Anti-4-1bb antibodies and methods of making and using the same

Abstract

The present application provides anti-4-1BB monoclonal antibodies, antigen-binding portions thereof, therapeutic compositions thereof, and / or nucleic acids encoding the same, and their use in upregulating T cell function to enhance cell-mediated immune responses in the treatment of cancer and other T cell dysfunction.

Description

[0001] This application is a divisional application of Chinese invention patent application (application number: 2018800383857; invention title: anti-4-1BB antibody and its preparation and use method).

[0002] Cross-references to related applications This application claims the entire disclosures of U.S. Provisional Patent Application No. 62551065, filed August 28, 2017; U.S. Provisional Patent Application No. 62551032, filed August 28, 2017; U.S. Provisional Patent Application No. 62524554, filed June 25, 2017; U.S. Provisional Patent Application No. 62524557, filed June 25, 2017; U.S. Provisional Patent Application No. 62524558, filed June 25, 2017; U.S. Provisional Patent Application No. 62545603, filed August 15, 2017; U.S. Provisional Patent Application No. 62551032, filed August 28, 2017; and U.S. Provisional Patent Application No. 62551035, filed August 28, 2017, which are expressly incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to the field of antibody technology, and more specifically to the preparation and use of anti-4-1BB antibodies, and the application of said antibodies in cancer treatment and therapy. Background Technology

[0004] Cancer is a major health problem worldwide. In the United States alone, an estimated 1,685,210 new cancer cases were diagnosed in 2016, with 595,690 deaths (http: / / www.cancer.gov). Therefore, any drug that can reduce the severity or mortality of cancer is ideal.

[0005] In the immune system, resting T cells are activated to respond to antigens via primary signals delivered by T cell receptors (TCRs) from exogenous antigenic peptides presented by antigen-presenting cells (APCs). In addition to this primary signal, secondary positive and negative co-stimulatory signals further influence T cell responses. Complete T cell activation requires secondary positive signals (Lafferty et al., Ausl. J. Exp. Biol. Med. Sci. 5327-42 (1975)). Negative secondary signals can lead to T cell suppression and tolerance.

[0006] 4-1BB is a costimulatory immune checkpoint molecule capable of activating T cells. Also known as CD137, 4-1BB is a member of the tumor necrosis factor receptor superfamily 9 (TNFRSF9), induced by lymphocyte activation (ILA), and is a member of the tumor necrosis factor (TNF) receptor family. Crosslinking of CD137 has been reported to enhance T cell proliferation, IL-2 secretion, survival, and cytolytic activity. Furthermore, it can enhance immune activity to eliminate tumors in mice.

[0007] Pfizer's Utomilumab (PF-05082566), which targets 4-1BB, has been shown to stimulate a stronger immune system attack against cancer in a small clinical trial when used in combination with Merck's Keytruda (https: / / www.reuters.com / article / us-health-cancer-pfizer-immunotherapy-idUSKCN0Y92W2). PF-05082566 is currently undergoing seven clinical trials (www.clinicaltrials.gov). Summary of the Invention

[0008] This disclosure provides, in particular, the use of anti-4-1BB monoclonal antibodies, their antigen-binding moieties, their therapeutic compositions, and / or nucleic acids encoding them, and their use in treating cancer and other T-cell dysfunction disorders to upregulate T-cell function to enhance cell-mediated immune responses.

[0009] In one embodiment, an isolated monoclonal antibody (mAb) or an antigen-binding fragment thereof that specifically binds to human or cynomolgus monkey 4-1BB is provided.In one embodiment, the isolated mAb or antigen-binding fragment comprises an amino acid sequence having a percentage homology with SEQ ID NO:4, SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, SEQ ID NO:20, SEQ ID NO:24, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:36, SEQ ID NO:40, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:52, SEQ ID NO:56, SEQ ID NO:60, SEQ ID NO:64, SEQ ID NO:68, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:80, SEQ ID NO:84, SEQ ID NO:88, SEQ ID NO:88, SEQ ID NO:92, SEQ ID NO:96, SEQ ID NO:100, SEQ ID NO:104, SEQ ID NO:108, SEQ ID NO:112, SEQ ID NO:116, SEQ ID NO:120, SEQ ID NO:124, SEQ ID NO:128, SEQ ID NO:132, SEQ ID NO:136, SEQ ID NO:140, SEQ ID NO:144, SEQ ID NO:148, SEQ ID NO:152, SEQ ID NO:156, SEQ ID NO:160, SEQ ID NO:164, SEQ ID NO:168, SEQ ID NO:172, SEQ ID NO:176, SEQ ID NO:180, SEQ ID NO:184, SEQ ID NO:188, SEQ ID NO:192, SEQ ID NO:196, SEQ ID NO:200, SEQ ID NO:204, SEQ ID NO:208, SEQ ID NO:212, SEQ ID NO:216, SEQ ID NO:220, SEQ ID NO:224, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:236, SEQ ID NO:240, SEQ ID NO:244, SEQ ID NO:248, SEQ ID NO:252, SEQ ID NO:256, SEQ ID NO:260, SEQ ID NO:264, SEQ ID NO:268 or SEQ ID NO:272.The percentage of homology is not less than 70%, 80%, 90%, 95%, 98%, or 99%.

[0010] In one embodiment, the binding affinity Kd of the isolated mAb or antigen-binding fragment to 4-1BB is no greater than 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, or 100 nM.

[0011] In one embodiment, the isolated mAb or antigen-binding fragment exhibits one or more functional properties, such as, but not limited to, high affinity binding to human or cynomolgus monkey 4-1BB, inhibition of human or cynomolgus monkey 4-1BB activity, induction of apoptosis, regulation of the EGFR signaling pathway, upregulation of EMT genes, enhancement of T cell activation, stimulation of antibody responses, reversal of the suppressive function of immunosuppressive cells, or a combination thereof. In one embodiment, immunosuppressive cells include regulatory cells. In one embodiment, the isolated mAb or antigen-binding fragment enhances T cell activation through mechanisms or pathways including T cell proliferation, IFN-γ and / or IL-2 secretion, or a combination thereof.

[0012] In some embodiments, the isolated mAb or antigen-binding fragment may include a human framework region. In one embodiment, the isolated mAb or antigen-binding fragment may include a humanized antibody, a chimeric antibody, or a recombinant antibody.

[0013] In one embodiment, the isolated mAb or antigen-binding fragment is IgG. In one embodiment, the antigen-binding fragment may include Fv, Fab, F(ab')2, scFV, or scFV2 ​​fragments. In one embodiment, the isolated mAb may be a bispecific antibody, a trispecific antibody, or a multispecific antibody.

[0014] In one implementation, the isolated mAb or antigen-binding fragment may include the IgG1 heavy chain. In one embodiment, the IgG1 heavy chain comprises SEQ ID NO:7, SEQ ID NO:15, SEQ ID NO:23, SEQ ID NO:31, SEQ ID NO:39, SEQ ID NO:47, SEQ ID NO:55, SEQ ID NO:63, SEQ ID NO:71, SEQ ID NO:79, SEQ ID NO:87, SEQ ID NO:95, SEQ ID NO:103, SEQ ID NO:111, SEQ ID NO:119, SEQ ID NO:127, SEQ ID NO:135, SEQ ID NO:143, SEQ ID NO:151, SEQ ID NO:159, SEQ ID NO:167, SEQ ID NO:175, SEQ ID NO:183, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:207, SEQ ID NO:215, SEQ ID NO:223, SEQ ID NO:231, SEQ ID NO:239, SEQ ID NO:247, SEQ ID The amino acid sequences NO:255, SEQ ID NO:263, or SEQ ID NO:271 have a homology percentage of not less than 70%, 80%, 90%, 95%, 98%, or 99%.

[0015] In one implementation, the isolated mAb or antigen-binding fragment may include a κ light chain. In one embodiment, the kappa light chain comprises SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:19, SEQ ID NO:27, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:51, SEQ ID NO:59, SEQ ID NO:67, SEQ ID NO:75, SEQ ID NO:83, SEQ ID NO:91, SEQ ID NO:99, SEQ ID NO:107, SEQ ID NO:115, SEQ ID NO:123, SEQ ID NO:131, SEQ ID NO:139, SEQ ID NO:147, SEQ ID NO:155, SEQ ID NO:163, SEQ ID NO:171, SEQ ID NO:179, SEQ ID NO:187, SEQ ID NO:195, SEQ ID NO:203, SEQ ID NO:211, SEQ ID NO:219, SEQ ID NO:1 SEQ ID NO:227, SEQ ID NO:235, SEQ ID The amino acid sequences NO:243, SEQ ID NO:257, or SEQ ID NO:263 have a homology percentage of not less than 70%, 80%, 90%, 95%, 98%, or 99%.

[0016] In one implementation, the isolated mAb or antigen-binding fragment may include a variable light chain. The variable light chain includes SEQ ID NO:4, SEQ ID NO:12, SEQ ID NO:20, SEQ ID NO:28, SEQ ID NO:36, SEQ ID NO:44, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:68, SEQ ID NO:76, SEQ ID NO:84, SEQ ID NO:92, SEQ ID NO:100, SEQ ID NO:108, SEQ ID NO:116, SEQ ID NO:124, SEQ ID NO:132, SEQ ID NO:140, SEQ ID NO:148, SEQ ID NO:156, SEQ ID NO:164, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:188, SEQ ID NO:196, SEQ ID NO:204, SEQ ID NO:212, SEQ ID NO:220, SEQ ID NO:228, SEQ ID NO:236, SEQ ID NO:244, SEQ ID The amino acid sequences NO:252, SEQ ID NO:260, or SEQ ID NO:268 have a homology percentage of not less than 70%, 80%, 90%, 95%, 98%, or 99%.

[0017] In one implementation, the isolated mAb or antigen-binding fragment may include a variable heavy chain. In one embodiment, the variable heavy chain comprises SEQ ID NO:8, SEQ ID NO:16, SEQ ID NO:24, SEQ ID NO:32, SEQ ID NO:40, SEQ ID NO:48, SEQ ID NO:56, SEQ ID NO:64, SEQ ID NO:72, SEQ ID NO:80, SEQ IDNO:88, SEQ ID NO:96, SEQ ID NO:104, SEQ ID NO:112, SEQ ID NO:120, SEQ ID NO:128, SEQ ID NO:136, SEQ ID NO:144, SEQ ID NO:152, SEQ ID NO:160, SEQ ID NO:168, SEQ ID NO:176, SEQ ID NO:184, SEQ ID NO:192, SEQ ID NO:200, SEQ ID NO:208, SEQ ID NO:216, SEQ ID NO:224, SEQ ID NO:232, SEQ ID NO:240, SEQ ID NO:248, SEQ ID The amino acid sequences NO:256, SEQ ID NO:264, or SEQ ID NO:272 have a homology percentage of not less than 70%, 80%, 90%, 95%, 98%, or 99%.

[0018] This application also provides isolated nucleic acids encoding at least a portion of the isolated mAb or antigen-binding fragment disclosed herein. In one embodiment, the nucleic acid encodes an IgG1 heavy chain, the IgG1 heavy chain comprising SEQ ID NO:7, SEQ ID NO:15, SEQ ID NO:23, SEQ ID NO:31, SEQ ID NO:39, SEQ ID NO:47, SEQ ID NO:55, SEQ ID NO:63, SEQ ID NO:71, SEQ ID NO:79, SEQ ID NO:87, SEQ ID NO:95, SEQ ID NO:103, SEQ ID NO:111, SEQ ID NO:119, SEQ ID NO:127, SEQ ID NO:135, SEQ ID NO:143, SEQ ID NO:151, SEQ ID NO:159, SEQ ID NO:167, SEQ ID NO:175, SEQ ID NO:183, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:207, SEQ ID NO:215, SEQ ID NO:223, SEQ ID NO:231, SEQ ID NO:239, SEQ ID NO:249, SEQ ID NO:259, SEQ ID NO:269, SEQ ID NO:279, SEQ ID NO:289, SEQ ID NO:29 ... The amino acid sequences NO:247, SEQ ID NO:255, SEQ ID NO:263 or SEQ ID NO:271 have a percentage of homology.In one embodiment, the nucleic acid encodes a κ light chain, the κ light chain comprising SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:19, SEQ ID NO:27, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:51, SEQ ID NO:59, SEQ ID NO:67, SEQ ID NO:75, SEQ ID NO:83, SEQ ID NO:91, SEQ ID NO:99, SEQ ID NO:107, SEQ ID NO:115, SEQ ID NO:123, SEQ ID NO:131, SEQ ID NO:139, SEQ ID NO:147, SEQ ID NO:155, SEQ ID NO:163, SEQ ID NO:171, SEQ ID NO:179, SEQ ID NO:187, SEQ ID NO:195, SEQ ID NO:203, SEQ ID NO:211, SEQ ID NO:219, SEQ ID NO:1, SEQ ID NO:227, SEQ ID NO:227, SEQ ID NO:195, SEQ ID NO:203, SEQ ID NO:211, SEQ ID NO:219 ... The amino acid sequences NO:235, SEQ ID NO:243, SEQ ID NO:257 or SEQ ID NO:263 have a percentage of homology. In one embodiment, the nucleic acid encodes a variable light chain, the variable light chain comprising SEQ ID NO:4, SEQ ID NO:12, SEQ ID NO:20, SEQ ID NO:28, SEQ ID NO:36, SEQ ID NO:44, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:68, SEQ ID NO:76, SEQ ID NO:84, SEQ ID NO:92, SEQ ID NO:100, SEQ ID NO:108, SEQ ID NO:116, SEQ ID NO:124, SEQ ID NO:132, SEQ ID NO:140, SEQ ID NO:148, SEQ ID NO:156, SEQ ID NO:164, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:188, SEQ ID NO:196, SEQ ID NO:204, SEQ ID NO:212, SEQ ID NO:220, SEQ ID NO:228, SEQ ID NO:236, SEQ ID NO:12, SEQ ID NO:12, SEQ ID NO:20, SEQ ID NO:28, SEQ ID NO:36, SEQ ID NO:44, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:68, SEQ ID NO:76, SEQ ID NO:84, SEQ ID NO:92, SEQ ID NO:100, SEQ ID NO:108, SEQ ID NO:116, SEQ ID NO:124, SEQ ID NO:132, SEQ ID NO:140, SEQ ID NO:148, SEQ ID NO:156, SEQ ID NO:164, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:188, SEQ ID NO:196, SEQ ID NO:204, SEQ ID NO:212, SEQ ID The amino acid sequences NO:244, SEQ ID NO:252, SEQ ID NO:260 or SEQ ID NO:268 have a percentage of homology.In one embodiment, the nucleic acid encodes a variable heavy chain, the variable heavy chain comprising SEQ ID NO:8, SEQ ID NO:16, SEQ ID NO:24, SEQ ID NO:32, SEQ ID NO:40, SEQ ID NO:48, SEQ ID NO:56, SEQ ID NO:64, SEQ ID NO:72, SEQ ID NO:80, SEQ ID NO:88, SEQ ID NO:96, SEQ ID NO:104, SEQ ID NO:112, SEQ ID NO:120, SEQ ID NO:128, SEQ ID NO:136, SEQ ID NO:144, SEQ ID NO:152, SEQ ID NO:160, SEQ ID NO:168, SEQ ID NO:176, SEQ ID NO:184, SEQ ID NO:192, SEQ ID NO:200, SEQ ID NO:208, SEQ ID NO:216, SEQ ID NO:224, SEQ ID NO:232, SEQ ID NO:240, SEQ ID NO:16, SEQ ID NO:27, SEQ ID NO:18, SEQ ID NO:29, SEQ ID NO:200, SEQ ID NO:208, SEQ ID NO:216, SEQ ID NO:224, SEQ ID NO:232, SEQ ID NO:240, SEQ ID NO:16 ...08, SEQ ID NO:208, SEQ ID NO:208, SEQ ID NO:208, SEQ ID NO:208, SEQ ID NO:208, SEQ ID NO:208, SEQ ID NO:208, SEQ ID NO:2 The amino acid sequences NO:248, SEQ ID NO:256, SEQ ID NO:264, or SEQ ID NO:272 have a homology percentage of not less than 70%, 80%, 90%, 95%, 98%, or 99%.

