LCDR1-3 sequences of a second antibody that binds to the antigen. Such a CAR containing HCDR and LCDR sequences derived from two different antigen-binding antibodies may have the advantage of preferential binding to a specific conformation of the antigen (e.g., a conformation preferentially associated with cancer cells compared to normal tissue).

[0220] Alternatively, the CAR may be manipulated using VH and VL chains derived from different mAbs to generate a panel of CAR+ immunoeffector cells. The antigen-binding domain of the CAR may contain any combination of the LCDR1-3 sequences of the first antibody and the HCDR1-3 sequences of the second antibody.

[0221] B. Hinged Domain CAR polypeptides may contain a hinge domain located between the antigen-binding domain and the transmembrane domain. In some cases, the hinge domain may be included in the CAR polypeptide to provide sufficient distance between the antigen-binding domain and the cell surface, or to mitigate steric interference that could adversely affect antigen binding or effector function in CAR-modified immunoeffector cells. The hinge domain may contain sequences that bind to Fc receptors, such as FcγR2a or FcγR1a. For example, the hinge sequence may contain an Fc domain derived from a human immunoglobulin (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD, or IgE) that binds to the Fc receptor.

[0222] The CAR hinge domain may originate from the human immunoglobulin (Ig) constant region or a portion thereof including the Ig hinge, or from the human CD8α transmembrane domain and CD8a hinge region. The CAR hinge domain may contain the hinge-CH2-CH3 region of antibody isotype IgG4. The hinge domain (and / or CAR) does not necessarily contain wild-type human IgG4 CH2 and CH3 sequences. Point mutations may be introduced into the antibody heavy chain CH2 domain to reduce glycosylation and nonspecific Fcγ receptor binding in CAR-modified immunoeffector cells.

[0223] A CAR hinge domain may contain an IgFc domain with at least one mutation compared to a wild-type IgFc domain that reduces Fc receptor binding. For example, a CAR hinge domain may contain an IgG4-Fc domain with at least one mutation compared to a wild-type IgG4-Fc domain that reduces Fc receptor binding. A CAR hinge domain may contain an IgG4-Fc domain having a mutation (such as an amino acid deletion or substitution) at the position correspondi...

Claims

1. GYX 1 FTX 2 The VHCDR1 amino acid sequence of YG (SEQ ID NO:214), where X 1 is T, S or I, and X 2 is N or K, the VHCDR1 amino acid sequence, and INTYTGEX 1 The VHCDR2 amino acid sequence of (SEQ ID NO:215), where X 1 is P, S, T or A, the VHCDR2 amino acid sequence, and X 1 RYDHX 2 The VHCDR3 amino acid sequence of MDY (SEQ ID NO:216), where X 1 is A, T, V or G, and X 2 is A, R, F, T, P, V, S, D, N, H, L, Y or G, the VHCDR3 amino acid sequence; and QSLX 1 The VLCDR1 amino acid sequence of NSGTRKNY (SEQ ID NO:212), where X 1 is L, F or V, the VLCDR1 amino acid sequence, and the VLCDR2 amino acid sequence of SEQ ID NO:5, and KQSYX 1 The VLCDR3 amino acid sequence of LYT (SEQ ID NO:213), where X 1 is T, N or S, the VLCDR3 amino acid sequence, a monoclonal antibody or antibody fragment.

2. (i) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (ii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (iii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (iv) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (v) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (vi) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:172; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (vii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (viii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:173; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (ix) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (x) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:175; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (xii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:176; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xiii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:177; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:178; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvi) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:179; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:179; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:180; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xx) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:181; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (xxi) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:182; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:181; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:185; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:169, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:160, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxx) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxi) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:175; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:169, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxvi) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxvii) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxviii) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxix) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xl) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:178; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (xli) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (xlii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xliii) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xliv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; or (xlvi) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:

6. A monoclonal antibody or antibody fragment according to claim 1, comprising:

3. A monoclonal antibody or antibody fragment according to claim 1 or 2, comprising: a heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:

6.

