Anti-monomethylauristatin antibodies and antibody fragments

Abstract

Compositions and methods are provided for reducing the off-target toxicity of antibody-drug conjugates (ADCs). The compositions include an ADC and an agent that targets the drug (payload) delivered by or derived from the ADC. The ADC and the agent that targets the payload can be delivered together or separately in the treatment of various conditions (such as tumors) by the ADC. Examples of agents that target the payload include antibodies, their fragments, or modified versions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 373,367, filed August 24, 2022, and U.S. Provisional Patent Application No. 63 / 520,689, filed August 21, 2023, the entire disclosures of each of which are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing which has been submitted in .xml format and is incorporated herein by reference in its entirety. The .xml copy was created on August 24, 2023, is named "011520_01784_Balthasar_PCT.xml", and is 183,732 bytes in size. [Background technology]

[0003] Anticancer antibody-drug conjugates (ADCs) have been used for targeted delivery of drugs, which may be toxins or other cell growth inhibitors (herein referred to as drugs or payload molecules), to cancer cells. Currently, 12 ADCs are on the market in the United States, and approximately 100 ADCs are under development (Chau et al., Lancet. 2019; 394(10200):793-804; Coats et al., Clin Cancer Res. 2019. Epub 2019 / 04 / 14. doi:10.1158 / 1078-0432. CCR-19-0272; Wolska-Washer et al., Drug Saf. 2019; 42(2):295-314; Beck et al., Nat Rev Drug Discov. 2017; 16(5):315-37). However, clinical use of ADCs has been somewhat disappointing. Many ADCs have failed in clinical trials as a result of substantial off-target toxicity and have limited tolerated doses below the levels required for tumor eradication (Coats et al., Clin Cancer Res. 2019. Epub 2019 / 04 / 14. doi:10.1158 / 1078-0432. CCR-19-0272; Kim et al., Biomol Ther (Seoul). 2015;23(6):493-509; de Goeij et al., Curr Opin Immunol. 2016;40:14-23; Khera et al., BioDrugs. 2018;32(5):465-80). As a result of the associated toxicity at non-target sites, the early promise of ADCs has not been fully realized, and therefore the field of cancer therapy needs to continue to develop new approaches to minimize the non-target toxicity of therapeutic payload drug molecules without compromising their anti-tumor efficacy. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Chau et al.,Lancet.2019;394(10200):793-804 [Non-patent document 2] Coats et al.,Clin Cancer Res.2019.Epub 2019 / 04 / 14.doi:10.1158 / 1078-0432.CCR-19-0272 [Non-patent document 3] Wolska-Washer et al.,Drug Saf.2019;42(2):295-314; [Non-patent document 4] Beck et al., Nat Rev Drug Discov.2017;16(5):315-37) [Non-patent document 5] Kim et al.,Biomol Ther(Seoul).2015;23(6):493-509 [Non-patent document 6] de Goeij et al.,Curr Opin Immunol.2016;40:14-23 [Non-Patent Document 7] Khera et al.,BioDrugs.2018;32(5):465-80) Summary of the Invention

[0005] The present disclosure provides compositions and methods for reducing the off-target toxicity of ADCs. For example, the compositions and methods can be used to treat tumors with ADCs while reducing the off-target toxicity of the ADCs. The drug in the ADC may be referred to herein as a "payload." The composition includes an ADC and an agent that targets the payload delivered by or derived from the ADC. The agent that targets the payload is referred to herein as a "payload binding agent" or PBA. The ADC and payload binding agent may be provided in the same or different compositions. The payload binding agent may be a peptide, antibody, fragment, or antibody mimic, or modified version thereof, directed against the ADC payload and binds to the payload. When the payload binding agent is an antibody, or a fragment or modified version thereof, it may be referred to as an "anti-payload antibody."

[0006] In one aspect, the present disclosure provides a method for inhibiting or preventing the growth of one or more tumors, comprising administering to an individual in need of treatment an ADC and a payload binding agent, wherein the payload binding agent has specific affinity for the ADC payload. The ADC and payload binding agent can be administered in the same composition or different compositions, via the same route or different routes, or using the same regimen or different regimens.

[0007] In one aspect, the present disclosure provides peptides or antibodies, or antibody fragments or modifications, specific for ADC payload molecules. The anti-payload antibody can be a whole immunoglobulin molecule, such as a polyclonal or monoclonal antibody, or a chimeric antibody, including a humanized antibody. The antibody fragment or modification can be an antigen-binding fragment thereof, including, but not limited to, Fab, F(ab'), F(ab')2, Fv, dAb, Fd, CDR fragments, single-chain antibodies (scFv), bivalent single-chain antibodies, single-chain phage antibodies, diabodies, or single-domain antibodies (nanobodies). Antibody mimics can include affibodies, nanophytins, and the like. Antibody fragments can be produced synthetically, by enzymatic or chemical cleavage of intact immunoglobulins, or genetically engineered by recombinant DNA technology. These techniques are well known in the art. Antibodies, or fragments or modifications thereof, can also be modified to confer longer half-lives, stability, etc. In one embodiment, the present disclosure provides antibodies or fragments or derivatives thereof directed against several ADC payloads, including full-length antibodies, scFvs, Fabs, and other fragments specifically directed against auristatins (e.g., monomethyl auristatin E [MMAE], monomethyl auristatin F [MMAF], monomethyl auristatin F methyl ester, monomethyl auristatin D, etc.). In non-limiting embodiments, the anti-payload specifically binds MMAE and / or MMAF. [Brief explanation of the drawings]