[0019] In one embodiment, an expression vector comprising at least one of the following isolated nucleic acids is provided. In one embodiment, the vector can be expressed in cells.

[0020] In one embodiment, a host cell comprising at least one of the following nucleic acids is provided. In one embodiment, a host cell comprising the following expression vector is provided. In one embodiment, the host cell may be a prokaryotic cell or a eukaryotic cell.

[0021] This application also provides a method for generating the isolated mAbs or antigen-binding fragments disclosed herein. In one embodiment, the method uses the host cells described above. In one embodiment, the method includes the steps of: providing a host cell containing an expression vector that can be expressed in a host cell, wherein the expression vector comprises at least one of the following nucleic acids; and culturing the host cell to generate antibodies by expressing the aforementioned nucleic acid.

[0022] This application also provides immunoconjugates comprising a pharmaceutical unit or imaging agent linked via a linker to a separate mAb or antigen-binding fragment having a sequence disclosed herein. The linker may be cleavable or non-cleavable. In one embodiment, the linker is a chemical linker. In one embodiment, the linker comprises covalent bonds such as ester bonds, ether bonds, amine bonds, amide bonds, disulfide bonds, imide bonds, sulfone bonds, phosphate bonds, phosphorus ester bonds, peptide bonds, hydrazone bonds, or combinations thereof. In one embodiment, the linker comprises a hydrophobic poly(ethylene glycol) linker. In one embodiment, the linker comprises a peptide bond.

[0023] In one embodiment, the pharmaceutical unit in the immunoconjugate includes a chemotherapeutic agent, a growth inhibitor, a calichiomycin-like pharmaceutical unit, an antimitotic agent, a toxin, a radioisotope, a therapeutic agent, or a combination thereof. In one embodiment, the therapeutic agent includes an antibody, an enzyme, or a combination thereof. In one embodiment, the pharmaceutical unit includes calichiomycin, ozogamicin, monomethylaurestatin E, emtansine, derivatives thereof, or a combination thereof.

[0024] In one embodiment, the pharmaceutical unit is selected from cytotoxic agents, immunomodulators, imaging agents, or combinations thereof. In one embodiment, the cytotoxic agent is selected from growth inhibitors or chemotherapeutic agents derived from microtubule-binding agents, DNA intercalating agents, DNA alkylating agents, enzyme inhibitors, immunomodulators, antimetabolites, radioisotopes, or combinations thereof. In one embodiment, the cytotoxic agent is selected from calichiomycin, ozomicin, monomethylaurestatin E, emtansine, derivatives thereof, or combinations thereof. In one embodiment, the immunomodulator activates or inhibits immune cells, T cells, NK cells, B cells, macrophages, or dendritic cells.

[0025] In one embodiment, the developing agent may be a radionuclide, a fluorescent agent, a quantum dot, or a combination thereof.

[0026] This application also provides pharmaceutical compositions. In one embodiment, the pharmaceutical composition comprises the isolated mAb or antigen-binding fragment disclosed herein and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition comprises an immunoconjugate and a pharmaceutically acceptable carrier.

[0027] On the other hand, this application provides methods for treating cancer. In one embodiment, the method includes administering to a subject an effective amount of an isolated mAb or antigen-binding fragment having the sequence disclosed herein. In one embodiment, the method includes directly injecting an effective amount of a monoclonal antibody, its antigen-binding fragment, and the immunoconjugate disclosed herein into a tumor site.

[0028] In some embodiments of this disclosure, the cancer has cells expressing 4-1BB. Examples of cancers that can be treated with the disclosed mAb or its antigen-binding fragment include, but are not limited to, breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, non-small cell lung cancer, glioma, esophageal cancer, nasopharyngeal cancer, anal cancer, rectal cancer, gastric cancer, bladder cancer, cervical cancer, or brain cancer.

[0029] In one embodiment, the method further includes co-administering an effective amount of the therapeutic agent. In some embodiments, the therapeutic agent may be an antibody, a chemotherapeutic agent, an enzyme, or a combination thereof. In one embodiment, the therapeutic agent may be capecitabine, cisplatin, trastuzumab, fulvestrant, tamoxifen, letrozole, exemestane, anastrozole, aminoglutethimide, testosterone, voroxycycline, formexane, fazodazole, letrozole, erlotinib, lafafatinib, dasatinib, gefitinib, imatinib, pazopanib, lapatinib, sunitinib, nilotinib, sorafenib, nab-paclitaxel, calichiomycin, an antimitotic agent, monomethylolpropionate E, methimazole (DM1), ozomicin, or derivatives or combinations thereof.

[0030] The subjects receiving treatment can be human. In one embodiment, a solution containing an effective concentration of isolated mAb or antigen-binding fragments is provided, wherein the solution is the subject's plasma.

[0031] Other embodiments will become apparent to those skilled in the art from the following detailed description, wherein the embodiments are described by showing the intended best mode. As will be appreciated, other and different embodiments are possible, and several details of the embodiments can be modified in a variety of obvious ways, all without departing from their spirit and scope. Therefore, the accompanying drawings and detailed description should be considered illustrative rather than limiting in nature. Attached Figure Description

[0032] The foregoing and other features of the invention will become more fully apparent from the accompanying drawings, the following description, and the appended claims. It should be understood that these drawings depict only a few embodiments of the arrangement according to this disclosure and are therefore not intended to be limiting of its scope. The disclosure will be described with additional features and details using the drawings, in which: Figure 1 This is the timeline for immunizing groups 1 and 2 rabbits with HEK293 cells transiently transfected with human 41BB or cynomolgus monkey 41BB.

[0033] Figure 2This indicates that the 41BB-specific rabbit IgG antibody in the B cell culture supernatant enhances the activation of anti-CD3 activated human T cells and that the chimeric rabbit / human IgG 41BB-specific antibody rescued from parental B cell culture wells binds to the corresponding recombinant human and cynomolgus monkey 41BB protein.

[0034] Figure 3 The chimeric rabbit / human IgG antibody specific to 41BB enhanced T cell activation, proliferation, and interferon-gamma secretion.

[0035] Figure 4 This is an octet analysis of the dissociation rate of humanized 41BB-specific IgG antibodies.

[0036] Figure 5 The results indicate that the humanized 41BB-specific IgG antibody enhanced T cell activation, proliferation, and interferon-gamma secretion.

[0037] Figure 6 The assay analyzes 41BB-specific IgG antibodies that bind to parental CHO cells or human or cynomolgus monkey 41BB transfected CHO cells. These antibodies are derived from rabbit serum immunized with HEK293 cells expressing human or cynomolgus monkey 41BB.

[0038] Figure 7 This indicates the correlation between the enhancement of interferon-gamma secretion and human T cell proliferation by 41BB-specific IgG antibody in B cell culture supernatant. Detailed Implementation

[0039] In the following detailed description, reference is made to the accompanying drawings, which form a part of this document. In the drawings, similar symbols generally identify similar parts unless the context otherwise requires. The illustrative embodiments described in the detailed description, drawings, and claims are not intended to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that these aspects of the present disclosure, as generally described herein and shown in the drawings, may be arranged, substituted, combined, separated, and designed into a variety of different configurations, all of which are expressly contemplated herein.

[0040] This disclosure particularly provides methods for isolating antibodies, preparing such antibodies, bispecific or multispecific molecules, antibody-drug conjugates and / or immunoconjugates composed of such antibodies or antigen-binding fragments, and pharmaceutical compositions containing such antibodies, bispecific or multispecific molecules, antibody-drug conjugates and / or immunoconjugates.

[0041] In one aspect, this disclosure provides isolated monoclonal antibodies that bind to human or cynomolgus monkey 4-1BB. The antibodies may exhibit one or more desired functional properties, such as the ability to bind with high affinity to 4-1BB, enhance T cell activation including proliferation, IFN-γ and / or CD3+ T cell proliferation, IL-2 secretion, survival and cytolysis, stimulate antibody responses, and / or reverse the suppressive function of immunosuppressive cells (e.g., regulatory T cells). Furthermore, the antibodies of this disclosure are derived from specific heavy and light chain amino acid sequences and / or structural features, such as complementarity-determining regions (CDRs) composed of specific amino acid sequences.

[0042] The term "antibody" is used in the broadest sense and specifically covers single monoclonal antibodies (including agonist and antagonist antibodies), antibody compositions with multi-epitope specificity, and antibody fragments (e.g., Fab, F(ab')2, and Fv), provided they exhibit the desired biological activity. In some embodiments, antibodies can be monoclonal antibodies, polyclonal antibodies, chimeric antibodies, single-chain antibodies, bispecific or bifunctional antibodies, simianized antibodies, human antibodies, and humanized antibodies, as well as their active fragments. Examples of active fragments of molecules that bind to known antigens include Fab, F(ab')2, scFv, and Fv fragments, as well as products of Fab immunoglobulin expression libraries and epitope-binding fragments of any of the aforementioned antibodies and fragments. In some embodiments, antibodies may include immunoglobulin molecules and immunoactive portions of immunoglobulin molecules, i.e., molecules containing binding sites that specifically bind to antigens. Immunoglobulins can be any type (IgG, IgM, IgD, IgE, IgA, and IgY) or class (IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass of immunoglobulin molecules. In one embodiment, an antibody can be a complete antibody and any antigen-binding fragment derived from that complete antibody. A typical antibody is a heterotetrameric protein chain that typically comprises two heavy (H) chains and two light (L) chains. Each heavy chain consists of a heavy chain variable domain (abbreviated as VH) and a heavy chain constant domain. Each light chain consists of a light chain variable region (abbreviated as VL) and a light chain constant region. The VH and VL regions can be further subdivided into a hypervariable complementarity-determining region (CDR) domain and a more conserved region called a framework region (FR). Each variable region (VH or VL) typically consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Binding regions that interact with the antigen exist within the variable regions of both the light and heavy chains.

[0043] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous group of antibodies, meaning that individual antibodies comprising that group are identical except for the possibility of naturally occurring mutations present in small amounts.

[0044] Monoclonal antibodies are highly specific for a single antigenic site. Furthermore, unlike conventional (polyclonal) antibody formulations, which typically comprise different antibodies targeting different determinants (epitopes), each monoclonal antibody targets a single determinant on the antigen. In addition to their specificity, monoclonal antibodies have the advantage of being synthesized from hybridoma cultures, free from contamination by other immunoglobulins. The modifier “monoclonal” indicates the characteristic of antibodies obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the production of the antibody by any particular method. For example, monoclonal antibodies used according to this disclosure can be prepared by a hybridoma method first described in Kohler & Milstein, Nature, 256:495 (1975), or by a recombinant DNA method (see, for example, U.S. Patent No. 4,816,567).

[0045] Monoclonal antibodies may include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular class or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequence in an antibody derived from another class or belonging to another antibody class or subclass, as well as fragments of those antibodies, provided they exhibit the desired biological activity (US Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855

[1984] ). Monoclonal antibodies can be produced using various methods, including mouse hybridoma or phage display (see Siegel. Transfus. Clin. Biol. 9:15-22 (2002) review) or molecular cloning of antibodies directly from primary B cells (see Tiller. New Biotechnol. 28:453-7 (2011)). In this disclosure, antibodies were produced by immunizing rabbits with cells transiently expressing human or cynomolgus monkey 4-1BB on their cell surface. Rabbits are known to produce antibodies with high affinity, diversity, and specificity (Weber et al., Exp. Mol. Med. 49:e305). B cells from the immunized animals were cultured in vitro and screened for anti-4-1BB antibodies. Antibody variants were isolated using recombinant DNA technology, the resulting antibodies were recombinantly expressed, and further screened for desired characteristics, such as the ability to enhance human T cell activation. This general approach to antibody discovery is similar to that of Seeber et al., PLOS One. 9:e86184 (2014).