4. Here, X 1 is Q or E, and X 2 is I or V, X 3 is V or Q, and X 4 is Q or E, and X 5 is A, P, or G, and X 6 is E or G, X 7 is V or L, X 8 is V or K, and X 9 is A, E, G or S, and X 10 is V or L, X 11 is K or R, X 12 is V, L, or I, and X 13 is A or T, and X 14 is K or Q, and X 15 is E or K, and X 16 is M or V, X 17 is F or V, X 18 is F, M or I, X 19 is T or S, X 20 is T, R, or A, X 21 is T, D, or E, and X 22 is T, A or K, and X 23 is S or N, X 24 is L or A, X 25 is M or L, X 26 is E or Q, and X 27 is L or M, X 28 is R, S, T or N, and X 29 is S or G, X 30 is R, K or M, X 31 is S or T, X 32 is D or E, X 33 is L, S, or T; and A light chain variable sequence having the sequence X 1 is E or D, X 2 is I or V, X 3 is V or Q, and X 4 is L or M, X 5 is D or S, X 6 is A or S, X 7 is V or A, X 8 is L or V, X 9 is E or D, X 10 is A or V, and X 11 is N or T, X 12 is A or P, X 13 is Q or K, and X 14 is S, V or P, X 15 is K or R, X 16 is D or S, X 17 is S, D, or N, X 18 is S or T, X 19 is A or P, X 20 is V or T, X 21 is Q or G, X 22 The light chain variable arrangement is L or V. A monoclonal antibody or antibody fragment according to any one of claims 1 to 3, comprising:

5. (i) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (ii) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (iii) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (iv) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (v) A heavy chain variable sequence having the sequence described in SEQ ID NO:12, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:12; and a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (vi) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (vii) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (viii) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (ix) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (x) A heavy chain variable sequence having the sequence described in SEQ ID NO:13, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:13; and a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (xi) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (xii) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (xiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (xiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (xv) A heavy chain variable sequence having the sequence described in SEQ ID NO:14, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:14; and a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (xvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (xvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (xviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (xix) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; (xx) A heavy chain variable sequence having the sequence described in SEQ ID NO:15, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:15; and a light chain variable sequence having the sequence described in SEQ ID NO:23, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:23; (xxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and a light chain variable sequence having the sequence described in SEQ ID NO:19, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:19; (xxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and a light chain variable sequence having the sequence described in SEQ ID NO:20, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:20; (xxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and a light chain variable sequence having the sequence described in SEQ ID NO:21, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:21; (xxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:16, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and a light chain variable sequence having the sequence described in SEQ ID NO:22, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:22; or (xxv) Heavy chain variable sequences having the sequence described in SEQ ID NO:16, or heavy chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:16; and light chain variable sequences having the sequence described in SEQ ID NO:23, or light chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:

23. A monoclonal antibody or antibody fragment according to claim 4, comprising: A heavy chain variable sequence having the sequence of

6. , wherein X 1 is Q or H, and X 2 is A, D, T, V, S or P, X 3 is T, S or I, and X 4 is N or K, and X 5 is P, S, T or A, X 6 is T, R, K or I, X 7 is A, T, V, S or G, X 8 is S, R, or T, X 9 is A, V, or G, and X 10 is E or D, X 11 is L or V, X 12 is A, T, V or G, and X 13 is A, R, F, T, P, V, S, D, N, H, L, Y or G, X 14 The heavy chain variable array is T or S; and A light chain variable array having the array of X 1 is A, T or S, and X 2 is N or K, and X 3 is L, F or V, and X 4 is A, S or T, and X 5 is Q or K, and X 6 is A, P or S, and X 7 is K or N, and X 8 is L, V or I, and X 9 is G or A, and X 10 is T or S, and X 11 is S or R, and X 12 is A or T, and X 13 is V, I or L, and X 14 is T, N or S, the said light chain variable array A monoclonal antibody or antibody fragment according to any one of claims 1 to 3, comprising:

7. (i) A heavy chain variable sequence having the sequence described in SEQ ID NO:26, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:26; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (ii) A heavy chain variable sequence having the sequence described in SEQ ID NO:27, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:27; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (iii) A heavy chain variable sequence having the sequence described in SEQ ID NO:28, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:28; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (iv) A heavy chain variable sequence having the sequence described in SEQ ID NO:29, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:29; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (v) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and a light chain variable sequence having the sequence described in SEQ ID NO:106, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:106; (vi) A heavy chain variable sequence having the sequence described in SEQ ID NO:31, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:31; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (vii) A heavy chain variable sequence having the sequence described in SEQ ID NO:32, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:32; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (viii) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and a light chain variable sequence having the sequence described in SEQ ID NO:107, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:107; (ix) A heavy chain variable sequence having the sequence described in SEQ ID NO:33, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:33; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (x) A heavy chain variable sequence having the sequence described in SEQ ID NO:34, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:34; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xi) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and a light chain variable sequence having the sequence described in SEQ ID NO:108, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:108; (xii) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (xiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:35, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:35; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:36, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:36; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xv) A heavy chain variable sequence having the sequence described in SEQ ID NO:37, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:37; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:26, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:26; and a light chain variable sequence having the sequence described in SEQ ID NO:107, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:107; (xvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:38, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:38; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:31, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:31; and a light chain variable sequence having the sequence described in SEQ ID NO:110, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:110; (xix) A heavy chain variable sequence having the sequence described in SEQ ID NO:39, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:39; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xx) A heavy chain variable sequence having the sequence described in SEQ ID NO:40, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:40; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:34, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:34; and a light chain variable sequence having the sequence described in SEQ ID NO:111, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:111; (xxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:41, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:41; and a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (xxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:30, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:30; and a light chain variable sequence having the sequence described in SEQ ID NO:112, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:112; (xxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:28, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:28; and a light chain variable sequence having the sequence described in SEQ ID NO:113, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:113; or (xxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:32, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:32; and a light chain variable sequence having the sequence described in SEQ ID NO:114, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:114; (xxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:42, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:42; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:36, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:36; and a light chain variable sequence having the sequence described in SEQ ID NO:115, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:115; (xxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:43, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:43; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:32, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:32; and a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (xxx) A heavy chain variable sequence having the sequence described in SEQ ID NO:44, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:44; and a light chain variable sequence having the sequence described in SEQ ID NO:116, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:116; (xxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:35, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:35; and a light chain variable sequence having the sequence described in SEQ ID NO:117, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:117; (xxxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:45, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:45; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xxxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:46, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:46; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xxxiv) A heavy chain variable sequence having the sequence described in SEQ ID NO:36, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:36; and a light chain variable sequence having the sequence described in SEQ ID NO:118, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:118; (xxxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:47, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:47; and a light chain variable sequence having the sequence described in SEQ ID NO:115, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:115; (xxxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:48, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:48; and a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (xxxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:49, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:49; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xxxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:50, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:50; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xxxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:51, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:51; and a light chain variable sequence having the sequence described in SEQ ID NO:106, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:106; (xl) A heavy chain variable sequence having the sequence described in SEQ ID NO:52, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:52; and a light chain variable sequence having the sequence described in SEQ ID NO:119, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:119; (xli) A heavy chain variable sequence having the sequence described in SEQ ID NO:53, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:53; and a light chain variable sequence having the sequence described in SEQ ID NO:108, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:108; (xlii) A heavy chain variable sequence having the sequence described in SEQ ID NO:54, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:54; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (xliii) A heavy chain variable sequence having the sequence described in SEQ ID NO:55, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:55; and a light chain variable sequence having the sequence described in SEQ ID NO:116, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:116; (xliv) Heavy chain variable sequences having the sequence described in SEQ ID NO:56, or heavy chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:56; and light chain variable sequences having the sequence described in SEQ ID NO:116, or light chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:116; (xlv) A heavy chain variable sequence having the sequence described in SEQ ID NO:57, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:57; and a light chain variable sequence having the sequence described in SEQ ID NO:120, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:120; (xlvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:58, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:58; and a light chain variable sequence having the sequence described in SEQ ID NO:121, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:121; (xlvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:59, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:59; and a light chain variable sequence having the sequence described in SEQ ID NO:122, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:122; (xlviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:60, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:60; and a light chain variable sequence having the sequence described in SEQ ID NO:108, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:108; (xlix) A heavy chain variable sequence having the sequence described in SEQ ID NO:61, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:61; and a light chain variable sequence having the sequence described in SEQ ID NO:123, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:123; (l) A heavy chain variable sequence having the sequence described in SEQ ID NO:62, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:62; and a light chain variable sequence having the sequence described in SEQ ID NO:114, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:114; (i) A heavy chain variable sequence having the sequence described in SEQ ID NO:63, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:63; and a light chain variable sequence having the sequence described in SEQ ID NO:124, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:124; (lii) A heavy chain variable sequence having the sequence described in SEQ ID NO:64, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:64; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (liii) A heavy chain variable sequence having the sequence described in SEQ ID NO:65, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:65; and a light chain variable sequence having the sequence described in SEQ ID NO:125, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:125; (liv) A heavy chain variable sequence having the sequence described in SEQ ID