[0008] [Figure 1] Shown are the top five scFv clones identified after biopanning and screening of an immune mouse scFv phage library. The binding fraction represents the ELISA signal of phage bound to MMAF-biotin-streptavidin immobilized on an ELISA plate for each clone spiked with or without MMAE or T-vc-MMAE. Bars represent the average of duplicate samples with standard deviation error bars. Clones 1B3, 1H2, 3B8, 2E8, and 2C2 had a greater than 50% decrease in binding fraction with the addition of 30–100 nM free MMAE and no change in binding with the addition of 100 nM T-vc-MMAE. [Figure 2] Sequences from the top five clones identified from the first round of panning are shown. Complementarity-determining regions identified using the North definition are shown in boxed regions. Clone 1H2 has a sequence identical to clones 2E8 and 2C2 in Figure 1. The sequence on the top line is SEQ ID NO: 31. [Figure 3] To identify clones with increased MMAE binding affinity, a randomly mutagenized scFv library was constructed from clones 1B3, 1H2, and 3B8 (Figures 1 and 2). The fractional binding signals of four 96-well plates from two different panning dissociation steps (3 h and 24 h) are shown. The fractional binding signal of the 3 h plate is the signal observed with spiked 10 nM free MMAE divided by the control wells without MMAE. The fractional binding signal of the 24 h plate is the signal observed with spiked 1 nM free MMAE. [Figure 4-1]Sequencing of clones from the screening results in Figure 3 is shown. The parental scFv sequences used to construct the mutagenesis library are shown (1B3, 1H2, 3B8), with the 1H2 set as reference sequences. Complementarity determining regions identified using the North definition are shown in boxed regions. The amino acid sequence of the variable domain of clone MA24E2 was used to inform the development of humanized variant ABC3315. The sequence of the 1B3 construct in the top row is SEQ ID NO: 31. [Figure 4-2] Sequencing of clones from the screening results in Figure 3 is shown. The parental scFv sequences used to construct the mutagenesis library are shown (1B3, 1H2, 3B8), with the 1H2 set as reference sequences. Complementarity determining regions identified using the North definition are shown in boxed regions. The amino acid sequence of the variable domain of clone MA24E2 was used to inform the development of humanized variant ABC3315. The sequence of the 1B3 construct in the top row is SEQ ID NO: 31. [Figure 4-3] Sequencing of clones from the screening results in Figure 3 is shown. The parental scFv sequences used to construct the mutagenesis library are shown (1B3, 1H2, 3B8), with the 1H2 set as reference sequences. Complementarity determining regions identified using the North definition are shown in boxed regions. The amino acid sequence of the variable domain of clone MA24E2 was used to inform the development of humanized variant ABC3315. The sequence of the 1B3 construct in the top row is SEQ ID NO: 31. [Figure 5] Binding of ABC3315 to MMAF-biotin-streptavidin decreased with increasing concentrations of free MMAE and MMAF (IC50: approximately 1 nM), whereas trastuzumab-vc-MMAE (T-vc-MMAE) did not compete for binding. Points represent the average of triplicate samples with standard deviation error bars. [Figure 6]Kinetic titration binding SPR sensorgrams are shown for ABC3315 to MMAF-PEG11-biotin neutravidin (left), MMAE to ABC3315-PEG12-biotin-streptavidin (center), and polatuzumab vedotin (PV) to ABC3315-PEG12-biotin-streptavidin (right). Best-fit values ​​for the association rate constant (K), dissociation rate constant (k), and equilibrium dissociation rate constant (K) are shown in the inset. No binding signal was observed for PV to ABC3315-PEG12-biotin-streptavidin. [Figure 7] ABC3315 selectively inhibits MMAE toxicity. (A) RAMOS cells were incubated with MMAE (10 pM–100 nM) with or without co-incubation with 500 nM ABC3315. ABC3315 increased the IC50 of free MMAE by 800-fold. (B) Polatuzumab vedotin (PV), a clinically approved anti-CD79b ADC incorporating MMAE as a payload molecule, was incubated with CD79b+ Ramos cells at concentrations ranging from 3 pM to 30 nM with or without co-incubation with 500 nM ABC3315. ABC3315 did not alter the on-target cytotoxicity of PV (IC50: 0.12 nM alone, 0.13 nM with ABC3315). (C) ABC3315 (500 nM) increased the IC50 of free MMAE against SKBR3 cells by more than 500-fold. (D) HER2+ SKBR3 cells were incubated with T-vc-MMAE with and without anti-MMAE Fab, with negligible change in cytotoxicity (IC50: 0.03 nM alone, 0.04 nM with ABC3315). Points represent the mean of triplicate wells with standard deviation error bars. [Figure 8]This shows that ABC3315 does not alter the efficacy of PV. Nu / J mice bearing Ramos xenografts with a volume of approximately 250 mm were randomized to receive PBS, 1, or 3 mg / kg PV, with or without a 12-fold molar excess of ABC3315 (n=8 / group). (A) Standard deviation error bars are shown for tumor volume over time for each group. Mice were sacrificed at a tumor volume of 2000 mm. (B) The probability of survival over time for each group is shown. Based on the log-rank test, cotreatment with ABC3315 did not significantly alter survival of the groups of mice treated with PV at doses of 1 mg / kg (p=0.075) or 3 mg / kg (p=0.89). [Figure 9] ABC3315 reduces weight loss in mice treated with 120 mg / kg PV. Swiss Webster mice were intravenously injected with 120 mg / kg PV in PBS or a 3-fold molar excess of ABC3315 (n=5 / group). (A) Weight loss over time for each group is shown. Points represent the mean percent change in weight, and error bars indicate standard deviation. (B) The mean percent weight change at nadir for each group is shown with standard deviation error bars. Mice treated with ABC3315 with PV significantly reduced weight loss at nadir, from an average of 11.9 ± 7.0% in mice treated with PV + PBS to 4.1 ± 2.1% in mice treated with PV + ABC3315 (p=0.045). [Figure 10] Evaluation of ABC3315-WEDD HSA binding. Graphs show ABC3315-WEDD injected onto an SPR chip containing a range of immobilized human serum albumin concentrations. Top: The observed association and dissociation curves were fitted to a 1:1 Langmuir binding model to obtain binding rate constants. (Bottom) For each concentration, the observed Rmax was used to estimate the equilibrium dissociation rate constant. Fitted values ​​of the binding parameters are shown in the inset of each panel. [Figure 11]Evaluation of ABC3315-WE human serum albumin (HSA) binding is shown. ABC3315-WE was injected onto an SPR chip containing a range of immobilized human serum albumin concentrations. Top: The observed association and dissociation curves were fitted to a 1:1 Langmuir binding model to obtain the binding rate constants. (Bottom) For each concentration, the observed Rmax was used to estimate the equilibrium dissociation rate constant. Fitted values ​​of the binding parameters are shown in the inset of each panel. [Figure 12-1] Affinity matured scFv sequences are shown using ABC3315 as the reference sequence. The top line sequence is SEQ ID NO: 31. [Figure 12-2] Affinity matured scFv sequences are shown using ABC3315 as the reference sequence. The top line sequence is SEQ ID NO: 31. [Figure 13] ELISA comparison of ABC3315 variants. ABC3315 variants were assessed for retained binding activity using an indirect ELISA. All variants except VH_F37V showed similar binding signals with MMAF-PEG11-biotin-neutravidin at the Fab concentrations tested. [Figure 14]