[0046] The term "antigen or epitope binding portion or fragment" refers to an antibody fragment capable of binding an antigen (in this case, 4-1BB). These fragments can possess both the antigen-binding function and additional functions of a complete antibody. Examples of binding fragments include, but are not limited to, single-chain Fv fragments (scFv) or Fab fragments. A single-chain Fv fragment consists of the VL and VH domains of a single arm of an antibody in a single polypeptide chain linked by a synthetic linker. A Fab fragment is a monovalent fragment consisting of the VL, constant light chain (CL), VH, and constant heavy chain 1 (CH1) domains. Antibody fragments can be even smaller subfractions and can consist of domains as small as a single CDR domain, particularly the CDR3 region from the VL and / or VH domains (see, for example, Beiboer et al., J. Mol. Biol. 296:833-49 (2000)). Antibody fragments are generated using conventional methods known to those skilled in the art. The utility of antibody fragments can be screened using the same techniques as for complete antibodies.

[0047] The “antigen or epitope binding fragment” can be derived from the antibody disclosed herein using many techniques known in the art. For example, purified monoclonal antibodies can be cleaved with an enzyme such as pepsin and subjected to HPLC gel filtration. The appropriate fraction containing the Fab fragment can then be collected and concentrated by membrane filtration or the like. For a further description of general techniques for isolating active antibody fragments, see, for example, Khaw, BA et al. J. nucl. Med. 23:1011-1019 (1982); Rousseaux et al. Methods Enzymology, 121:663-69, Academic Press, 1986.

[0048] Antibody digestion with papain produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, the name reflecting its tendency to crystallize. Pepsin treatment produces the F(ab')2 fragment, which has two antigen-binding sites and is still capable of cross-linking the antigen.

[0049] Fab fragments may contain a constant domain of the light chain and a first constant domain (CH1) of the heavy chain. Fab' fragments differ from Fab fragments in that they have residues added to the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteine ​​residues from the antibody hinge region. Fab'-SH in this paper refers to Fab', where the cysteine ​​residues in the constant domain have a free thiol group. F(ab')2 antibody fragments are initially generated as Fab' fragment pairs with a hinge cysteine ​​residue between them. Furthermore, chemical coupling of antibody fragments is also known.

[0050] "Fv" is the smallest antibody fragment containing a complete antigen recognition and binding site. This region consists of a dimer of a tightly non-covalently bound heavy chain and a light chain variable domain. In this configuration, the three CDRs of each variable domain interact to define the antigen-binding site on the surface of the VH-VL dimer. In total, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only the three antigen-specific CDRs) has the ability to recognize and bind antigens, although with lower affinity than the entire binding site.

[0051] Based on the amino acid sequence of their constant structural domains, the “light chains” of antibodies (immunoglobulins) from any vertebrate species can be classified into one of two distinct types, known as kappa (κ) and lambda (λ).

[0052] Immunoglobulins can be classified into different classes based on the amino acid sequence of their heavy chain constant domains. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM. Some of these can be further subdivided into subclasses (isotypes), such as IgG-1, IgG-2, IgG-3, and IgG-4; and IgA-1 and IgA-2. The heavy chain constant domains corresponding to different classes of immunoglobulins are designated α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional conformations of different classes of immunoglobulins are well-known.

[0053] "Humanized antibodies" refer to a class of engineered antibodies whose CDRs are derived from non-human donor immunoglobulins, and whose remaining immunoglobulin-derived portions are derived from one (or more) human immunoglobulins. Furthermore, the framework support residues can be modified to maintain binding affinity. Methods for obtaining "humanized antibodies" are well known to those skilled in the art. (See, for example, Queen et al., Proc. Natl Acad Sci USA, 86:10029-10032 (1989), Hodgson et al., Bio / Technology, 9:421 (1991)).

[0054] As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably and are defined as referring to a biomolecule composed of amino acids linked together by peptide bonds.

[0055] As used herein, the terms “a” and “the” are defined to mean “one or more” and include plural forms, unless the context is inappropriate.

[0056] "Isolated" refers to a biomolecule that does not contain at least some of its naturally occurring components. When used to describe the various polypeptides disclosed herein, "isolated" refers to a polypeptide that has been identified and isolated and / or recovered from the cells or cell cultures in which it is expressed. Typically, isolated polypeptides are prepared through at least one purification step. "Isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities.

[0057] "Recombination" refers to the use of recombinant nucleic acid technology to produce antibodies in foreign host cells.

[0058] The term "antigen" refers to an entity or segment thereof that can induce an immune response in an organism, particularly animals, and more particularly mammals, including humans. This term includes immunogens and the regions responsible for antigenicity or antigenic determinants.

[0059] As used herein, the term "immunogenicity" refers to a substance that induces or enhances the production of antibodies, T cells, or other reactive immune cells against an immunogenic agent and contributes to an immune response in a human or animal. An immune response occurs when an individual produces sufficient antibodies, T cells, and other reactive immune cells in response to an application of the immunogenic composition of this disclosure to alleviate or reduce the condition to be treated.

[0060] "Specific binding" or "specific for" refers to binding to a specific antigen or epitope that is significantly different from nonspecific interactions. Specific binding can be measured, for example, by measuring the binding of a molecule to a control molecule, typically a molecule with a similar structure that does not have binding activity. For instance, specific binding can be determined by competition with a target-like control molecule.

[0061] Specific binding to a particular antigen or epitope can be represented, for example, by the KD of the antibody against the antigen or epitope, said KD being at least about 10. -4 M, at least about 10 -5 M, at least about 10 -6 M, at least about 10 -6 M, at least about 10 -7 M, at least about 10 -8 M, at least about 10 -9 M, or at least about 10 -10 M, at least about 10 -11 M, at least about 10 -12 M or higher, where KD refers to the dissociation rate of a specific antibody-antigen interaction. Typically, an antibody that specifically binds to an antigen will have a KD of 20, 50, 100, 500, 1000, 5,000, 10,000 or more times relative to the antigen or epitope compared to a control molecule.

[0062] Similarly, specific binding to a particular antigen or epitope can be represented, for example, by the KA or Ka of the antibody against the antigen or epitope, which is at least 20, 50, 100, 500, 1000, 5,000, 10,000 or more times greater than that of the control against the epitope, wherein KA or Ka refers to the binding rate of the specific antibody-antigen interaction.

[0063] The "homology" between two sequences is determined by sequence identity. If the two sequences being compared are of different lengths, sequence identity preferably involves the percentage of nucleotide residues in the shorter sequence that are identical to those in the longer sequence. Sequence identity can be routinely determined using computer programs. Deviations that occur in comparisons between a given sequence and the sequences described above in this disclosure can be caused by, for example, additions, deletions, substitutions, insertions, or recombinations.

[0064] In another aspect, this application provides pharmaceutical compositions comprising the mAbs disclosed herein and their antigen-binding fragments. In one embodiment, the pharmaceutical composition may include the isolated antibody or antigen-binding fragment disclosed herein and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition includes the immunoconjugate disclosed herein and a pharmaceutically acceptable carrier. Formulations of the pharmaceutical compositions according to this disclosure can be obtained according to standard methods known to those skilled in the art.

[0065] Antibodies according to the present invention can be prepared in physiologically acceptable formulations using known techniques, and may contain pharmaceutically acceptable carriers, diluents, and / or excipients. For example, antibodies according to this disclosure may include any functionally equivalent antibody or its functional portion, and in particular, monoclonal antibodies comprising any functionally equivalent antibody or its functional portion may be combined with pharmaceutically acceptable carriers, diluents, and / or excipients to form therapeutic compositions.

[0066] Suitable drug carriers, diluents and / or excipients are well known in the art, including, for example, phosphate-buffered saline solutions, water, and emulsions such as oil / water emulsions.

[0067] "Pharmaceutical acceptable" means that compounds, materials, compositions, and dosage forms are suitable for use in contact with human or animal tissues without excessive toxicity, irritation, or other problems or complications, within the bounds of reasonable medical judgment, and in proportion to a reasonable benefit / risk ratio.

[0068] In one embodiment, the pharmaceutical composition may include a protein carrier, such as, for example, serum albumin or immunoglobulin, particularly of human origin. Other bioactive agents may be present in the pharmaceutical compositions of this disclosure, depending on the intended use. The protein pharmaceutically active substance may be present in amounts from 1 ng to 10 mg per dose. In some embodiments, the administration regimen may be in the range of 0.1 μg to 10 mg of the antibody according to this disclosure, particularly in the range of 1.0 μg to 1.0 mg, and more particularly in the range of 1.0 μg to 100 μg, and all individual numbers falling within these ranges are also part of this disclosure. If administration is by continuous infusion, a more suitable dose may be in the range of 0.01 μg to 10 mg units / kg body weight / hour, and all individual values ​​falling within these ranges are also part of this disclosure.

[0069] On the other hand, this application provides a method for treating a subject using an anti-4-1BB antibody or other molecules containing an antigen-binding moiety of an anti-4-1BB antibody. In one embodiment, the method is used to inhibit the growth of tumor cells. In one embodiment, this application provides a method for stimulating a protective autoimmune response, a modified immune response, or an antigen-specific immune response using an antibody.

[0070] In one embodiment, a method of treating cancer includes administering an effective amount of the mAb or antigen-binding fragment thereof disclosed herein to a subject in need of such treatment. In one embodiment, the composition may be administered in combination with other compositions comprising a bioactive substance or compound. In one embodiment, the bioactive substance may include capecitabine, cisplatin, trastuzumab, fulvestrant, tamoxifen, letrozole, exemestane, anastrozole, aminoglutethimide, testosterone, vortexilazole, formexane, fazodazole, letrozole, erlotinib, lafazhenib, dasatinib, gefitinib, imatinib, pazopanib, lapatinib, sunitinib, nilotinib, sorafenib, nab-paclitaxel, derivatives thereof, or combinations thereof.

[0071] The composition can be administered to a subject in a suitable pharmaceutically effective dose in solid, liquid, or aerosol form. Examples of solid compositions include pills, creams, and implantable dosing units. Pills can be administered orally. Therapeutic creams can be applied topically. Implantable dosing units can be applied topically, such as at a tumor site, or can be implanted, for example, subcutaneously, to systemically release the therapeutic composition. Examples of liquid compositions include formulations suitable for intramuscular, subcutaneous, intravenous, and intra-arterial injection, as well as formulations for topical and intraocular administration. Examples of aerosol formulations include inhaled formulations for administration to the lungs.

[0072] The composition can be administered via standard routes of administration. For example, the composition can be administered topically, orally, rectally, nasally, intradermally, intraperitoneally, or parenterically (e.g., intravenously, subcutaneously, or intramuscularly). In one embodiment, administration may be parenterial, such as intravenous administration. Formulations for parenterial administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Non-aqueous solvents include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous solvents may be selected from water, alcohol / aqueous solutions, emulsions, or suspensions (including saline and buffer media). Parenterial carriers include sodium chloride solution, Ringer's glucose, glucose and sodium chloride, lactated Ringer's, or non-volatile oils. Intravenous carriers include fluids and nutritional supplements, electrolyte supplements (e.g., those based on Ringer's glucose), etc. Preservatives, such as antibacterial agents, antioxidants, chelating agents, inert gases, etc., may also be present.

[0073] In one embodiment, the composition can be incorporated into a sustained-release matrix such as a biodegradable polymer, and the polymer can be implanted near the site of delivery, such as a tumor site. The method may include administering a single dose, administering repeated doses at predetermined time intervals, or administering the polymer continuously for a predetermined duration.

[0074] As is well known to those skilled in the art, the dosage of a composition will depend on various factors, such as the condition being treated, the specific composition used, and other clinical factors, such as the patient’s weight, size, sex and general health status, body surface area, the specific compound or composition to be applied, other drugs being administered concurrently, and the route of administration.

[0075] In one embodiment, the term "therapeutic effective amount" refers to the amount of antibody that, when administered to a human or animal, elicits a response sufficient to produce a therapeutic effect in said human or animal. The effective amount is readily determined by those skilled in the art using conventional methods.

[0076] The mAbs disclosed herein, their antigen-binding fragments, and compositions can be used to treat a variety of cancers. Examples of treatable cancers include, but are not limited to, breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, non-small cell lung cancer, glioma, esophageal cancer, nasopharyngeal cancer, anal cancer, rectal cancer, gastric cancer, bladder cancer, cervical cancer, or brain cancer. In one embodiment, the cancer may express the 4-1BB gene. Inhibition of 4-1BB activity with an anti-4-1BB monoclonal antibody or antigen-binding fragment provides a therapeutic effect. In one embodiment, administration of a therapeutically effective amount of a composition comprising an anti-4-1BB monoclonal antibody or antigen-binding fragment may cure, prevent, improve, or delay the development or metastasis of cancer through the action of the pharmaceutical unit.

[0077] This disclosure can be more readily understood by referring to the detailed description of the specific embodiments included herein. Although the invention has been described in detail with reference to certain embodiments thereof, such details should not be construed as limiting the scope of the invention.

[0078] Example Example 1: Production of anti-4-1BB antibodies Develop monoclonal antibodies against human 4-1BB by immunizing New Zealand white rabbits. Figure 1 As shown, animals were immunized with recombinant human embryonic kidney 293 (HEK) cells via subcutaneous injection. The recombinant human embryonic kidney 293 (HEK) cells were transiently transfected with human or cynomolgus monkey 4-1BB at a 1:1 v / v ratio with TiterMax Gold (Group 1) or complete or incomplete Freund's adjuvant (Group 2), and alternatingly supplemented with 2% aluminum gelatin and CpG2007. Figure 1 As shown, blood samples were drawn at different time points during the immunization program. Figure 6 As shown, serum samples taken from all four animals on day 62 were analyzed by FACS assay for human or cynomolgus monkey 4-1BB-specific IgG. All four animals produced human or cynomolgus monkey-specific IgG after immunization.