NO:66, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:66; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lv) A heavy chain variable sequence having the sequence described in SEQ ID NO:67, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:67; and a light chain variable sequence having the sequence described in SEQ ID NO:125, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:125; (lvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:68, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:68; and a light chain variable sequence having the sequence described in SEQ ID NO:126, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:126; (lvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:69, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:69; and a light chain variable sequence having the sequence described in SEQ ID NO:127, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:127; (lviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:70, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:70; and a light chain variable sequence having the sequence described in SEQ ID NO:128, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:128; (lix) A heavy chain variable sequence having the sequence described in SEQ ID NO:71, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:71; and a light chain variable sequence having the sequence described in SEQ ID NO:117, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:117; (lx) A heavy chain variable sequence having the sequence described in SEQ ID NO:72, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:72; and a light chain variable sequence having the sequence described in SEQ ID NO:129, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:129; (lxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:73, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:73; and a light chain variable sequence having the sequence described in SEQ ID NO:130, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:130; (lxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:74, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:74; and a light chain variable sequence having the sequence described in SEQ ID NO:131, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:131; (lxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:73, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:73; and a light chain variable sequence having the sequence described in SEQ ID NO:132, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:132; (lxiv) Heavy chain variable sequences having the sequence described in SEQ ID NO:75, or heavy chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:75; and light chain variable sequences having the sequence described in SEQ ID NO:133, or light chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:133; (lxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:76, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:76; and a light chain variable sequence having the sequence described in SEQ ID NO:134, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:134; (lxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:77, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:77; and a light chain variable sequence having the sequence described in SEQ ID NO:107, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:107; (lxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:78, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:78; and a light chain variable sequence having the sequence described in SEQ ID NO:135, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:135; (lxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:79, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:79; and a light chain variable sequence having the sequence described in SEQ ID NO:136, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:136; (lxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:80, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:80; and a light chain variable sequence having the sequence described in SEQ ID NO:137, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:137; (lxx) A heavy chain variable sequence having the sequence described in SEQ ID NO:41, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:41; and a light chain variable sequence having the sequence described in SEQ ID NO:138, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:138; (lxxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:81, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:31; and a light chain variable sequence having the sequence described in SEQ ID NO:139, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:139; (lxxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:82, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:82; and a light chain variable sequence having the sequence described in SEQ ID NO:105, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:105; (lxxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:83, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:83; and a light chain variable sequence having the sequence described in SEQ ID NO:126, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:126; (lxxiv) Heavy chain variable sequences having the sequence described in SEQ ID NO:84, or heavy chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:84; and light chain variable sequences having the sequence described in SEQ ID NO:140, or light chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:140; (lxxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:85, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:85; and a light chain variable sequence having the sequence described in SEQ ID NO:141, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:141; (lxxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:86, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:86; and a light chain variable sequence having the sequence described in SEQ ID NO:141, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:141; (lxxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:87, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:87; and a light chain variable sequence having the sequence described in SEQ ID NO:117, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:117; (lxxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:88, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:88; and a light chain variable sequence having the sequence described in SEQ ID NO:142, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:142; (lxxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:89, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:89; and a light chain variable sequence having the sequence described in SEQ ID NO:143, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:143; (lxxx) A heavy chain variable sequence having the sequence described in SEQ ID NO:90, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:90; and a light chain variable sequence having the sequence described in SEQ ID NO:144, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:144; (lxxxi) A heavy chain variable sequence having the sequence described in SEQ ID NO:91, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:91; and a light chain variable sequence having the sequence described in SEQ ID NO:109, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:109; (lxxxii) A heavy chain variable sequence having the sequence described in SEQ ID NO:92, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:92; and a light chain variable sequence having the sequence described in SEQ ID NO:145, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:145; (lxxxiii) A heavy chain variable sequence having the sequence described in SEQ ID NO:93, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:93; and a light chain variable sequence having the sequence described in SEQ ID NO:146, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:146; (lxxxiv) Heavy chain variable sequences having the sequence described in SEQ ID NO:94, or heavy chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:94; and light chain variable sequences having the sequence described in SEQ ID NO:147, or light chain variable sequences having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:147; (lxxxv) A heavy chain variable sequence having the sequence described in SEQ ID NO:95, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:95; and a light chain variable sequence having the sequence described in SEQ ID NO:148, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:148; (lxxxvi) A heavy chain variable sequence having the sequence described in SEQ ID NO:96, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:96; and a light chain variable sequence having the sequence described in SEQ ID NO:149, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:149; (lxxxvii) A heavy chain variable sequence having the sequence described in SEQ ID NO:97, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:97; and a light chain variable sequence having the sequence described in SEQ ID NO:150, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:150; (lxxxviii) A heavy chain variable sequence having the sequence described in SEQ ID NO:98, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:98; and a light chain variable sequence having the sequence described in SEQ ID NO:151, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:151; (lxxxix) A heavy chain variable sequence having the sequence described in SEQ ID NO:99, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:99; and a light chain variable sequence having the sequence described in SEQ ID NO:152, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:152; (xc) A heavy chain variable sequence having the sequence described in SEQ ID NO:100, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:100; and a light chain variable sequence having the sequence described in SEQ ID NO:136, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:136; (xci) A heavy chain variable sequence having the sequence described in SEQ ID NO:91, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:91; and a light chain variable sequence having the sequence described in SEQ ID NO:153, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:153; (xcii) A heavy chain variable sequence having the sequence described in SEQ ID NO:101, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:101; and a light chain variable sequence having the sequence described in SEQ ID NO:154, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:154; (xciii) A heavy chain variable sequence having the sequence described in SEQ ID NO:102, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:102; and a light chain variable sequence having the sequence described in SEQ ID NO:155, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:155; (xciv) A heavy chain variable sequence having the sequence described in SEQ ID NO:36, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:36; and a light chain variable sequence having the sequence described in SEQ ID NO:156, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:156; or (xc) A heavy chain variable sequence having the sequence described in SEQ ID NO:103, or a heavy chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:103; and a light chain variable sequence having the sequence described in SEQ ID NO:157, or a light chain variable sequence having at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:

157. A monoclonal antibody or antibody fragment according to claim 6, comprising:

8. A monoclonal antibody or antibody fragment according to any one of claims 1 to 3, comprising a heavy chain variable sequence having at least 70%, at least 80%, or at least 90% identity with SEQ ID NO:7, and a light chain variable sequence having at least 70%, at least 80%, or at least 90% identity with SEQ ID NO:

8.

9. A monoclonal antibody or antibody fragment according to claim 8, comprising a heavy chain variable sequence having at least 95% identity with SEQ ID NO:7 and a light chain variable sequence having at least 95% identity with SEQ ID NO:

8.

10. A monoclonal antibody or antibody fragment according to claim 9, comprising a heavy chain variable sequence having the sequence described in SEQ ID NO:7 and a light chain variable sequence having the sequence described in SEQ ID NO:

8.

11. A monoclonal antibody or antibody fragment according to any one of claims 1 to 10, encoded by a heavy chain variable sequence having at least 70%, at least 80%, or at least 90% identity with SEQ ID NO:9 and a light chain variable sequence having at least 70%, at least 80%, or at least 90% identity with SEQ ID NO:

10.

12. A monoclonal antibody or antibody fragment according to claim 11, encoded by a heavy chain variable sequence having at least 95% identity with SEQ ID NO:9 and a light chain variable sequence having at least 95% identity with SEQ ID NO:

10.

13. A monoclonal antibody or antibody fragment according to claim 12, encoded by the heavy chain variable sequence described in SEQ ID NO:9 and the light chain variable sequence described in SEQ ID NO:

10.

14. A monoclonal antibody or antibody fragment according to any one of claims 1 to 13, which can bind to HSP70.

15. A monoclonal antibody or antibody fragment according to any one of claims 1 to 14, which is a humanized antibody.

16. The antibody fragments include monovalent scFv (single-chain fragment variable) antibody, bivalent scFv, Fab fragment, and F(ab'). 2 Fragment, F(ab') 3 A monoclonal antibody or antibody fragment according to any one of claims 1 to 15, which is a fragment, an Fv fragment, or a single-chain antibody.