[0033] Figure 1 shows a competitive cytotoxicity assay. The inhibition of MMAE-mediated cytotoxicity of the VH_F27L mutant compared to ABC3315 was evaluated. Higher cell survival was observed across a range of MMAE concentrations with VH_F27L co-treatment compared to ABC3315 co-treatment. [Figure 15] Figure 11 is a graph assessing the concentration of free MMAE in plasma and red blood cells after administration of 100 mg / kg TvcMMAE alone or in combination with ABC3315. ABC3315 reduced free MMAE concentrations in plasma by 85% and red blood cells by 73%. [Figure 16]

[0023] Figure 1 shows the results of administering TvcMMAE at a dose of 80 mg / kg alone or in combination with ABC3315. TvcMMAE administered alone resulted in a significant decrease in white blood cell and red blood cell counts compared to mice administered the PBS vehicle. Mice administered TvcMMAE in combination with ABC3315 did not exhibit a significant decrease in white blood cells or red blood cells compared to control mice. [Figure 17] Data demonstrating the effect of ABC3315 on the efficacy of TvcMMAE in a HER2+ / HER2- bystander xenograft model were evaluated. No significant differences were observed between mice receiving 3 mg / kg TvcMMAE alone or in combination with ABC3315. Representative tumors are shown on the right. [Figure 18] Figure 1 shows that ABC3320 reduces MMAE ADC toxicity to differentiating neutrophils. Human peripheral blood mononuclear cells were incubated with trastuzumab-vc-MMAE (TvcMMAE) alone or in combination with ABC3320. Flow cytometry was used to assess neutrophil numbers after TvcMMAE treatment using CD66b+ as a neutrophil marker. ABC3320 increased the IC50 of TvcMMAE from 1.9 nM to 27 nM. [Figure 19] 1 is a graph showing that co-treatment with ABC3320 reduced the weight loss observed in rats treated with 25 mg / kg trastuzumab-vc-MMAE (ADC) compared to rats treated with TvcMMAE alone. [Figure 20] 1 is a graph showing that ABC3320 reduces hematotoxicity in rats after a 25 mg / kg dose of TvcMMAE. [Figure 21] ABC3320 reduces trastuzumab-vc-MMAE (25 mg / kg)-mediated hepatotoxicity in rats. [Figure 22-1]10 is a graph showing that ABC3320 does not reduce the efficacy of polatuzumab vedotin (PV) in Ramos xenograft-bearing mice, nor does it reduce the efficacy of trastuzumab-vc-MMAE (TvcMMAE) in mice bearing a mixed xenograft model of HER2+ NCI-N87 cells and HER2- MCF7 cells. [Figure 22-2] 10 is a graph showing that ABC3320 does not reduce the efficacy of polatuzumab vedotin (PV) in Ramos xenograft-bearing mice, nor does it reduce the efficacy of trastuzumab-vc-MMAE (TvcMMAE) in mice bearing a mixed xenograft model of HER2+ NCI-N87 cells and HER2- MCF7 cells. [Figure 23] This graph shows that ABC3320 reduces plasma free MMAE concentrations after TvcMMAE administration. Swiss-Webster mice were intravenously injected with a 25 mg / kg dose of TvcMMAE administered with phosphate-buffered saline (labeled as PBS) or ABC3320 (98 mg / kg, 65.3 mg / kg combined with TvcMMAE given at time = 0 and 32.7 mg / kg at 24 hours). Mice were sacrificed at a range of time points, and whole blood was collected. Plasma and red blood cells were separated by centrifugation. Plasma samples (100 μl) were placed into the wells of a rapid equilibrium dialysis device (Thermo Scientific™, 90006), and free MMAE was separated from bound MMAE (plasma protein-bound or ABC3320-bound) according to the manufacturer's recommendations. Free and bound MMAE concentrations were determined using LC-MS / MS. Free concentrations of MMAE were on average 200-fold lower in samples from mice treated with ABC3320 when compared with samples from mice administered TvcMMAE with PBS. Increased concentrations of bound MMAE in plasma were observed in mice administered ABC3320, consistent with pharmacokinetic predictions (binding to ABC3320 is expected to decrease the apparent volume of distribution of released MMAE). DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure provides compositions and methods for treating diseases (e.g., cancer) using ADCs while reducing off-target toxicity associated with the ADC. The methods involve administering to an individual in need of treatment an ADC and one or more payload-binding agents directed against the drug moiety of the ADC. The payload-binding agents are effective in reducing non-target toxicity of the ADC or non-target toxicity resulting from free drug dissociated from the ADC. The compositions include antibodies (including fragments or modifications thereof) directed against the drug of the ADC. Also provided are compositions comprising an ADC and an agent (e.g., an antibody) directed against the drug constituting the ADC. The agent binds to the free drug; if the drug is part of the ADC, the agent may or may not be bound to the drug. The present disclosure relates to U.S. Patent No. 2020 / 063453 and its publication published as International Publication No. WO 2021 / 113740, published June 10, 2021, the entire disclosures of which are incorporated herein by reference.