[0079] Antigen-specific B cells were labeled with biotinylated human and cynomolgus monkey 4-1BB recombinant protein, then labeled with streptavidin-AlexaFluor647, and sorted into multiple 96-well tissue culture plates with one antigen-specific IgG+ B cell per well. The cells were cultured for 9 days to allow differentiation into plasma cells and antibody secretion. The presence of 4-1BB-specific antibodies in the supernatant from these B cell culture (BCC) plates was screened by ELISA and functional assays, as follows: Recombinant human and cynomolgus monkey 4-1BB-IgG ELISA Enhanced CD3-induced T cell activation of purified human CD3+ T cells - γ-interferon secretion detected by ELISA and CD3+ T cell proliferation quantified by Alamar Blue cell viability assay. A total of 693 wells from the BCC plate contained human and cynomolgus monkey 4-1BB-specific IgG. The agonist activity of the 4-1BB-specific antibodies from these 693 BCC wells was then analyzed to enhance anti-CD3-induced CD3+ human T cell activation. Fixed concentrations of control anti-human CD3-specific antibody were combined with fixed concentrations of 4-1BB-specific antibody from the BCC supernatant, and then captured on ELISA plates pre-coated with goat anti-rabbit IgG Fc polyclonal antibody. Purified human CD3+ T cells were added to each well at a concentration of 100,000, and the plates were incubated for 5 days. Figure 7 As shown, on day 5 of the experiment, the contents of each assay well were collected to analyze the amount of interferon-gamma secreted into the culture supernatant and the number of CD3+ T cells in each assay well. From these data, the best 92 BCC wells were used for molecular rescue of the rabbit antibody heavy and light chain variable regions by RT-PCR.

[0080] On day 9 of B cell culture, the supernatant was separated from the B cells and stored in individual plates for later analysis. RNAlater tissue storage reagent was added to each well of the B cell culture plate to preserve RNA from the B cells for RT-PCR amplification of the antibody variable region. This set of 92 BCC wells was used for molecular "rescue" of the antibody variable region. Light and heavy chain variable region sequences were amplified by multiplex RT-PCR using degenerate primers designed to anneal to the leader sequences and constant regions of rabbit IgG and rabbit κ sequences. A second PCR was performed on the light and heavy chains, respectively, using nested primers containing restriction sites. Amplicons from the variable heavy chain PCR were cloned into an expression vector containing human IgG1. Light chain amplicons were cloned into an expression vector containing human IgK. The resulting clones were sequenced and analyzed.

[0081] Rabbit / human chimeric antibodies were generated by transient co-transfection of heavy and light chain expression plasmids produced from each well. Biolayer interferometry analysis on a Fortebio Octt Red 96 instrument confirmed the presence of human and cynomolgus 4-1BB-specific antibodies in the recombinant antibody supernatant. Antibodies in the supernatant were captured using an anti-human Fc biosensor (Pall Fortebio). Association with human or cynomolgus 4-1BB was observed via real-time interferometry by placing the biosensor in wells containing the recombinant human or cynomolgus 4-1BB extracellular domain protein. Dissociation was measured after transferring the biosensor to wells containing 10X kinetic buffer (Pall Fortebio). Software provided by the manufacturer was used to analyze the interferometry data. Figure 2 This paper presents primary BCC screening data and a summary of the corresponding screening data for 34 recombinant chimeric rabbit / human IgG antibodies. Thirty-four chimeric antibodies were rescued from the initial 92 BCC wells and their binding to human and cynomolgus monkey recombinant 4-1BB protein was demonstrated. Figure 2 ).

[0082] Then, the agonist activity of 34 human and cynomolgus monkey 4-1BB specific chimeric rabbit / human IgG antibody groups was measured. This agonist activity enhanced anti-CD3-induced human CD3+ T cell activation. Figure 3 As shown, the EC50 of interferon-gamma secretion was calculated for each chimeric antibody and the background fold increase in human CD3+ T cell proliferation. 50 Without adding other 4-1BB antibodies, the proliferation of human CD3+ T cells using only anti-CD3 antibodies was set to a background value of 1.0, and the background fold increases for different concentrations of chimeric 4-1BB antibodies were calculated. Based on these data, 18 chimeric 4-1BB-specific antibodies were humanized.

[0083] like Figure 4 As shown, 18 chimeric rabbit / human IgG antibodies were successfully humanized from a group of 34 human and cynomolgus monkey 4-1BB-specific chimeric rabbit / human IgG antibodies, and their binding to human and recombinant 4-1BB was determined by octet genome analysis. The agonist activity of these 18 human or cynomolgus monkey 4-1BB-specific humanized antibodies was then measured, and this agonist activity enhanced anti-CD3-induced human CD3+ T cell activation. Figure 5 As shown, the EC50 of interferon-gamma secretion was calculated for each humanized antibody and the background fold increase in human CD3+ T cell proliferation. 50 Without adding other 4-1BB antibodies, the proliferation of human CD3+ T cells using only anti-CD3 antibodies was set to a background value of 1.0, and the background fold increase for different concentrations of humanized 4-1BB antibodies was calculated. Based on these data, 17 out of 18 humanized 4-1BB-specific antibodies showed enhanced anti-CD3-induced human CD3+ T cell activation.

[0084] Although this disclosure has been specifically shown and described with reference to embodiments thereof, those skilled in the art will understand that the foregoing and other changes in form and detail may be made without departing from its spirit and scope. All references cited or referenced in this disclosure are incorporated herein by reference in their entirety.