17. A monoclonal antibody or antibody fragment according to any one of claims 1 to 16, which is a chimeric antibody, a bispecific antibody, or a BiTE.

18. A monoclonal antibody or antibody fragment according to any one of claims 1 to 17, which is an IgG antibody or a recombinant IgG antibody or antibody fragment.

19. The monoclonal antibody or antibody fragment according to any one of claims 1 to 18, wherein the antibody is an IgG1, IgG2, IgG3, or IgG4 antibody, or a recombinant IgG1, IgG2, IgG3, or IgG4 antibody or antibody fragment.

20. A monoclonal antibody or antibody fragment according to any one of claims 1 to 19, comprising SEQ ID NO: 217 to 221.

21. A monoclonal antibody or antibody fragment according to any one of claims 1 to 20, which is conjugated or fused to an imaging agent or a cytotoxic agent.

22. A labeled monoclonal antibody or antibody fragment according to any one of claims 1 to 21.

23. The monoclonal antibody or antibody fragment according to claim 22, wherein the label is a fluorescent label, an enzyme label, or a radioactive label.

24. A monoclonal antibody or antibody fragment that competes for binding to the same epitope as the monoclonal antibody or antibody fragment described in any one of claims 1 to 23.

25. A monoclonal antibody or antibody fragment that binds to an epitope on HSP70 recognized by the antibody or antibody fragment according to any one of claims 1 to 24.

26. A monoclonal antibody or antibody fragment that binds to the epitope of HSP70, defined by the peptides corresponding to K573–Q601 of SEQ ID NO:

11.

27. The monoclonal antibody or antibody fragment according to claim 26, which, when bound to HSP70, binds to one or two of the following residues: H594, K595, and Q601 of SEQ ID NO:

11.

28. A monoclonal antibody or antibody fragment according to claim 26 or 27, which, when bound to HSP70, binds to all of the following residues: H594, K595, and Q601 of SEQ ID NO:

11.

29. The monoclonal antibody or antibody fragment according to claim 27 or 28, which, when bound to HSP70, further binds to at least one of the following residues: K573, E576, W580, R596, and E598 of SEQ ID NO:

11.

30. A monoclonal antibody or antibody fragment according to claim 27 or 28, which, when bound to HSP70, binds to at least two, three, four, or five of the following residues: K573, E576, W580, R596, and E598 of SEQ ID NO:

11.

31. A monoclonal antibody or antibody fragment according to any one of claims 26 to 30, which, when bound to HSP70, binds to all of the following residues: SEQ ID NO: 11, K573, E576, W580, H594, K595, R596, E598 and Q601.

32. A monoclonal antibody or antibody fragment that, upon binding to HSP70, enhances the uptake of tumor-derived ADP-HSP70-peptide antigen complexes by immune effector cells.

33. A monoclonal antibody or antibody fragment according to any one of claims 24 to 43, which is a humanized antibody.

34. The antibody fragments include monovalent scFv (single-chain fragment variable) antibody, bivalent scFv, Fab fragment, and F(ab'). 2 Fragment, F(ab') 3 A monoclonal antibody or antibody fragment according to any one of claims 24 to 33, which is a fragment, an Fv fragment, or a single-chain antibody.

35. A monoclonal antibody or antibody fragment according to any one of claims 24 to 34, which is a chimeric antibody or a bispecific antibody.

36. The monoclonal antibody or antibody fragment according to any one of claims 24 to 35, wherein the antibody is an IgG antibody, a recombinant IgG antibody, or an antibody fragment.

37. The monoclonal antibody or antibody fragment according to any one of claims 24 to 36, wherein the antibody is an IgG1, IgG2, IgG3, or IgG4 antibody, or a recombinant IgG1, IgG2, IgG3, or IgG4 antibody or antibody fragment.

38. A monoclonal antibody or antibody fragment according to any one of claims 24 to 37, comprising SEQ ID NO: 217 to 221.

39. A monoclonal antibody or antibody fragment according to any one of claims 24 to 38, which is conjugated or fused to an imaging agent or a cytotoxic agent.

40. A monoclonal antibody or antibody fragment according to any one of claims 24 to 39, wherein the monoclonal antibody or antibody fragment is according to any one of claims 1 to 23.

41. An isolated nucleic acid encoding the antibody heavy chain variable region and / or antibody light chain variable region of an antibody or antibody fragment according to any one of claims 1 to 41.