[0010] ADC comprises an antibody group, a linking group and a drug group.The antibody group targets antigens such as tumor cell antigens, and the linking group is used to attach the drug group to the antibody group, and the drug group is an agent that is cytotoxic to target cells.The antibody group can be called antibody or can be called by the name of antibody.Similarly, the drug group can be called drug or by the name of drug.

[0011] As used herein, the term "treatment" refers to the alleviation or delay of one or more symptoms or characteristics associated with the presence of the particular condition being treated. Treatment does not necessarily imply a complete cure, and does not exclude recurrence, although it may be used in connection with any such recurrence.

[0012] As used herein, the term "therapeutically effective amount" is an amount sufficient to achieve the intended therapeutic purpose in single or multiple doses. The exact amount desired or required will vary depending on the mode of administration, patient specifications, etc. An appropriate effective amount can be determined by one of ordinary skill in the art (e.g., a clinician) with the benefit of this disclosure.

[0013] Where a range of values ​​is provided in this disclosure, it is understood that each intervening value, to one-tenth of the lower limit of that range, and any other intervening value and range within that stated range, is encompassed within the disclosure unless otherwise stated. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges encompassed within the disclosure.

[0014] As used in this disclosure, the singular includes the plural and vice versa unless the context clearly dictates otherwise. The indefinite articles "a" and "an," as used in this specification and claims, should be understood to mean "at least one," unless clearly indicated otherwise.

[0015] A general reference to an antibody in this disclosure is also intended to include all full-length antibodies, antibody fragments containing antigen-binding domains, and modified antibodies or fragments containing amino acid residue substitutions or modifications, including modified or unmodified antibody fragments that can be covalently linked together with or without a linker. When referring to "payload targeting" or "directed against a payload" or similar phrases, it means that the antibody has specific affinity for the payload when the payload is in the form of a free payload (including when cleaved from the ADC). When the payload is conjugated to the antibody portion of the ADC, the anti-payload antibody may or may not bind to the payload.

[0016] The terms "off-target" and "non-target" in relation to toxicity refer to the toxicity associated with the administration of many chemotherapeutic agents. The intended purpose of administering a chemotherapeutic agent is to reduce or inhibit the growth of a tumor or any associated metastasis, but the growth, function, and / or physiology of normal cells are often adversely affected during the course of cancer treatment. Reduced off-target or non-target toxicity is intended to reduce any adverse effects on non-tumor or non-metastatic cells.

[0017] The term "payload binding agent" (PBA) as used in this disclosure refers to an agent that specifically binds to the payload (drug) portion of an ADC. The PBA can be an antibody, a fragment or modification thereof, a peptide, an aptamer, a Spiegelmer, a fibronectin, a DARPin, a cyclodextrin, or an afftin. When the PBA is an antibody, it may be referred to herein as an anti-drug antibody or an anti-payload antibody. The anti-payload antibody may be a whole immunoglobulin molecule, such as a polyclonal or monoclonal antibody, or a chimeric antibody, including a humanized antibody, or an antigen-binding fragment thereof, including, but not limited to, Fab, F(ab'), F(ab'), Fv, dAb, Fd, CDR fragment, single-chain antibody (scFv), bivalent single-chain antibody, single-chain phage antibody, diabody, single-domain antibody (nanobody), etc. Antibody fragments can be produced synthetically, by enzymatic or chemical cleavage of intact immunoglobulins, or genetically engineered by recombinant DNA technology. These techniques are well known in the art.