[0085] sequence list SEQ ID NO:1 411H11 chimeric light chain full-length nucleotide sequence GATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGAGAGCCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTGGTGCTGATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGC CTCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGTATTTATTATGGTACTGATGATGTCATATACCATACTTTCGGCGGAGGGACCGAGGTGG TGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:2 411H11 chimeric light chain variable light chain nucleotide sequence GATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGAGAGCCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTGGTGCTGATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGCCTCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGTATTTATTATGGTACTGATGATGTCATATACCATACTTTCGGCGGAGGGACCGAGGTGGTGTTCAAA SEQ ID NO:3 The full-length amino acid sequence of the 411H11 chimeric light chain. The human κ constant domain is underlined. DVVMTQTPASVSEPVRATVTIKCQASQSIGADLAWYQQKPGQPPKLLIYRASTLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQCIYYGTDDVIYHTFGGGTEVVFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:4 411H11 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DVVMTQTPASVSEPVRATVTIKC QASQSIGADLA WYQQKPGQPPKLLIY RASTLAS GVPSRFSGSGSGTEFTLTISDLECADAATYYC QCIYYGTDDVIYHT FGGGTEVVFK SEQ ID NO:5 411H11 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:6 411H11 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTAACACTCACCTGCACAGTATCTGGATTCACCATCAGTAGCCACCACATGATCTGGGTCCGCCAGGCTCCAGGAGAGGGGCTGCAATACATCGGATTCATTAATGATGGTGACTATACATACTACACGAACTGGGCAAAAGGCCGATTCACCATCTCCAGAACCTCGACTACGGTGGACCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGGGGTTGATGGTACTAGTTATCCTGGCTTGTGGGGCCCAGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:7 The full-length amino acid sequence of the 411H11 chimeric heavy chain. The human γ-1 constant domain is underlined. QSVEESGGRLVTPGTPLTLTCTVSGFTISSHHMIWVRQAPGEGLQYIGFINDGDYTYYTNWAKGRFTISRTSTTVDLKMTSLTAADTATYFCARGVDGTSYPGLWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:8 411H11 chimeric heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are indicated by underlined portions. QSVEESGGRLVTPGTPLTLTCTVSGFTIS SHHMI WVRQAPGEGLQYIG FINDGDYTYYTNWAKG RFTISRTSTTVDLKMTSLTAADTATYFCAR GVDGTSYPGL WGPGTLVTVSS SEQ ID NO:9 413F3 chimeric light chain full-length nucleotide sequence GACGTCGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTTACAGCAATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAACTCCTAATCTATTCTACATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCCGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAACTATTATGGTAGTAGTACTGATAGTTATGGGAATCCTTTCGGCGGAGGCACCGAGGTGGTGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:10 413F3 chimeric light chain variable light chain nucleotide sequence GACGTCGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTTACAGCAATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAACTCCTAATCTATTCTACATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCCGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAACTATTATGGTAGTAGTACTGATAGTTATGGGAATCCTTTCGGCGGAGGCACCGAGGTGGTGTTCAAA SEQ ID NO:11 The full-length amino acid sequence of the 413F3 chimeric light chain. The human κ constant domain is underlined. DVVMTQTPASVEAAVGGTVTIKCQASQSIYSNLAWYQQKPGQPPKLLIYSTSTLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQNYYGSSTDSYGNPFGGGTEVVFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:12 413F3 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DVVMTQTPASVEAAVGGTVTIKC QASQSIYSNLA WYQQKPGQPPKLLIY STSTLAS GVPSRFSGSGSGTEFTLTISDLECADAATYYC QNYYGSSTDSYGNP FGGGTEVVFK SEQ ID NO:13 413F3 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:14 413F3 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGAGGGATCCCTGACACTCACCTGCACAGGCTCTGGAATCGACTTCAGTAGCAACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGGTGATAGTAGTGATAATAGTTACTCCGCGAGCTGGGCGAAAGGGCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGATCTGGTTATAGCTATTTAGGCTACTTTAACTTGTGGGGCCCAGGGACCCTGGTCACCGTCTCGAGC SEQ ID NO:15 The full-length amino acid sequence of the 413F3 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGDLVKPEGSLTLTCTGSGIDFSSNYMCWVRQAPGKGLEWIACIYGDSSDNSYSASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARSGYSYLGYFNLWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:16 413F3 chimeric heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. QSLEESGGDLVKPEGSLTLTCTGSGIDFS SNYMC WVRQAPGKGLEWIA CIYGDSSDNSYSASWAKG RFTISKTSSTTVTLQMTSLTAADTATYFCAR SGYSYLGYFNL WGPGTLVTVSS SEQ ID NO:17 416F8 chimeric light chain full-length nucleotide sequence GCGCAAGTGCTGACCCAGACTGCATCGTCCGTGTCTGCACCTGTGGGCGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGACTGTTTATAATAACAACTTGTTATCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATTATGCATCCACTCTGGCATTTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTTCTGTCAAGGCGGTTATAGTGGTTGGATTTATGTTTTCGGCGGAGGCACCGAGGTGGAGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:18 416F8 chimeric light chain variable light chain nucleotide sequence GCGCAAGTGCTGACCCAGACTGCATCGTCCGTGTCTGCACCTGTGGGCGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGACTGTTTATAATAACAACTTGTTATCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATTATGCATCCACTCTGGCATTTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTTCTGTCAAGGCGGTTATAGTGGTTGGATTTATGTTTTCGGCGGAGGCACCGAGGTGGAGGTCAAA SEQ ID NO:19 The full-length amino acid sequence of the 416F8 chimeric light chain. The human κ constant domain is underlined. AQVLTQTASSVSAPVGGTVTISCQSSQTVYNNNLLSWYQQKPGQRPKLLIYYASTLAFGVPSRFKGSGSGTEFTLTISDLECDDAATYFCQGGYSGWIYVFGGGTEVEVK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:20 The 416F8 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. AQVLTQTASSVSAPVGGTVTISC QSSQTVYNNNLLS WYQQKPGQRPKLLIY YASTLAF GVPSRFKGSGSGTEFTLTISDLECDDAATYFC QGGYSGWIYV FGGGTEVEVK SEQ ID NO:21 416F8 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:22 416F8 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAACTACTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAATCATTAGTAGTAGTGGTAGCGCATACTACGCGAGCTGGGCTAAAGGCCGATTCACCATCTCCAGAACCTCGACCACGGTGGACCTGAGAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGGACTACGGCATGGACCTCTGGGGCCAAGGGACCCTGGTCACCGTCTCGAGC SEQ ID NO:23 The full-length amino acid sequence of the 416F8 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGRLVTPGTPLTLTCTASGFSLSNYYMNWVRQAPGKGLEYIGIISSSGSAYYASWAKGRFTISRTSTTVDLRITSPTTEDTATYFCARGDYGMDLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:24 The amino acid sequence of the 416F8 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QSLEESGGRLVTPGTPLTLTCTASGFSLS NYYMN WVRQAPGKGLEYIG IISSSGSAYYASWAKG RFTISRTSTTVDLRITSPTTEDTATYFCAR GDYGMDL WGQGTLVTVSS SEQ ID NO:25 416G1 chimeric light chain full-length nucleotide sequence GACGTCGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGGGAGGCGCAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTGGTAGTGATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGTATTTATTATGGTAGTGATGATGTCATATACCATACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:26 416G1 chimeric light chain variable light chain nucleotide sequence GACGTCGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGGGAGGCGCAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTGGTAGTGATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGTATTTATTATGGTAGTGATGATGTCATATACCATACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA SEQ ID NO:27 The full-length amino acid sequence of the 416G1 chimeric light chain. The human κ constant domain is underlined. DVVMTQTPASVSEPVGGAVTIKCQASQSIGSDLAWYQQKPGQPPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQCIYYGSDDVIYHTFGGGTEVVVK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:28 416G1 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DVVMTQTPASVSEPVGGAVTIKC QASQSIGSDLA WYQQKPGQPPKLLIY RASTLAS GVSSRFKGSGSGTEFTLTISDLECADAATYYC QCIYYGSDDVIYHT FGGGTEVVVK SEQ ID NO:29 416G1 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:30 416G1 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCACTATCAATAGCTACCACATGATCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAATACATCGGATTCATTAATGATGGTGGTTTCACATACTACGCGAGCTGGGCAAAAGGCCGATTTATCATCTCCAGAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGTCGCGGACACGGCCACCTATTTCTGTGCCAGAGGGGTTGATGGTACTAGTTATCCTGACTTATGGGGCCCGGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:31 The full-length amino acid sequence of the 416G1 chimeric heavy chain. The human γ-1 constant domain is underlined. QSVEESGGRLVTPGTPLTLTCTVSGFTINSYHMIWVRQAPGEGLEYIGFINDGGFTYYASWAKGRFIISRTSTTVDLKMTSLTVADTATYFCARGVDGTSYPDLWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:32 416G1 chimeric heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. QSVEESGGRLVTPGTPLTLTCTVSGFTIN SYHMI WVRQAPGEGLEYIG FINDGGFTYYASWAKG RFIISRTSTTVDLKMTSLTVADTATYFCAR GVDGTSYPDL WGPGTLVTVSS SEQ ID NO:33 418E10 chimeric light chain full-length nucleotide sequence GCCCTGGTGATGACCCAGACTCCATCCCCTGTGTCTGCGGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGCATTGGTAGTAACTTGAACTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATTTATTATGTATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGACGGTACTGCTTTCGGCGGAGGCACCGAGGTGGAGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:34 418E10 chimeric light chain variable light chain nucleotide sequence GCCCTGGTGATGACCCAGACTCCATCCCCTGTGTCTGCGGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGCATTGGTAGTAACTTGAACTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATTTATTATGTATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGACGGTACTGCTTTCGGCGGAGGCACCGAGGTGGAGGTCAAA SEQ ID NO:35 The full-length amino acid sequence of the 418E10 chimeric light chain. The human κ constant domain is underlined. ALVMTQTPSPVSAAVGGTVTINCQASQSIGSNLNWYQQKPGQPPKLLIYYVSTLASGVPSRFKGSGSGTEYTLTISGVQCDDAATYYCLGVWNYWGDDGTAFGGGTEVEVK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:36 The 418E10 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. ALVMTQTPSPVSAAVGGTVTINC QASQSIGSNLN WYQQKPGQPPKLLIY YVSTLAS GVPSRFKGSGSGTEYTLTISGVQCDDAATYYC LGVWNYWGDDGTA FGGGTEVEVK SEQ ID NO:37 418E10 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:38 418E10 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGATTTCTCCCTCAGTACCTATTATATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAAGTATTTATGATAGTGGTGCCGCATACTACGCGACCTGGGCGAAGGGCCGATTCACCATCTCCAGAACGTCGACCACGGTGGATCTGAGAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATCCTATTAATAATGCCATCTGGGGCCAAGGGACCCTCGTCACCGTCTCGAGC SEQ ID NO:39 The full-length amino acid sequence of the 418E10 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGRLVTPGTPLTLTCTASDFSLSTYYMSWVRQAPGKGLEWIGSIYDSGAAYYATWAKGRFTISRTSTTVDLRMTSLTAADTATYFCARDPINNAIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:40 The amino acid sequence of the 418E10 chimeric heavy chain variable heavy chain. Complementarity-determining regions are indicated by underlined portions. QSLEESGGRLVTPGTPLTLTCTASDFSLS TYYMS WVRQAPGKGLEWIG SIYDSGAAYYATWAKG RFTISRTSTTVDLRMTSLTAADTATYFCAR DPINNAI WGQGTLVTVSS SEQ ID NO:41 418E4 chimeric light chain full-length nucleotide sequence GCCCTGGTGATGACCCAGACTCCATCCCCTGTGTCTGCGGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTATTGCTACTAACTTGAACTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTATACATCCAGTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGCACAGAGTTCACTCTCACCATCAGCGGTGTGCAGTGTGACGATGCTGCCACTTACTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGATGGTACTGCTTTCGGCGGAGGGACCGAGGTGGAGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:42 418E4 chimeric light chain variable light chain nucleotide sequence GCCCTGGTGATGACCCAGACTCCATCCCCTGTGTCTGCGGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTATTGCTACTAACTTGAACTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTATA CATCCAGTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGCACAGAGTTCACTCTCACCATCAGCGGTGTGCAGTGTGACGATGCTGCCACTTACTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGATGGTACTGCTTTCGGCGGAGGGACCGAGGTGGAGTTCAAA SEQ ID NO:43 The full-length amino acid sequence of the 418E4 chimeric light chain. The human κ constant domain is underlined. ALVMTQTPSPVSAAVGGTVTINCQASQSIATNLNWYQQKPGQPPKLLIYYTSSLASGVPSRFSGSGSGTEFTLTISGVQCDDAATYYCLGVWNYWGDDGTAFGGGTEVEFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:44 The 418E4 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. ALVMTQTPSPVSAAVGGTVTINC QASQSIATNLN WYQQKPGQPPKLLIY YTSSLAS GVPSRFSGSGSGTEFTLTISGVQCDDAATYYC LGVWNYWGDDGTA FGGGTEVEFK SEQ ID NO:45 418E4 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:46 418E4 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGAATTCTCCCTCAGTAGCTACTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAAGTATTTATGCTAGTGGTAGCGCATACTACGCGAGTTGGGCGAAGGGCCGATTCACCATCTCCAGAACGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGTCAGAGATCCTATTAACAATGACATCTGGGGCCCAGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:47 The full-length amino acid sequence of the 418E4 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGRLVTPGTPLTLTCTASEFSLSSYYMSWVRQAPGKGLEWIGSIYASGSAYYASWAKGRFTISRTSTTVDLKMTSLTAADTATYFCVRDPINNDIWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:48 The amino acid sequence of the 418E4 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QSLEESGGRLVTPGTPLTLTCTASEFSLS SYYMS WVRQAPGKGLEWIG SIYASGSAYYASWAKG RFTISRTSTTVDLKMTSLTAADTATYFCVR DPINNDI WGPGTLVTVSS SEQ ID NO:49 418H5 chimeric light chain full-length nucleotide sequence GCCCAAGTGCTGACCCAGACTCCAGCCTCCGTGTCTGCAACTGTGGGAAGCACAGTCACCATCAGTTGCCAGTCCAGTCCGAGTGTTTATAAGAACAACCAATTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAACTCCTGATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTGCAGGCGGTTATAGTAGTAGTAGTGATACTGCTTTCGGCGGAGGGACCGAGGTGGAGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:50 418H5 chimeric light chain variable light chain nucleotide sequence GCCCAAGTGCTGACCCAGACTCCAGCCTCCGTGTCTGCAACTGTGGGAAGCACAGTCACCATCAGTTGCCAGTCCAGTCCGAGTGTTTATAAGAACAACCAATTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAACTCCTGATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTGCAGGCGGTTATAGTAGTAGTAGTGATACTGCTTTCGGCGGAGGGACCGAGGTGGAGGTCAAA SEQ ID NO:51 The full-length amino acid sequence of the 418H5 chimeric light chain. The human κ constant domain is underlined. AQVLTQTPASVSATVGSTVTISCQSSPSVYKNNQLAWYQQKPGQPPKLLIYLASTLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCAGGYSSSSDTAFGGGTEVEVK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:52 The 418H5 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. AQVLTQTPASVSATVGSTVTISC QSSPSVYKNNQLA WYQQKPGQPPKLLIY LASTLAS GVPSRFKGSGSGTEFTLTISDLECADAATYYC AGGYSSSSDTA FGGGTEVEVK SEQ ID NO:53 418H5 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:54 418H5 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTGCCTACCACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAATGATTGGTAGTAGTGGTACCATACACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGGACAGTTATAATAGTGATTATGCCTTTAACTTATGGGGCCCAGGGACCCTGGTCACCGTCTCGAGC SEQ ID NO:55 The full-length amino acid sequence of the 418H5 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGRLVTPGTPLTLTCTVSGIDLSAYHMSWVRQAPGKGLEYIGMIGSSGTIHYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARDSYNSDYAFNLWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:56 The amino acid sequence of the 418H5 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QSLEESGGRLVTPGTPLTLTCTVSGIDLS AYHM SWVRQAPGKGLEYIG MIGSSGTIHYANWAKG RFTISKTSTTVDLKITSPTTEDTATYFCAR DSYNSDYAFNL WGPGTLVTVSS SEQ ID NO:57 419D9 chimeric light chain full-length nucleotide sequence GCTCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCCGCTGTGGGAGGCACAGTCACCATCAACTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCGCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTATAATACTGTTACTGATACTTTTGCTTTCGGCAGAGGCACCGAGGTGGAGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:58 419D9 chimeric light chain variable light chain nucleotide sequence GCTCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCCGCTGTGGGAGGCACAGTCACCATCAACTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCGCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTATAATACTGTTACTGATACTTTTGCTTTCGGCAGAGGCACCGAGGTGGAGGTCAAA SEQ ID NO:59 The full-length amino acid sequence of the 419D9 chimeric light chain. The human κ constant domain is underlined. AQVLTQTASPVSAAVGGTVTINCQSSQSVYSNWLSWYQQKPGQPPKRLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGYNTVTDTFAFGRGTEVEVK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:60 419D9 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. AQVLTQTASPVSAAVGGTVTINC QSSQSVYSNWLS WYQQKPGQPPKRLIY SASTLAS GVPSRFKGSGSGTQFTLTISDLECDDAATYYC AGGYNTVTDTFA FGRGTEVEVK SEQ ID NO:61 419D9 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:62 419D9 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCTTCAGTAGCAGGCACTACATGTGTTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAGTGGATCGCATGCATTTATACTGGTAGTAGTGGTACTCCTCACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCCAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTTCGAGCGAAGGTAACCTGTGGGGCCCAGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:63 The full-length amino acid sequence of the 419D9 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGDLVKPGASLTLTCTASGFSFSSRHYMCWVRQAPGEGLEWIACIYTGSSGTPHYASWAKGRFTISQTSSTTVTLQMTSLTAADTATYFCSSEGNLWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:64 419D9 chimeric heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. QSLEESGGDLVKPGASLTLTCTASGFSFS SRHYMC WVRQAPGEGLEWIA CIYTGSSGTPHYASWAKG RFTISQTSSTTVTLQMTSLTAADTATYFCSS EGNL WGPGTLVTVSS SEQ ID NO:65 420H5 chimeric light chain full-length nucleotide sequence GCCCTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGTGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGCACCGAGGTGGTGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:66 420H5 chimeric light chain variable light chain nucleotide sequence GCCCTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGTGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGCACCGAGGTGGTGGTCAAA SEQ ID NO:67 The full-length amino acid sequence of the 420H5 chimeric light chain. The human κ constant domain is underlined. ALVMTQTPASVSAAVGGTVTINCQASEDIDTYLAWYQQKPGQPPKLLIFYASDLASGVPSRFKGSGSGTEFTLTISGVQCDDAATYYCQGGYYTSSADTRGAFGGGTEVVVK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:68 The amino acid sequence of the 420H5 chimeric light chain variable light chain. Complementarity-determining regions are underlined. ALVMTQTPASVSAAVGGTVTINC QASEDIDTYLA WYQQKPGQPPKLLIF YASDLAS GVPSRFKGSGSGTEFTLTISGVQCDDAATYYC QGGYYTSSADTRGA FGGGTEVVVK SEQ ID NO:69 420H5 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:70 420H5 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGGACCCTGGTCACCGTCTCGAGC SEQ ID NO:71 The full-length amino acid sequence of the 420H5 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGDLVKPGASLTLTCTASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARDSSSYYMFNLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:72 The amino acid sequence of the 420H5 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QSLEESGGDLVKPGASLTLTCTASGFSFS SNYWIC WVRQAPGKGLEWIA CIYVGSSGDTYYASWAKG RFTISKTSSTTVTLQMTSLTAADTATYFCAR DSSSYYMFNL WGQGTLVTVSS SEQ ID NO:73 420H6 chimeric light chain full-length nucleotide sequence GCTCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCCGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTGTTTATAGTAACTGGTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCGCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCAT TAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:74 420H6 chimeric light chain variable light chain nucleotide sequence GCTCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCCGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTGTTTATAGTAACTGGTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCGCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATTAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAA SEQ ID NO:75 The full-length amino acid sequence of the 420H6 chimeric light chain. The human κ constant domain is underlined. AQVLTQTASPVSAAVGGTVTINCQASQSVYSNWLSWYQQKPGQPPKRLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGYNTVIDTFAFGGGTEVEFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:76 420H6 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. AQVLTQTASPVSAAVGGTVTINC QASQSVYSNWLS WYQQKPGQPPKRLIY SASTLAS GVPSRFKGSGSGTQFTLTISDLECDDAATYYC AGGYNTVIDTFA FGGGTEVEFK SEQ ID NO:77 420H6 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:78 420H6 chimeric heavy chain variable heavy chain nucleotide sequence CAGCAGCAGCTGGAGGAGTCCGGGGGAGGCCTGGTCAAGCCTGGAGGAACCCTGACACTCACCTGCAAAGCCTCTGGAATTGACTTCAGTAGTAGTTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAGTGGATCGCATGCATTTATACTGGTGGTAGTGGTACTCCTCACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCCAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:79 Full-length amino acid sequence of the 420H6 chimeric heavy chain. The human γ-1 constant domain is underlined. QQQLEESGGGLVKPGGTLTLTCKASGIDFSSSYYMCWVRQAPGEGLEWIACIYTGGSGTPHYASWAKGRFTISQTSSTTVTLQMTSLTAADTATYFCAREGSLWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:80 The amino acid sequence of the 420H6 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QQQLEESGGGLVKPGGTLTLTCKASGIDFS SSYYMC WVRQAPGEGLEWIA CIYTGGSGTPHYASWAKG RFTISQTSSTTVTLQMTSLTAADTATYFCAR EGSL WGQGTLVTVSS SEQ ID NO:81 459F1 chimeric light chain full-length nucleotide sequence GCTCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCCGCTGTGGGAGGCACAGTCACCATCAACTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCCTCGCGGTTTAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTACAATACTGTAACTGATACTTTTGCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:82 459F1 chimeric light chain variable light chain nucleotide sequence GCTCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCCGCTGTGGGAGGCACAGTCACCATCAACTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCCTCGCGGTTTAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTACAATACTGTAACTGATACTTTTGCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAA SEQ ID NO:83 The full-length amino acid sequence of the 459F1 chimeric light chain. The