42. The isolated nucleic acid according to claim 41, comprising a nucleotide sequence that is at least 85% identical to SEQ ID NO:9 or 10.

43. An expression vector comprising the nucleic acid according to claim 41 or 42.

44. A hybridoma or engineered cell comprising a nucleic acid encoding an antibody or antibody fragment according to any one of claims 1 to 40.

45. A hybridoma or engineered cell comprising the nucleic acid according to claim 41 or 42.

46. A method for producing a monoclonal antibody or antibody fragment according to any one of claims 1 to 36, comprising the step of culturing a hybridoma or engineered cell according to claim 44 or 45 under conditions that enable the expression of the antibody or antibody fragment, and optionally comprising the step of isolating the antibody from the culture.

47. A pharmaceutical preparation comprising one or more antibodies or antibody fragments according to any one of claims 1 to 40.

48. A method for treating a patient having cancer, comprising the step of administering an effective amount of an antibody or antibody fragment according to any one of claims 1 to 40.

49. The method according to claim 48, which enhances the uptake of HSP70 by antigen-presenting cells.

50. The method according to claim 49, wherein the uptake of HSP70 by antigen-presenting cells is mediated by human FcγR2A and / or human FcγR2B.

51. The method according to any one of claims 48 to 50, further defined as a method for enhancing cytotoxic T cell-mediated antitumor immunity.

52. The method according to any one of claims 48 to 51, further defined as a method for increasing sensitivity to immunotherapy.

53. The method according to any one of claims 48 to 52, further defined as a method for enhancing the uptake of tumor-derived ADP-HSP70-peptide antigen complexes by immune effector cells.

54. The method according to any one of claims 48 to 53, further defined as a method for enhancing antigen presentation by dendritic cells.

55. The method according to any one of claims 48 to 54, further defined as a method for enhancing the CD4+ and CD8+ T cell response to a tumor antigen.

56. The method according to any one of claims 48 to 55, wherein the cancer is pancreatic cancer or prostate cancer.

57. The method according to any one of claims 48 to 56, further comprising the step of administering at least a second anti-cancer therapy.

58. The method according to claim 57, wherein the second anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, gene therapy, surgery, hormone therapy, anti-angiogenic therapy, or cytokine therapy.

59. A chimeric antigen receptor (CAR) protein containing an antigen-binding domain that binds to human HSP70.

60. (i) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (ii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (iii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (iv) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (v) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (vi) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:172; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (vii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (viii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:173; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (ix) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (x) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:175; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (xii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:176; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xiii) A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:171; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:177; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:178; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvi) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:179; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:179; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:159, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:180; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xx) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:181; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (xxi) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:182; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:181; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:185; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxvi) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xvii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxviii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxix) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:169, and the VHCDR3 amino acid sequence of SEQ ID NO:174; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:160, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxx) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxi) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:175; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxiii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:169, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxiv) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:167, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxvi) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxvii) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxviii) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xxxix) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:184; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xl) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:178; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:163; (xli) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:164, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:170; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; (xlii) Heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xliii) Heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xliv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:166, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:6; (xlv) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:165, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:161, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:162; or (xlvi) Heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:168, and the VHCDR3 amino acid sequence of SEQ ID NO:183; and light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:

6. The CAR protein according to claim 59, comprising:

61. The CAR protein according to claim 59 or 60, wherein the antigen-binding domain comprises a heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO:1, the VHCDR2 amino acid sequence of SEQ ID NO:2, and the VHCDR3 amino acid sequence of SEQ ID NO:3; and a light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO:4, the VLCDR2 amino acid sequence of SEQ ID NO:5, and the VLCDR3 amino acid sequence of SEQ ID NO:

6.

62. The CAR according to any one of claims 59 to 61, wherein the antigen-binding domain comprises a heavy chain variable sequence having at least 70%, at least 80%, or at least 90% identity with SEQ ID NO:7 and a light chain variable sequence having at least 70%, at least 80%, or at least 90% identity with SEQ ID NO:

8.

63. The CAR according to any one of claims 59 to 62, wherein the antigen-binding domain comprises a heavy chain variable sequence having at least 95% identity with SEQ ID NO:7 and a light chain variable sequence having at least 95% identity with SEQ ID NO:

8.