[0018] The term "chimeric antibody" refers to an antibody having framework residues from one species, such as human, and complementarity-determining regions (CDRs, which generally confer antigen binding) from another species, such as a murine antibody, that specifically bind to a payload. In a chimeric antibody, some portions of the heavy and / or light chain may be identical or homologous to sequences from a particular species, while other portions may be identical or homologous to sequences from a different species. Chimeric antibodies generally exhibit reduced immunogenicity and increased stability. Techniques for cloning murine immunoglobulin variable domains are known in the art. See, for example, Orlandi et al., Proc. Natl. Acad. Sci. USA 86:3833 (1989), and Leung et al., Hybridoma 13:469 (1994). As an example of a chimeric antibody, a polynucleotide (e.g., DNA) encoding the light or heavy chain variable domain of an antibody derived from a non-human animal (e.g., mouse, rat, or chicken) can be linked to a polynucleotide encoding the light or heavy chain constant domain derived from a human antibody to produce a polynucleotide (e.g., DNA) encoding the chimeric antibody.

[0019] A "human" antibody (also called a "fully human" antibody) is an antibody that contains all of the human framework regions and CDRs from a single or different human immunoglobulins. Thus, the framework from one human antibody can be engineered to contain CDRs from a different human antibody. Methods for producing human antibodies are known in the art; see, for example, Mancini et al., 2004, New Microbiol. 27:315-28; Conrad and Scheller, 2005, Comb. Chem. High Throughput Screen. 8:117-26.

[0020] A "humanized antibody" is typically a human antibody into which one or more amino acid residues have been imported from (i.e., introduced into) a non-human source. For example, a humanized antibody is a recombinant protein in which the CDRs of an antibody from a species such as a rodent, rabbit, dog, goat, or horse are imported into human heavy and light chain variable domains. The constant domains (also called framework regions) of an antibody molecule are generally identical to those of a human antibody. The non-human immunoglobulin providing the CDRs can be referred to as the "donor," and the human immunoglobulin providing the framework can be referred to as the "acceptor." For example, all CDRs can be derived from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not always be present, but if present, they can be substantially identical to human immunoglobulin constant regions, i.e., at least about 85-90%, e.g., about 95% or more identical. A humanized antibody binds the same payload as the donor antibody that provided the CDRs. The acceptor framework of a humanized immunoglobulin or antibody can have a limited number of substitutions by amino acids removed from the donor framework. Humanized antibodies or other monoclonal antibodies can have additional conservative amino acid substitutions that do not substantially affect antigen binding or other immunoglobulin functions.Humanized immunoglobulins can be constructed by genetic engineering (e.g., U.S. Patent Publication No. 5,585,089 and U.S. Patent Application Publication No. 2010 / 0196266).For example, mouse monoclonal antibodies can be isolated or produced and then humanized.

[0021] Antibody fragments can be produced by enzymatic digestion. For example, papain digestion of an antibody produces two identical antigen-binding fragments, called "Fab" and "Fc" fragments. Fab fragments contain the entire L chain and the variable region domain (VH) of the H chain, as well as the first constant domain of one heavy chain. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody produces a single large F(ab')2 fragment, which roughly corresponds to two disulfide-linked Fab fragments with bivalent antigen-binding activity and is capable of cross-linking antigen. "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and binding site. Single-chain Fv, also abbreviated as "sFv" or "scFv," is an antibody fragment containing the VH and VL antibody domains connected in a single polypeptide chain. The term "diabody" refers to small antibody fragments prepared by constructing sFv fragments with a short linker between the VH and VL domains so that interchain pairing, rather than intrachain pairing, is achieved, resulting in bivalent fragments, i.e., fragments with two antigen-binding sites. Single-domain antibodies (sdAbs) are antibody fragments containing a single monomeric variable antibody domain. sdAbs can be generated from heavy-chain antibodies found in camelids. The antibody fragment can be a single variable region or a peptide consisting of or containing a single CDR. Single-chain antibodies have heavy and light-chain variable domains linearly linked to each other via a linker. Polynucleotides (e.g., DNA) encoding single-chain antibodies can be produced by combining a polynucleotide encoding the heavy-chain variable domain, a polynucleotide encoding a linker (typically 10-20 nucleotides), and a polynucleotide encoding the light-chain variable domain, where both the heavy-chain variable domain and the light-chain variable domain are derived from a human antibody.

[0022] Antibodies useful in the methods of the present invention can be obtained from humans or non-human animals. Antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). In one embodiment, single-domain antibodies or nanobodies produced by camelids in response to the introduction of APP cleavage products (or peptide fragments thereof) into camelids can be used. Nanobodies are typically heavy-chain antibodies and therefore contain heavy-chain homodimers and no antibody light chains. These antibodies typically contain a single variable domain and two constant domains (CH2 and CH3).

[0023] The present disclosure also provides sequences that are homologous to the protein or peptide sequences (such as antibody sequences) described herein. In various embodiments, the homologous sequence has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a protein or peptide sequence of the present disclosure.

[0024] The payload molecule can be a drug molecule that causes cytotoxicity. For example, any molecule used in the treatment of cancer can be used. Examples include chemical compounds, DNA, RNA, peptides, etc. In one embodiment, the drug molecule can be covalently attached to the N-terminal amino acid of the antibody via a reactive group or linker. Reactive groups (e.g., light or heavy chains) that crosslink with the alpha amine group at the N-terminus of the antibody include isothiocyanates, isocyanates, acyl azides, NHS esters, sulfonyl esters, aldehydes, glyoxal, epoxides, carbonates, aryl halides, imidoesters, carbodiimides, anhydrides, fluorophenyl esters, etc. Reactive groups such as aldehydes or NHS esters are commonly used. Reduced cysteines (free sulfhydryls) can also be used. Methods for conjugating payload molecules to antibodies are known. For example, conjugation of payload molecules to antibodies is described in U.S. Pat. No. 10,071,170, the disclosure of which is incorporated herein by reference.