human κ constant domain is underlined. AQVLTQTASPVSAAVGGTVTINCQSSQSVYSNWFSWYQQKPGQPPKLLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGYNTVTDTFAFGGGTEVEFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:84 The amino acid sequence of the 459F1 chimeric light chain variable light chain. Complementarity-determining regions are underlined. AQVLTQTASPVSAAVGGTVTINC QSSQSVYSNWFS WYQQKPGQPPKLLIY SASTLAS GVPSRFKGSGSGTQFTLTISDLECDDAATYYC AGGYNTVTDTFA FGGGTEVEFK SEQ ID NO:85 459F1 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:86 459F1 chimeric heavy chain variable heavy chain nucleotide sequence GAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCACCTGCACAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATGTATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTGGGCGAAAGGCCGGTTCACCATCTCCCAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGAGAAGGTAACCTGTGGGGCCCGGGGACCCTGGTCACCGTCTCGAGC SEQ ID NO:87 The full-length amino acid sequence of the 459F1 chimeric heavy chain. The human γ-1 constant domain is underlined. ESLEESGGDLVKPGASLTLTCTASGIDFSRRYYMCWVRQAPGKGLEWIACMYTGSRDTPHYASWAKGRFTISQTSSTTVTLQMTSLTAADTATYFCAREGNLWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:88 The amino acid sequence of the 459F1 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. ESLEESGGDLVKPGASLTLTCTASGIDFS RRYYMC WVRQAPGKGLEWIA CMYTGSRDTPHYASWAKG RFTISQTSSTTVTLQMTSLTAADTATYFCAR EGNL WGPGTLVTVSS SEQ ID NO:89 460C3 chimeric light chain full-length nucleotide sequence GCCCAAGTGCTGACCCAGACTCCATCGTCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCCTCGCGGTTTAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:90 460C3 chimeric light chain variable light chain nucleotide sequence GCCCAAGTGCTGACCCAGACTCCATCGTCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCCTCGCGGTTTAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAA SEQ ID NO:91 The full-length amino acid sequence of the 460C3 chimeric light chain. The human κ constant domain is underlined. AQVLTQTPSSVSAAVGGTVSISCQSSQSVYSNWFSWYQQKPGQPPKLLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGYNTVIDTFAFGGGTEVEFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:92 The amino acid sequence of the 460C3 chimeric light chain variable light chain is shown. Complementarity-determining regions are underlined. AQVLTQTPSSVSAAVGGTVSISC QSSQSVYSNWFS WYQQKPGQPPKLLIY SASTLAS GVPSRFKGSGSGTQFTLTISDLECDDAATYYC AGGYNTVIDTFA FGGGTEVEFK SEQ ID NO:93 460C3 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:94 460C3 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCACCTGCACAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCCAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:95 The full-length amino acid sequence of the 460C3 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGDLVKPGASLTLTCTASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASWAKGRFTISQTSSTTVTLQMTSLTAADTATYFCAREGSLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:96 The amino acid sequence of the 460C3 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QSLEESGGDLVKPGASLTLTCTASGIDFS RRYYMC WVRQAPGKGLEWIA CIYTGSRDTPHYASWAKG RFTISQTSSTTVTLQMTSLTAADTATYFCAR EGSL WGQGTLVTVSS SEQ ID NO:97 464D11 chimeric light chain full-length nucleotide sequence GCGCAAGTGCTGACCCAGACTCCATCGCCTGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAGTAACAGCTTCTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCGCCTGATCTATTCTGCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGTTTATAGTGATAATACTTATGTTTTCGGCGGAGGCACCGAGGTGGAGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:98 464D11 chimeric light chain variable light chain nucleotide sequence GCGCAAGTGCTGACCCAGACTCCATCGCCTGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAGTAACAGCTTCTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCGCCTGATCTATTCTGCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGTTTATAGTGATAATACTTATGTTTTCGGCGGAGGCACCGAGGTGGAGTTCAAA SEQ ID NO:99 The full-length amino acid sequence of the 464D11 chimeric light chain. The human κ constant domain is underlined. AQVLTQTPSPVSAAVGGTVTINCQSSQSVYSNSFLSWYQQKPGQPPKRLIYSASDLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGVYSDNTYVFGGGTEVEFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:100 464D11 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. AQVLTQTPSPVSAAVGGTVTINC QSSQSVYSNSFLS WYQQKPGQPPKRLIY SASDLAS GVPSRFKGSGSGTQFTLTISDLECDDAATYYC AGVYSDNTYV FGGGTEVEFK SEQ ID NO:101 464D11 chimeric heavy chain full-length nucleotide sequence CAGTCGGTGGAGGAGTCCGGCGGTCGCCTGGTAAAGCCTGACGAATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTCACTACTGGATGACTTGGGTCCGACAGGCTCCAGGGAAGGGACTGGAATACATCGGATTCATTA SEQ ID NO:102 464D11 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGGTGGAGGAGTCCGGCGGTCGCCTGGTAAAGCCTGACGAATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTCACTACTGGATGACTTGGGTCCGACAGGCTCCAGGGAAGGGACTGGAATACATCGGATTCATTAATGTTGGTGGTGACACATCTTACGCGAGCTGGTCGAAAGGCCGATTCACCATCTCCAAGGCCTCGACCACGGTGGATCTGAAGATCAGTAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGGCAGAGGTGGTCTGACTTTTGGTTGGGACTTGTGGGGCCCAGGGACCCTCGTCACCGTCTCGAGC SEQ ID NO:103 The full-length amino acid sequence of the 464D11 chimeric heavy chain. The human γ-1 constant domain is underlined. QSVEESGGRLVKPDESLTLTCTASGFSLSHYWMTWVRQAPGKGLEYIGFINVGGDTSYASWSKGRFTISKASTTVDLKISSLTTEDTATYFCGRGGLTFGWDLWGPGTLVTVSSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:104 464D11 chimeric heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. QSVEESGGRLVKPDESLTLTCTASGFSLS HYWMT WVRQAPGKGLEYIG FINVGGDTSYASWSKG RFTISKASTTVDLKISSLTTEDTATYFCGR GGLTFGWDL WGPGTLVTVSS SEQ ID NO:105 466F6 chimeric light chain full-length nucleotide sequence GATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTAGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTATTGTCAGTGTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:106 466F6 chimeric light chain variable light chain nucleotide sequence GATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTAGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTATTGTCAGTGTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAA SEQ ID NO:107 The full-length amino acid sequence of the 466F6 chimeric light chain. The human κ constant domain is underlined. DVVMTQTPASVSEPVGGTVTIKCQASQNIRTYLSWYQQKPGQRPKLLIYAAANLASGVPSRFSGSRSGTEFTLTISDLECADAATYYCQCTYLGTDYVGGAFGGGTEVEFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:108 The 466F6 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DVVMTQTPASVSEPVGGTVTIKC QASQNIRTYLS WYQQKPGQRPKLLIY AAANLAS GVPSRFSGSRSGTEFTLTISDLECADAATYYC QCTYLGTDYVGGA FGGGTEVEFK SEQ ID NO:109 466F6 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:110 466F6 chimeric heavy chain variable heavy chain nucleotide sequence CGGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTGGGCGAGAGGCCGATTCACCATCTCCAGACCCTCGTCGACCACGGTGGATCTGAAGATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCCGGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:111 The full-length amino acid sequence of the 466F6 chimeric heavy chain. The human γ-1 constant domain is underlined. RSLEESGGRLVTPGTPLTLTCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASWARGRFTISRPSSTTVDLKMTSLTTEDTATYFCARDSGYSDPMWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:112 The amino acid sequence of the 466F6 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. RSLEESGGRLVTPGTPLTLTCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASWARG RFTISRPSSTTVDLKMTSLTTEDTATYFCAR DSGYSDPM WGPGTLVTVSS SEQ ID NO:113 470B6 chimeric light chain full-length nucleotide sequence GCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAGTAACAACCAATTATCCTGGTTTCAGCAGAAATCAGGGCAGCCTCCCAAGCTCCTGATCTATGATGCATCCAATCTGGCATCTGGGGTCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCAGCGTGCAGTGTGACGATGCTGCCACTTACCACTGTCTAGGCGGTAGTGATGATGATGGTGATATTGCTTTCGGCGGAGGCACCGAGGTGGTGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:114 470B6 chimeric light chain variable light chain nucleotide sequence GCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAGTAACAACCAATTATCCTGGTTTCAGCAGAAATCAGGGCAGCCTCCCAAGCTCCTGATCTATGATGCATCCAATCTGGCATCTGGGGTCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCAGCGTGCAGTGTGACGATGCTGCCACTTACCACTGTCTAGGCGGTAGTGATGATGATGGTGATATTGCTTTCGGCGGAGGCACCGAGGTGGTGTTCAAA SEQ ID NO:115 The full-length amino acid sequence of the 470B6 chimeric light chain. The human κ constant domain is underlined. AAVLTQTPSPVSAAVGGTVTISCQSSQSVYSNNQLSWFQQKSGQPPKLLIYDASNLASGVPSRFSGSGSGTQFTLTISSVQCDDAATYHCLGGSDDDGDIAFGGGTEVVFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:116 The 470B6 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. AAVLTQTPSPVSAAVGGTVTISC QSSQSVYSNNQLS WFQQKSGQPPKLLIY DASNLAS GVPSRFSGSGSGTQFTLTISSVQCDDAATYHC LGGSDDDGDIA FGGGTEVVFK SEQ ID NO:117 470B6 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:118 470B6 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCACTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAGCTACTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAATGGATCGGAAGTATTTATGGTAGTGGTGCCGCATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAGAACGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATCCTATTAACAATGCCATGTGGGGCCCAGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:119 The full-length amino acid sequence of the 470B6 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGRLVTPGTPLTLTCTASGFSLSSYYMSWVRQAPGKGLEWIGSIYGSGAAYYASWAKGRFTISRTSTTVDLKMTSLTAADTATYFCARDPINNAMWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:120 The amino acid sequence of the 470B6 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QSLEESGGRLVTPGTPLTLTCTASGFSLS SYYMS WVRQAPGKGLEWIG SIYGSGAAYYASWAKG RFTISRTSTTVDLKMTSLTAADTATYFCAR DPINNAM WGPGTLVTVSS SEQ ID NO:121 470C6 chimeric light chain full-length nucleotide sequence GCCCTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATAACTATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCTCAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGTGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCGGTTACTATACTAGTAGTACTGATACGAGGGGTGCTTTCGGCGGAGGCACCGAGGTGGTGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:122 470C6 chimeric light chain variable light chain nucleotide sequence GCCCTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATAACTATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCTCAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGTGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCGGTTACTATACTAGTAGTACTGATACGAGGGGTGCTTTCGGCGGAGGCACCGAGGTGGTGGTCAAA SEQ ID NO:123 The full-length amino acid sequence of the 470C6 chimeric light chain. The human κ constant domain is underlined. ALVMTQTPASVSAAVGGTVTINCQASEDIDNYLAWYQQKPGQPPKLLIFYASDLASGVPSRFSGSGSGTQFTLTISGVQCDDAATYYCQGGYYTSSTDTRGAFGGGTEVVVK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:124 The 470C6 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. ALVMTQTPASVSAAVGGTVTINC QASEDIDNYLA WYQQKPGQPPKLLIF YASDLAS GVPSRFSGSGSGTQFTLTISGVQCDDAATYYC QGGYYTSSTDTRGA FGGGTEVVVK SEQ ID NO:125 470C6 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:126 470C6 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCATTGGAGGAGGCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCACCTGCACAGCCTCTGGCTTCTCCTTCACTAGCAGCTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATACTGGTAGTAGTGGTAGCACTTACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGCACCCTCGTCACCGTCTCGAGC SEQ ID NO:127 The full-length amino acid sequence of the 470C6 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEEAGGDLVKPGASLTLTCTASGFSFTSSYYMCWVRQAPGKGLEWIACIYTGSSGSTYYANWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARDSSSYYMFNLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:128 The amino acid sequence of the 470C6 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QSLEEAGGDLVKPGASLTLTCTASGFSFT SSYYMC WVRQAPGKGLEWIA CIYTGSSGSTYYANWAKG RFTISKTSSTTVTLQMTSLTAADTATYFCAR DSSSYYMFNL WGQGTLVTVSS SEQ ID NO:129 472E4 chimeric light chain full-length nucleotide sequence GCAGCCGTGCTGACCCAGACTCCATCTTCCACGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAACAATGCTTTAGCCTGGTATCAGAAAAAACCAGGACAGCCTCCCAAGCTCCTGATCTATTTGGCTTCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTATTATTGTCTAGGTGTTTATAATGATGATGTTGATAATGGTTTCGGCGGAGGCACCGAGGTGGTGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:130 472E4 chimeric light chain variable light chain nucleotide sequence GCAGCCGTGCTGACCCAGACTCCATCTTCCACGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAACAATGCTTTAGCCTGGTATCAGAAAAAACCAGGACAGCCTCCCAAGCTCCTGATCTATTTGGCTTCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTATTATTGTCTAGGTGTTTATAATGATGATGTTGATAATGGTTTCGGCGGAGGCACCGAGGTGGTGTTCAAA SEQ ID NO:131 The full-length amino acid sequence of the 472E4 chimeric light chain. The human κ constant domain is underlined. AAVLTQTPSSTSAAVGGTVTISCQSSQSVYNNNALAWYQKKPGQPPKLLIYLASTLASGVPSRFSGSGSGTQFTLTISDLECDDAATYYCLGVYNDDVDNGFGGGTEVVFK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:132 The 472E4 chimeric light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. AAVLTQTPSSTSAAVGGTVTISC QSSQSVYNNNALA WYQKKPGQPPKLLIY LASTLAS GVPSRFSGSGSGTQFTLTISDLECDDAATYYC LGVYNDDVDNG FGGGTEVVFK SEQ ID NO:133 472E4 chimeric heavy chain full-length nucleotide sequence SEQ ID NO:134 472E4 chimeric heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGAGGATCCCTGACACTCACCTGCACCGTCTCTGGATTCTCCCTCAATAACAATGCAATAAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTTGCAATCATACAAAATACTGGTACCACAGACTACGCGAGGTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATTTGAAAATCAACAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGGCAGAGGGTATGGTTTTGAGTCGGAGCTTGTCATCTGGGGCCCGGGCACCCTGGTCACCGTCTCGAGC SEQ ID NO:135 The full-length amino acid sequence of the 472E4 chimeric heavy chain. The human γ-1 constant domain is underlined. QSLEESGGRLVTPGGSLTLTCTVSGFSLNNNAISWVRQAPGKGLEWVAIIQNTGTTDYARWAKGRFTISKTSTTVDLKINSPTTEDTATYFCGRGYGFESELVIWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:136 The amino acid sequence of the 472E4 chimeric heavy chain variable heavy chain. Complementarity-determining regions are underlined. QSLEESGGRLVTPGGSLTLTCTVSGFSLN NNAIS WVRQAPGKGLEWVA IIQNTGTTDYARWAKG RFTISKTSTTVDLKINSPTTEDTATYFCGR GYGFESELVI WGPGTLVTVSS SEQ ID NO:137 411H11 Humanized Light Chain Full-Length Nucleotide Sequence GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAGCATTGGTGCTGATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGCCTCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAAGCTATTTATTATGGTACTGATGATGTCATATACCATACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:138 411H11 Humanized Light Chain Variable Light Chain Nucleotide Sequence GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAGCATTGGTGCTGATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGCCTCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAAGCTATTTATTATGGTACTGATGATGTCATATACCATACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:139 The full-length amino acid sequence of the humanized light chain 411H11. The human κ constant domain is underlined. DVVMTQSPSSVSASVGDRVTITCQASQSIGADLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQAIYYGTDDVIYHTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:140 The 411H11 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DVVMTQSPSSVSASVGDRVTITC QASQSIGADLA WYQQKPGKAPKLLIY RASTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QAIYYGTDDVIYHT FGGGTKVEIK SEQ ID NO:141 411H11 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:142 411H11 Humanized Heavy Chain Variable Heavy Chain Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTAGCCACCACATGATCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGCAATACATCGGATTCATTAATGATGGTGACTATACATACTACACGAACTCCGCAAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGGGTTGATGGTACTAGTTATCCTGGCTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:143 The full-length amino acid sequence of the humanized heavy chain 411H11. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGGSLRLSCAASGFTISSHHMIWVRQAPGKGLQYIGFINDGDYTYYTNSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGVDGTSYPGLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:144 The 411H11 humanized heavy chain variable heavy chain amino acid sequence. The complementarity-determining region is indicated by underline. EVQLVESGGGLVQPGGSLRLSCAASGFTIS SHHMI WVRQAPGKGLQYIG FINDGDYTYYTNSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GVDGTSYPGL WGQGTLVTVSS SEQ ID NO:145 413F3 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTTACAGCAATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTCTACATCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAACTATTATGGTAGTAGTACTGATAGTTATGGGAATCCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:146 413F3 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTTACAGCAATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTCTACATCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAACTATTATGGTAGTAGTACTGATAGTTATGGGAATCCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:147 The full-length amino acid sequence of the 413F3 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSSLSASVGDRVTITCQASQSIYSNLAWYQQKPGKVPKLLIYSTSTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYYGSSTDSYGNPFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:148 413F3 humanized light chain variable light chain amino acid sequence. Complementation-determining regions are underlined. DIQMTQSPSSLSASVGDRVTITC QASQSIYSNLA WYQQKPGKVPKLLIY STSTLAS GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QNYYGSSTDSYGNP FGGGTKVEIK SEQ ID NO:149 413F3 humanized heavy chain full-length nucleotide sequence SEQ ID NO:150 413F3 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGCAACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGGTGATAGTAGTGATAATAGTTACTCCGCGAGCTCCGCTAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATCTGGTTATAGCTATTTAGGCTACTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:151 The full-length amino acid sequence of the 413F3 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGGSLRLSCAASGIDFSSNYMCWVRQAPGKGLEWIACIYGDSSDNSYSASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSGYSYLGYFNLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:152 413F3 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLVESGGGLVQPGGSLRLSCAASGIDFS SNYMC WVRQAPGKGLEWIA CIYGDSSDNSYSASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR SGYSYLGYFNL WGQGTLVTVSS SEQ ID NO:153 416F8 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGACTGTTTATAATAACAACTTGTTATCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCATCCACTCTGGCATTTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAGGCGGTTATAGTGGTTGGATTTATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:154 416F8 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGACTGTTTATAATAACAACTTGTTATCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCATCCACTCTGGCATTTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAGGCGGTTATAGTGGTTGGATTTATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:155 The full-length amino acid sequence of the 416F8 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSSLSASVGDRVTITCQSSQTVYNNNLLSWYQQKPGKVPKLLIYYASTLAFGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQGGYSGWIYVFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:156 The 416F8 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSSLSASVGDRVTITC QSSQTVYNNNLLS WYQQKPGKVPKLLIY YASTLAF GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC QGGYSGWIYV FGGGTKVEIK SEQ ID NO:157 416F8 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:158 416F8 humanized heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGTAACTACTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAATCATTAGTAGTAGTGGTAGCGCATACTACGCGAGCTCCGCTAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGGGACTACGGCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:159 The full-length amino acid sequence of the 416F8 humanized heavy chain. The human γ-1 constant domain is underlined. QSLVESGGGLVQPGGSLRLSCAASGFSLSNYYMNWVRQAPGKGLEYIGIISSSGSAYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDYGMDLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:160 The amino acid sequence of the 416F8 humanized heavy chain variable heavy chain. The complementarity-determining region is underlined. QSLVESGGGLVQPGGSLRLSCAASGFSLS NYYMN WVRQAPGKGLEYIG IISSSGSAYYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GDYGMDL WGQGTLVTVSS SEQ ID NO:161 416G1 Humanized Light Chain Full-Length Nucleotide Sequence GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAGCATTGGTAGTGATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAATCCATTTATTATGGTAGTGATGATGTCATATACCATACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:162 416G1 humanized light chain variable light chain nucleotide sequence GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAGCATTGGTAGTGATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAATCCATTTATTATGGTAGTGATGATGTCATATACCATACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:163 The full-length amino acid sequence of the 416G1 humanized light chain. The human κ constant domain is underlined. DVVMTQSPSSVSASVGDRVTITCQASQSIGSDLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQSIYYGSDDVIYHTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:164 416G1 humanized light chain variable light chain amino acid sequence. Complementation-determining regions are underlined. DVVMTQSPSSVSASVGDRVTITC QASQSIGSDLA WYQQKPGKAPKLLIY RASTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QSIYYGSDDVIYHT FGGGTKVEIK SEQ ID NO:165 416G1 humanized heavy chain full-length nucleotide sequence SEQ ID NO:166 416G1 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACTATCAATAGCTACCACATGATCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGATTCATTAATGATGGTGGTTTCACATACTACGCGAGCTCCGCTAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGGGTTGATGGTACTAGTTATCCTGACTTATGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:167 The full-length amino acid sequence of the 416G1 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGGSLRLSCAASGFTINSYHMIWVRQAPGKGLEYIGFINDGGFTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGVDGTSYPDLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:168 The 418E10 