64. The CAR according to any one of claims 59 to 63, wherein the antigen-binding domain comprises a heavy chain variable sequence having the sequence described in SEQ ID NO:7 and a light chain variable sequence having the sequence described in SEQ ID NO:

8.

65. The CAR according to any one of claims 59 to 64, wherein the antigen-binding domain is encoded by a heavy chain variable sequence having at least 70%, at least 80%, or at least 90% identity with SEQ ID NO:9 and a light chain variable sequence having at least 70%, at least 80%, or at least 90% identity with SEQ ID NO:

10.

66. The CAR according to any one of claims 59 to 65, wherein the antigen-binding domain is encoded by a heavy chain variable sequence having at least 95% identity with SEQ ID NO:9 and a light chain variable sequence having at least 95% identity with SEQ ID NO:

10.

67. The CAR according to any one of claims 59 to 66, wherein the antigen-binding domain is encoded by the heavy chain variable sequence described in SEQ ID NO:9 and the light chain variable sequence described in SEQ ID NO:

10.

68. A CAR according to any one of claims 59 to 67, which can be coupled to an HSP70.

69. The CAR according to any one of claims 59 to 68, wherein the antigen-binding domain is a humanized antigen-binding domain.

70. A CAR according to any one of claims 59 to 69, further comprising a hinge domain, a transmembrane domain, and an intracellular signaling domain.

71. The CAR according to claim 70, wherein the hinge domain is a CD8a hinge domain or an IgG4 hinge domain.

72. The CAR according to claim 70 or 71, wherein the transmembrane domain is a CD8a transmembrane domain or a CD28 transmembrane domain.

73. The CAR according to any one of claims 70 to 72, wherein the intracellular signaling domain includes a CD3z intracellular signaling domain.

74. A nucleic acid molecule encoding a CAR according to any one of claims 59 to 73.

75. The nucleic acid molecule according to claim 74, wherein the sequence encoding the CAR is functionally linked to an expression control sequence.

76. A nucleic acid molecule according to claim 74 or 75, further defined as an expression vector.

77. Engineered cells containing nucleic acid molecules encoding a chimeric antigen receptor (CAR) that includes an antigen-binding domain that binds to human HSP70.

78. The cell according to claim 77, wherein the nucleic acid molecule encodes a CAR according to any one of claims 59 to 73.

79. The cell according to claim 77 or 78, which is a T cell.

80. The cell according to claim 77 or 78, which is an NK cell.

81. The cell according to any one of claims 77 to 80, wherein the nucleic acid is incorporated into the genome of the cell.

82. A human cell, as described in any one of claims 77 to 81.

83. A pharmaceutical composition comprising a population of cells according to any one of claims 77 to 82 in a pharmaceutically acceptable carrier.

84. A method for treating cancer in a human patient in need thereof, comprising the step of administering to the patient an antitumor-effective amount of cell therapy comprising one or more cells according to any one of claims 78 to 82.

85. The method according to claim 84, wherein the cells are allogeneic cells.

86. The method according to claim 84, wherein the cells are the body's own cells.

87. The method according to any one of claims 84 to 86, wherein the cells are HLA-compatible with the subject.

88. The method according to any one of claims 84 to 87, wherein the cancer is pancreatic cancer or prostate cancer.

89. The method according to any one of claims 84 to 88, further comprising the step of administering at least a second anti-cancer therapy.

90. The method according to claim 89, wherein the second anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, gene therapy, surgery, hormone therapy, anti-angiogenic therapy, or cytokine therapy.

91. A method for detecting HSP70 in an in vitro sample, comprising the steps of contacting the in vitro sample with an antibody or antibody fragment according to any one of claims 1 to 36, and detecting the binding of the antibody or antibody fragment to the sample.

92. The method according to claim 91, wherein the detection step is performed by flow cytometry, mass spectrometry, Western blotting, immunohistochemistry, ELISA, or RIA.

93. An antibody or antibody fragment according to any one of claims 1 to 40, a pharmaceutical composition according to claim 47, a cell according to any one of claims 77 to 82, or a pharmaceutical composition according to claim 83, for use in the treatment of cancer in a subject.

94. Use of an antibody or antibody fragment according to any one of claims 1 to 40, a pharmaceutical composition according to claim 47, a cell according to any one of claims 77 to 82, or a pharmaceutical composition according to claim 83 in the manufacture of a pharmaceutical for treating cancer in a subject.

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