[0025] Examples of payload molecules include microtubule formation inhibitors, mitotic inhibitors, topoisomerase inhibitors, RNA polymerase inhibitors, DNA intercalators or alkylating agents, ribosome inhibitors, siRNA, enzymes (carboxypeptidase, alkaline phosphatase, cytosine deaminase), immunocytokines (e.g., interleukin-2), and the like. Examples of cytotoxic drugs include, but are not limited to, maytansinoids, auristatins, dolastatins, tubulysins, camptothecins, pyrrolobenzodiazepines, calicheamicin, gelonin, doxorubicin, duocamicin, carboplatin, cisplatin, cyclophosphamide, ifosfamide, nidran, bleomycin, mitomycin C, cytarabine, fluorouracil, methotrexate, trimetrexate, vinblastine, alimta, altretamine, procarbazine, taxol, taxotere, diphtheria toxin, pseudomonas exotoxin and derivatives (e.g., PE38, PE40), alpha emitters (Ac-225, At-211, Th-227, Ra-223, Pb-212, Bi-212, Ra-224). Compounds include their stereoisomers and derivatives. In embodiments, the antibodies or antigen-binding fragments thereof provided herein specifically bind to an auristatin, which can be monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

[0026] In various embodiments, ADCs comprising antibody-cytotoxic agent conjugates can comprise any antibody or its fragment or modified form that is useful against tumor antigens or that is useful for delivering cytotoxic drugs to tumor cells.For example, there are several monoclonal antibodies that have been demonstrated as successful therapeutic agents for the treatment of human cancer.These include rituximab, trastuzumab, cetuximab, panitumumab, and bevacizumab. Examples of monoclonal antibodies directed against solid tumors include pertuzumab, ramucirumab, nivolumab, pembrolizumab, necitumumab, dinutuximab, olaratumab, atezolizumab, avelumab, cemiplimab, carotuximab, margetuximab, bemarituzumab, naxitamab, leratolimab, brentuximab, lorvotuzumab, glembatumumab, BCD-100, spartalizumab, IBI308, CS1001, tremelimumab, TSR-042). Any of these antibodies can be used to produce antibody-drug conjugates.

[0027] Examples of antibodies and ADCs relevant to the present disclosure include, but are not limited to, gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine (TDM1), inotuzumab ozogamicin, polatuzumab vedotin, trastuzumab deruxtecan, trastuzumab duocarmazine, sactuzumab govitecan, loncastuximab tesirin, oportuzumab These include bumonatox, zolbetuximab, claudiximab, depatuximab mafodotin, mirvetuximab soravtansine, rovalpituzumab tesirin, enfortumab vedotin, radilatuzumab vedotin, zirobertamab vedotin, tisotumab vedotin, dicitamab vedotin, BAT8001, L19IL2, and L19TNF.

[0028] In embodiments where the PBA is an antibody, the anti-drug antibody may be directed against the toxin (also referred to herein as the drug or payload) portion of the ADC. In embodiments, the anti-drug antibody may be a fragment of a whole antibody. The anti-drug antibody fragment may be a Fab, Fab', F(ab')2, Fv, scFv, single domain antibody, or diabody, or any other epitope-binding fragment. The antibody fragment may be in the range of 0.5 kDa to 110 kDa (note: F(ab')2 is approximately 100 kDa), including all Da values ​​and ranges therebetween. In one embodiment, the antibody fragment is approximately 15 kDa. In one embodiment, the antibody is a single domain antibody (nanobody) comprising only a VHH (generally 13 kDa to 15 kDa). The anti-drug antibody has a binding affinity for the drug that can be expressed as a dissociation constant (KD). In one embodiment, the KD of the anti-drug antibody is between 1 pM and 50 nM, including all 0.1 pM values ​​and ranges therebetween. In one embodiment, the KD is less than 1 nM. In one embodiment, the KD is between 1 pM and 100 pM. In one embodiment, the KD can be between 1 and 100 pM. In one embodiment, the anti-drug antibody is a camelid, chimeric, or humanized single-domain antibody, also known as a nanobody. These antibodies possess many characteristics that make them ideal for the competitive inhibition approach of the present invention. Single-domain antibodies are a small antibody format (approximately 15 kDa), are highly stable, can be expressed in E. coli, and can be humanized to limit immunogenicity. Furthermore, camelid immunization and phage display technologies enable the rapid and inexpensive development of novel inhibitors.

[0029] The antibody (e.g., a fragment or modified antibody) may be attached to a free payload cleaved from the ADC or to a payload. When the payload is cleaved from the ADC by enzymatic action, hydrolysis, oxidation, or some other mechanism, the cleaved payload may contain a portion of the linking group, all of the linking group, or none of the linking group. The cleaved payload may further contain a substituent that may be added during or after cleavage, or a functional group formed as a result of the cleavage process. Examples of substituents and / or functional groups formed from the cleavage process include, but are not limited to, alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, etc.), alcohol groups, amines, thiols, sulfonic acids, sulfoxides, sulfides, sulfones, carboxylic acids, esters, amides, etc., and combinations thereof.

[0030] Several antibodies (including fragments or modifications) are described in the Examples herein, and sequences are disclosed. Full-length antibodies, scFvs, Fabs, etc., directed specifically against auristatins, including derivatives, are included in the disclosure. The generation of antibodies, screening of antibodies to identify candidates with desired binding specificity and affinity, and their binding and inhibitory properties are described.