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLVESGGGLVQPGGSLRLSCAASGFTIN SYHMI WVRQAPGKGLEYIG FINDGGFTYYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GVDGTSYPDL WGQGTLVTVSS SEQ ID NO:169 418E10 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTGGTAGTAACTTGAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTATGTATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGACGGTACTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:170 418E10 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTGGTAGTAACTTGAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTATGTATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGACGGTACTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:171 The full-length amino acid sequence of the 418E10 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSTLSASVGDRVTITCQASQSIGSNLNWYQQKPGKAPKLLIYYVSTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCLGVWNYWGDDGTAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:172 The 418E10 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSTLSASVGDRVTITC QASQSIGSNLN WYQQKPGKAPKLLIY YVSTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC LGVWNYWGDDGTA FGGGTKVEIK SEQ ID NO:173 418E10 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:174 418E10 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGTACCTATTATATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAAGTATTTATGATAGTGGTGCCGCATACTACGCGACCTCCGCGAAGGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCCTATTAATAATGCCATCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:175 The full-length amino acid sequence of the 418E10 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGGSLRLSCAASGFSLSTYYMSWVRQAPGKGLEWIGSIYDSGAAYYATSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPINNAIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:176 The 418E10 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLVESGGGLVQPGGSLRLSCAASGFSLS TYYMS WVRQAPGKGLEWIG SIYDSGAAYYATSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DPINNAI WGQGTLVTVSS SEQ ID NO:177 418E4 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGTATTGCTACTAACTTGAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTATACATCCAGTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGATGGTACTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:178 418E4 Humanized Light Chain Variable Light Chain Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGTATTGCTACTAACTTGAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTATACATCCAGTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGATGGTACTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:179 The full-length amino acid sequence of the 418E4 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSTLSASVGDRVTITCQASQSIATNLNWYQQKPGKAPKLLIYYTSSLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCLGVWNYWGDDGTAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:180 The 418E4 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSTLSASVGDRVTITC QASQSIATNLN WYQQKPGKAPKLLIY YTSSLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC LGVWNYWGDDGTA FGGGTKVEIK SEQ ID NO:181 418E4 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:182 418E4 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGTAGCTACTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAAGTATTTATGCTAGTGGTAGCGCATACTACGCGAGTTCCGCGAAGGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCCTATTAACAATGACATCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:183 The full-length amino acid sequence of the 418E4 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYYMSWVRQAPGKGLEWIGSIYASGSAYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPINNDIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:184 The 418E4 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLVESGGGLVQPGGSLRLSCAASGFSLS SYYMS WVRQAPGKGLEWIG SIYASGSAYYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DPINNDI WGQGTLVTVSS SEQ ID NO:185 418H5 humanized light chain full-length nucleotide sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCAGTCCAGTCCGAGTGTTTATAAGAACAACCAATTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTGCAGGCGGTTATAGTAGTAGTAGTGATACTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:186 418H5 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCAGTCCAGTCCGAGTGTTTATAAGAACAACCAATTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTGCAGGCGGTTATAGTAGTAGTAGTGATACTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:187 The full-length amino acid sequence of the humanized light chain 418H5. The human κ constant domain is underlined. DIQMTQSPSSVSASVGDRVTITCQSSPSVYKNNQLAWYQQKPGKAPKLLIYLASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAGGYSSSSDTAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:188 The 418H5 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSSVSASVGDRVTITC QSSPSVYKNNQLA WYQQKPGKAPKLLIY LASTLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC AGGYSSSSDTA FGGGTKVEIK SEQ ID NO:189 418H5 humanized heavy chain full-length nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTCAGTGCCTACCACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGGATGATTGGTAGTAGTGGTACCATACACTACGCGAACTCCGCGAAAGGCAGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACAGTTATAATAGTGATTATGCCTTTAACTTATGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT SEQ ID NO:190 418H5 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTCAGTGCCTACCACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGGATGATTGGTAGTAGTGGTACCATACACTACGCGAACTCCGCGAAAGGCAGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACAGTTATAATAGTGATTATGCCTTTAACTTATGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:191 The full-length amino acid sequence of the humanized heavy chain 418H5. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGGSLRLSCTASGIDLSAYHMSWVRQAPGKGLEYIGMIGSSGTIHYANSAKGRFTISKDNTKNTVDLQMNSLRAEDTAVYYCARDSYNSDYAFNLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:192 The amino acid sequence of the 418H5 humanized heavy chain variable heavy chain. The complementarity-determining region is underlined. EVQLVESGGGLVQPGGSLRLSCTASGIDLS AYHMS WVRQAPGKGLEYIG MIGSSGTIHYANSAKG RFTISKDNTKNTVDLQMNSLRAEDTAVYYCAR DSYNSDYAFNL WGQGTLVTVSS SEQ ID NO:193 419D9 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGAGACTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTATAATACTGTTACTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:194 419D9 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGAGACTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTATAATACTGTTACTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:195 The full-length amino acid sequence of the 419D9 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWLSWYQQKPGKAPKRLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVTDTFAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:196 419D9 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSTLSASVGDRVTITC QSSQSVYSNWLS WYQQKPGKAPKRLIY SASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC AGGYNTVTDTFA FGGGTKVEIK SEQ ID NO:197 419D9 humanized heavy chain full-length nucleotide sequence SEQ ID NO:198 419D9 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCTCCTTCAGTAGCAGGCACTACATGTGTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATACTGGTAGTAGTGGTACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCCAAGACAATTCCAAGAACACGGTGACTCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAACCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:199 The full-length amino acid sequence of the 419D9 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLLESGGGLVQPGGSLRLSCTASGFSFSSRHYMCWVRQAPGKGLEWIACIYTGSSGTPHYASSAKGRFTISQDNSKNTVTLQMNSLRAEDTAVYYCAREGNLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:200 419D9 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLLESGGGLVQPGGSLRLSCTASGFSFS SRHYMC WVRQAPGKGLEWIA CIYTGSSGTPHYASSAKG RFTISQDNSKNTVTLQMNSLRAEDTAVYYCAR EGNL WGQGTLVTVSS SEQ ID NO:201 420H5 humanized light chain full-length nucleotide sequence GCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:202 420H5 humanized light chain variable light chain nucleotide sequence GCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:203 The full-length amino acid sequence of the 420H5 humanized light chain. The human κ constant domain is underlined. ALVMTQSPSTLSASVGDRVTINCQASEDIDTYLAWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:204 The 420H5 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. ALVMTQSPSTLSASVGDRVTINC QASEDIDTYLA WYQQKPGKAPKLLIF YASDLA SGVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGGYYTSSADTRGA FGGGTKVEIK SEQ ID NO:205 420H5 humanized heavy chain full-length nucleotide sequence SEQ ID NO:206 420H5 humanized heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:207 The full-length amino acid sequence of the 420H5 humanized heavy chain. The human γ-1 constant domain is underlined. QSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:208 The amino acid sequence of the 420H5 humanized heavy chain variable heavy chain. The complementarity-determining region is underlined. QSLVESGGGLVQPGGSLRLSCAASGFSFS SNYWIC WVRQAPGKGLEWIA CIYVGSSGDTYYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DSSSYYMFNL WGQGTLVTVSS SEQ ID NO:209 420H6 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGTGTTTATAGTAACTGGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTAATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:210 420H6 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGTGTTTATAGTAACTGGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTAATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:211 The full-length amino acid sequence of the 420H6 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSTLSASVGDRVTITCQASQSVYSNWLSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:212 The 420H6 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSTLSASVGDRVTITC QASQSVYSNWLS WYQQKPGKAPKLLIY SASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC AGGYNTVIDTFA FGGGTKVEIK SEQ ID NO:213 420H6 humanized heavy chain full-length nucleotide sequence SEQ ID NO:214 420H6 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGTAGTTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATACTGGTGGTAGTGGTACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:215 The full-length amino acid sequence of the 420H6 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLLESGGGLVQPGGSLRLSCAASGIDFSSSYYMCWVRQAPGKGLEWIACIYTGGSGTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGSLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:216 The amino acid sequence of the 420H6 humanized heavy chain variable heavy chain. The complementarity-determining region is underlined. EVQLLESGGGLVQPGGSLRLSCAASGIDFS SSYYMC WVRQAPGKGLEWIA CIYTGGSGTPHYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EGSL WGQGTLVTVSS SEQ ID NO:217 459F1 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTAACTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:218 459F1 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTAACTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:219 The full-length amino acid sequence of the 459F1 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVTDTFAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:220 The 459F1 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSTLSASVGDRVTITC QSSQSVYSNWFS WYQQKPGKAPKLLIY SASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC AGGYNTVTDTFA FGGGTKVEIK SEQ ID NO:221 459F1 humanized heavy chain full-length nucleotide sequence SEQ ID NO:222 459F1 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATGTATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAACCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:223 The full-length amino acid sequence of the 459F1 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLLESGGGLVQPGGSLRLSCAASGIDFSRRYYMCWVRQAPGKGLEWIACMYTGSRDTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGNLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:224 459F1 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLLESGGGLVQPGGSLRLSCAASGIDFS RRYYMC WVRQAPGKGLEWIA CMYTGSRDTPHYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EGNL WGQGTLVTVSS SEQ ID NO:225 460C3 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:226 460C3 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:227 The full-length amino acid sequence of the 460C3 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:228 The 460C3 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSTLSASVGDRVTITC QSSQSVYSNWFS WYQQKPGKAPKLLIY SASTLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC AGGYNTVIDTFA FGGGTKVEIK SEQ ID NO:229 460C3 humanized heavy chain full-length nucleotide sequence SEQ ID NO:230 460C3 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:231 The full-length amino acid sequence of the 460C3 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLLESGGGLVQPGGSLRLSCAASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGSLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:232 460C3 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLLESGGGLVQPGGSLRLSCAASGIDFS RRYYMC WVRQAPGKGLEWIA CIYTGSRDTPHYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EGSL WGQGTLVTVSS SEQ ID NO:233 464C11 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACAGCTTCTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGTTTATAGTGATAATACTTATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:234 464C11 humanized light chain variable light chain nucleotide sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACAGCTTCTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGTTTATAGTGATAATACTTATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:235 The full-length amino acid sequence of the 464C11 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNSFLSWYQQKPGKAPKLLIYSASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGVYSDNTYVFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:236 The 464C11 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSTLSASVGDRVTITC QSSQSVYSNSFLS WYQQKPGKAPKLLIY SASDLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC AGVYSDNTYV FGGGTKVEIK SEQ ID NO:237 464C11 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:238 464C11 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCAGGGCCGTCCCTGAGACTCTCCTGTACAGCTTCTGGATTCTCCCTCAGTCACTACTGGATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGATTCATTAATGTTGGTGGTGACACATCTTACGCGAGCTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGGCAGAGGTGGTCTGACTTTTGGTTGGGACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:239 The full-length amino acid sequence of the 460C3 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGPSLRLSCTASGFSLSHYWMTWVRQAPGKGLEYIGFINVGGDTSYASSVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCGRGGLTFGWDLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:240 The 464C11 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLVESGGGLVQPGPSLRLSCTASGFSLS HYWMT WVRQAPGKGLEYIG FINVGGDTSYASSVKG RFTISRDDSKSIAYLQMNSLKTEDTAVYYCGR GGLTFGWDL WGQGTLVTVSS SEQ ID NO:241 466F6 Humanized Light Chain Full-Length Nucleotide Sequence GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:242 466F6 humanized light chain variable light chain nucleotide sequence GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:243 The full-length amino acid sequence of the 466F6 humanized light chain. The human κ constant domain is underlined. DVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:244 The 466F6 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DVVMTQSPSSVSASVGDRVTITC QASQNIRTYLS WYQQKPGKAPKLLIY AAANLAS GVPSRFSGSGSGTDFTLTISDLEPGDAATYYC QSTYLGTDYVGGA FGGGTKVEIK SEQ ID NO:245 466F6 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:246 466F6 humanized heavy chain variable heavy chain nucleotide sequence CGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:247 The full-length amino acid sequence of the 466F6 humanized heavy chain. The human γ-1 constant domain is underlined. RSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:248 The amino acid sequence of the 466F6 humanized heavy chain variable heavy chain. The complementarity-determining region is underlined. RSLVESGGGLVQPGGSLRLSCTASGFTIS SYHMQ WVRQAPGKGLEYIG TISSGGNVYYASSARG RFTISRPSSKNTVDLQMNSLRAEDTAVYYCAR DSGYSDPM WGQGTLVTVSS SEQ ID NO:249 470B6 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTACTAACTTGAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTATGCATCCAGTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGATGGTACTGATTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:250 470B6 Humanized Light Chain Variable Light Chain Nucleotide Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTACTAACTTGAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTATGCATCCAGTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCTAGGTGTTTGGAATTATTGGGGTGATGATGGTACTGATTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:251 The full-length amino acid sequence of the 470B6 humanized light chain. The human κ constant domain is underlined. DIQMTQSPSTLSASVGDRVTITCQASQSISTNLNWYQQKPGKAPKLLIYYASSLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCLGVWNYWGDDGTDFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:252 The 470B6 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSTLSASVGDRVTITC QASQSISTNLN WYQQKPGKAPKLLIY YASSLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC LGVWNYWGDDGTD FGGGTKVEIK SEQ ID NO:253 470B6 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:254 470B6 humanized heavy chain variable heavy chain nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGTAGCTACTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAAGTATTTATGGTAGTGGTGCCGCATACTACGCGAGCTCCGCTAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCCTATTAACAATGCCATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:255 The full-length amino acid sequence of the 470B6 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYYMSWVRQAPGKGLEWIGSIYGSGAAYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPINNAMWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:256 The 470B6 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLVESGGGLVQPGGSLRLSCAASGFSLS SYYMS WVRQAPGKGLEWIG SIYGSGAAYYASSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DPINNAM WGQGTLVTVSS SEQ ID NO:257 470C6 Humanized Light Chain Full-Length Nucleotide Sequence GCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATAACTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTACTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:258 470C6 Humanized Light Chain Variable Light Chain Nucleotide Sequence GCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATAACTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTACTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:259 The full-length amino acid sequence of the 470C6 humanized light chain. The human κ constant domain is underlined. ALVMTQSPSTLSASVGDRVTINCQASEDIDNYLAWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSTDTRGAFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:260 The 470C6 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. ALVMTQSPSTLSASVGDRVTINC QASEDIDNYLA WYQQKPGKAPKLLIF YASDLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QGGYYTSSTDTRGA FGGGTKVEIK SEQ ID NO:261 470C6 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:262 470C6 humanized heavy chain variable heavy chain nucleotide sequence CAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCACTAGCAGCTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATACTGGTAGTAGTGGTAGCACTTACTACGCGAACTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:263 The full-length amino acid sequence of the 470C6 humanized heavy chain. The human γ-1 constant domain is underlined. QSLVESGGGLVQPGGSLRLSCAASGFSFTSSYYMCWVRQAPGKGLEWIACIYTGSSGSTYYANSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:264 470C6 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. QSLVESGGGLVQPGGSLRLSCAASGFSFTS SYYMC WVRQAPGKGLEWIA CIYTGSSGSTYYANSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DSSSYYMFNL WGQGTLVTVSS SEQ ID NO:265 472E4 Humanized Light Chain Full-Length Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAATAACAATGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTTGGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCTAGGTGTTTATAATGATGATGTTGATAATGGTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT SEQ ID NO:266 472E4 Humanized Light Chain Variable Light Chain Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAATAACAATGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTA TTTGGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCTAGGTGTTTATAATGATGATGTTGATAATGGTTTCGGCGGAGGGACCAAGGTGGAGATCAAA SEQ ID NO:267 The full-length amino acid sequence of the humanized light chain 472E4. The human κ constant domain is underlined. DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNALAWYQQKPGKVPKLLIYLASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGVYNDDVDNGFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:268 The 472E4 humanized light chain variable light chain amino acid sequence. Complementarity-determining regions are underlined. DIQMTQSPSSLSASVGDRVTITC QSSQSVYNNNALA WYQQKPGKVPKLLIY LASTLAS GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC LGVYNDDVDNG FGGGTKVEIK SEQ ID NO:269 472E4 Humanized Heavy Chain Full-Length Nucleotide Sequence SEQ ID NO:270 472E4 Humanized Heavy Chain Variable Heavy Chain Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAATAACAATGCAATAAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGCAATCATACAAAATACTGGTACCACAGACTACGCGAGGTCCGCTAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGGTATGGTTTTGAGTCGGAGCTTGTCATCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC SEQ ID NO:271 The full-length amino acid sequence of the 472E4 humanized heavy chain. The human γ-1 constant domain is underlined. EVQLVESGGGLVQPGGSLRLSCAASGFSLNNNAISWVRQAPGKGLEWVAIIQNTGTTDYARSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYGFESELVIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:272 The 472E4 humanized heavy chain variable heavy chain amino acid sequence. Complementarity-determining regions are underlined. EVQLVESGGGLVQPGGSLRLSCAASGFSLN NNAIS WVRQAPGKGLEWVA IIQNTGTTDYARSAKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GYGFESELVI WGQGTLVTVSS

Claims

1. An isolated monoclonal antibody (mAb) or antigen-binding fragment thereof that specifically binds to human or cynomolgus monkey 4-1BB, comprising a variable heavy chain amino acid sequence and a variable light chain amino acid sequence, wherein the variable heavy chain amino acid sequence comprises the following complementarity-determining region (CDR) sequences: CDR1 represented by SNYWIC, CDR2 represented by CIYVGSSGDTYYASSAKG or CIYVGSSGDTYYASWAKG, and CDR3 represented by DSSSYYMFNL, and wherein the variable light chain amino acid sequence comprises the following complementarity-determining region (CDR) sequences: CDR1 represented by QASEDIDTYLA, CDR2 represented by YASDLAS, and CDR3 represented by QGGYYTSSADTRGA.

2. The isolated mAb or its antigen-binding fragment according to claim 1, comprising the humanized light chain variable light chain amino acid sequence shown in SEQ ID NO:204 and the humanized heavy chain variable heavy chain amino acid sequence shown in SEQ ID NO:208, or comprising a light chain variable light chain amino acid sequence having at least 98% identity with SEQ ID NO:204 and a heavy chain variable heavy chain amino acid sequence having at least 98% identity with SEQ ID NO:

208.

3. The isolated mAb or its antigen-binding fragment according to claim 1, comprising the chimeric light chain variable light chain amino acid sequence shown in SEQ ID NO:68 and the chimeric heavy chain variable heavy chain amino acid sequence shown in SEQ ID NO:72, or comprising a light chain variable light chain amino acid sequence having at least 98% identity with SEQ ID NO:68 and a heavy chain variable heavy chain amino acid sequence having at least 98% identity with SEQ ID NO:

72.

4. The isolated mAb or its antigen-binding fragment according to claim 2, comprising the humanized light chain full-length amino acid sequence shown in SEQ ID NO:203 and the humanized heavy chain full-length amino acid sequence shown in SEQ ID NO:207, or comprising a light chain full-length amino acid sequence having at least 98% identity with SEQ ID NO:203 and a heavy chain full-length amino acid sequence having at least 98% identity with SEQ ID NO:

207.

5. The isolated mAb or its antigen-binding fragment according to claim 3, comprising the chimeric light chain full-length amino acid sequence shown in SEQ ID NO:67 and the chimeric heavy chain full-length amino acid sequence shown in SEQ ID NO:71, or comprising a light chain full-length amino acid sequence having at least 98% identity with SEQ ID NO:67 and a heavy chain full-length amino acid sequence having at least 98% identity with SEQ ID NO:

71.

6. The isolated mAb or its antigen-binding fragment according to claim 1, wherein the isolated mAb is IgG.

7. The isolated mAb or its antigen-binding fragment according to claim 1, wherein the antigen-binding fragment is an Fv, Fab, F(ab')2, or scFV fragment.

8. An isolated nucleic acid encoding the isolated mAb or its antigen-binding fragment according to any one of claims 1-7.

9. An expression vector comprising the isolated nucleic acid of claim 8, wherein the vector is expressed in cells.

10. A host cell comprising the nucleic acid of claim 8, wherein the host cell is a prokaryotic cell or a eukaryotic cell.

11. A method for producing antibodies, comprising culturing host cells according to claim 10 to produce antibodies.

12. A pharmaceutical composition comprising the isolated mAb or antigen-binding fragment thereof according to any one of claims 1-7 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12, further comprising a radionuclide, a toxin, a therapeutic agent, or a combination thereof.

14. The pharmaceutical composition according to claim 13, wherein the radionuclide is a radioisotope.

15. The pharmaceutical composition of claim 13, wherein the therapeutic agent is a chemotherapeutic agent.

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