[0031] Any of the antibody or fragment sequences described herein may include a polyhistidine tag or linker; sequences may be used without a polyhistidine tag (e.g., to reduce immunogenicity); if a linker is used, the binding construct is not limited to a specific linker. Any specific sequence disclosed herein with a polyhistidine tag also includes the corresponding sequence without the polyhistidine tag, and any sequence disclosed herein without a polyhistidine tag also includes the sequence with the polyhistidine tag. Variants of the antibody or fragment sequences disclosed herein include sequences with at least 85% identity to the disclosed sequences, as long as binding affinity is not adversely affected. For example, the binding affinity of a variant may be 10% lower, the same, or better than the disclosed sequences. In embodiments, variants may have at least 90%, at least 95%, at least 98%, or at least 99% homology (identity) to the disclosed sequences without adversely affecting binding affinity. The present disclosure also includes nucleotide sequences that encode the amino acid sequences described herein or variants thereof.

[0032] The present disclosure includes all polynucleotides encoding the described antibodies and antigen-binding fragments thereof. Such polynucleotides include expression vectors containing the encoding polynucleotides. The disclosure includes cell cultures containing the expression vectors, as well as methods for producing the described antibodies and antigen-binding fragments by using the cell cultures to produce the antibodies or antigen-binding fragments and isolating the antibodies or antigen-binding fragments from the cell cultures. Bacterial and mammalian cell cultures are included. The disclosure also includes all polynucleotides capable of hybridizing to the polynucleotides encoding the described antibodies or antigen-binding fragments. Hybridization can occur in solution at a temperature of about 20°C. The solution can include a salt, such as sodium salt, which can be at a concentration of about 0.15M.

[0033] The PBA can be a peptide consisting of 10 or more amino acids and having an equilibrium dissociation constant (KD) for binding to a payload of 50.0 nM or less.

[0034] It was surprising that a binding agent, such as an antibody, directed against the payload (drug) portion of an ADC, such as MMAE, can reduce the toxicity associated with unconjugated payloads without adversely affecting their efficacy in terms of cytotoxicity against cancer cells. Without intending to be bound by any particular theory, it is possible that the entry and intracellular processes of the ADC may not be affected by binding to a payload binding agent, while the cellular entry of unconjugated payloads may be affected (reduced) by binding to a payload binding agent. However, the ability of a payload binding agent to reduce the toxicity of unconjugated payloads relative to the anticancer cytotoxicity of the ADC, thereby enabling enhanced anticancer selectivity, is unexpected. In one embodiment, the potency of an ADC may be increased when used conjugated with a PBA (such as an antibody). In such cases, not only is non-target toxicity reduced, but the efficacy of the ADC is unexpectedly enhanced. In some embodiments, the PBA, when part of an ADC, may not bind to the drug. Rather, it may bind only to the free drug. In this case, it is expected that there will be little or no impact on the efficacy of the ADC, but that non-target toxicity will be significantly reduced.

[0035] The present disclosure provides compositions for reducing off-target toxicity, including means for reducing the toxicity of unconjugated or cleaved payloads (e.g., drugs) from ADCs without adversely affecting the efficacy of the ADC in its intended treatment (e.g., treatment of cancer cells). Means for reducing off-target toxicity include anti-drug antibodies and fragments and modifications thereof, peptides, aptamers, Spiegelmers, fibronectin, DARPins, cyclodextrins, and / or affitins.

[0036] In non-limiting embodiments, the binding agents of the present disclosure specifically bind to MMAE and comprise a light chain and a heavy chain comprising the following sequences:

[0037] ABC3319 sequence

[0038] Light chain (bold, H55Y mutation) TIFF2025528390000001.tif29156

[0039] Heavy chain (bold, F27L mutation; underline, albumin binding sequence) TIFF2025528390000002.tif29155

[0040] In one embodiment, ABC3319 (or any other binding partner of the present disclosure) can be adapted to bind to a substance within an individual's blood, such as albumin or a blood cell surface protein, to increase its half-life. A non-limiting example of such a binding partner that binds to human serum albumin, an example of a substance within an individual (and also specifically binds MMAE), is referred to herein as ABC3320, and its light and heavy chains comprise the following sequences:

[0041] Light chain (bold, H55Y mutation) TIFF2025528390000003.tif28155

[0042] Heavy chain (bold, F27L mutation) TIFF2025528390000004.tif35156 In this example, the human serum albumin binding domain is shown in bold and italic font. Optional linker sequences, which may be substituted with any other suitable linker sequence, are shown in italics. In embodiments, suitable linkers may be 3 to 20 amino acids long and may include G, S, or a combination thereof.

[0043] In embodiments, any binding partner described herein, including but not necessarily limited to the binding partners designated herein as ABC3319, ABC3320, and ABC3315, which contain amino acid residues at the unchanged positions shown in Table 1 (i.e., in L_H55Y, H is the unchanged position and Y is the changed position in the light chain), can contain any one or combination of amino acid substitutions (i.e., mutations) shown in Table 1. As noted above, the positions of point mutations shown in Table 1 are applicable to the light and heavy chain sequences of any binding partner having the amino acid listed at the same position in ABC3315 and the binding partner. In Table 1, the prefix "L_" refers to the light chain and the prefix "H_" refers to the heavy chain. The same applies mutatis mutandis to all other amino acid changes described herein.

[0044] [Table 1]

[0045] Another amino acid change that can be used alone or in combination with those listed in Table 1 includes the I101F change in the heavy chain. Thus, the present disclosure expressly includes all binding partners containing one or more of these amino acid substitutions, and all sequences containing or consisting of any one or any combination of the listed substitutions. In a non-limiting embodiment, the binding partners of the present disclosure contain only one or only a combination of the amino acid substitutions shown in Figures 2, 4, and 12. Thus, the present disclosure expressly includes all binding partners containing one or more of these amino acid substitutions, and all sequences containing or consisting of any one or any combination of the listed substitutions. Furthermore, each of the amino acid sequences of the listed binding partners containing any one or any combination of the amino acid changes shown in Figures 2, 4, 12, and Table 1 is expressly included within the present disclosure. However, as discussed herein, the VH_F37V clone exhibited significantly reduced binding signals compared to ABC3315. Thus, in embodiments, any binding partner described herein may exclude the F37 mutation in its heavy chain.

[0046] As described above, in embodiments, PBAs can be engineered to bind to blood-formed elements (e.g., albumin, erythrocyte membrane proteins, etc.). PBAs engineered to bind to blood-formed elements can be expected to exhibit reduced clearance (i.e., greater convenience in administration) and increased blood:tumor exposure, thereby enabling greater pharmacokinetic selectivity (i.e., greater inhibition of released payload molecules in the blood compared to inhibition of released payload molecules in the tumor). In embodiments, components of the described binding agents comprise amino acid sequences that bind to albumin, further representative and non-limiting examples of which include the following sequences: QRLIEDICLPRWGCLWEDDF (SEQ ID NO: 6); QRLMEDICLPRWGCLWEDD (SEQ ID NO: 7); QRLMEDICLPRWGCLWE (SEQ ID NO: 8); and DICLPRWGCL (SEQ ID NO: 9).

[0047] In one embodiment, the binding partner described herein is adapted to bind to red blood cells. The adaptation can be in the form of another binding partner that is a component of an anti-payload agent. Thus, in an embodiment, the binding partner of the present disclosure comprises an amino acid sequence that confers the binding partner with the ability to bind to red blood cells. In an embodiment, the red blood cell-binding component comprises a single domain antibody.

[0048] In one aspect, the present disclosure provides a pharmaceutical composition comprising or consisting essentially of an ADC described herein and an anti-payload agent. The formulation typically includes a physiologically acceptable carrier, excipient, or stabilizer and may be in the form of an aqueous solution, lyophilized, or other dry or solid formulation. Examples of suitable pharmaceutical preparation components can be found in Remington: The Science and Practice of Pharmacy 22nd edition (2012). Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers, e.g., phosphate, citrate, histidine, and other organic acids; antioxidants, e.g., ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol butyl alcohol or benzyl alcohol; alkyl parabens, e.g., methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; Proteins such as serum albumin, gelatin, or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, or other carbohydrates such as glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, Pluronic®, polyethylene glycol (PEG), and the like. In one embodiment, the pharmaceutical composition may contain buffer components and stabilizers, including, but not limited to, sucrose, polysorbate 20, NaCl, KCl, sodium acetate, sodium phosphate, arginine, lysine, trehalose, glycerol, and maltose. In an embodiment, the ADC and anti-payload antibody, or a fragment or modification thereof, are the only protein molecules present in the composition.In embodiments, the ADC and the anti-payload antibody, or fragment or modification thereof, are the only antibodies present in the composition.

[0049] Compositions comprising an ADC and a payload-binding agent may be administered together or separately and independently using any suitable route, including parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Administration(s) may be continuous or intermittent. The appropriate dosage will depend on the particular tumor being treated, the details and condition of the individual patient, the mode of administration, and the like. Determining the appropriate dosage is within the purview of those skilled in the art, such as the treating physician. In one embodiment, the ADC may be delivered locally, and the PBA delivered so as to be systemically available. For example, the ADC may be delivered at or near the site of the tumor or intraperitoneally, while the PBA may be delivered intravenously. In one embodiment, the ADC may be delivered systemically, and the anti-payload antibody delivered so as to be systemically available. For example, the ADC may be delivered intravenously, while the anti-payload antibody may be delivered subcutaneously.

[0050] The ADC and PBA may be administered as a single composition or as separate compositions. When administered as separate compositions, the ADC and PBA may be administered sequentially or simultaneously. These two compositions may be administered at the same or different times, by the same or different routes, for the same or different periods of time, and in the same or different regimens.

[0051] In one embodiment, the amount of ADC and PBA, separately or together, is sufficient to reduce the non-target toxicity of the ADC by at least 5% compared to that expected with the ADC alone at the same concentration used in combination. In embodiments, the reduction in toxicity can be 10%, 20%, 30%, 40%, 50% or more. The reduction in non-target toxicity can be assessed by methods known in the art. For example, the reduction can be categorized as a reduction in the percentage of patients at a particular dose experiencing a grade 3 or higher adverse reaction with or without a PBA (Clin. Invest. (2013) 3(12), 1157-1165). Furthermore, in an individual patient, the reduction in non-target toxicity can be categorized as a reduction in the severity of adverse reactions (e.g., neutropenia) with or without a PBA.

[0052] The ADC and PBA can be administered to an individual in need of treatment at a dose(s) effective to treat solid tumors. Generally, suitable dosages of the PBA and ADC can range from about 0.1 mg / kg to 100 mg / kg, including all values ​​above 0.1 mg / kg and ranges therebetween. Exemplary dosages include 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg / kg. Various dosing regimens are contemplated, including dosing regimens (e.g., maintenance therapy) in which the ADC and PBA can be repeatedly administered, for example, on a daily, weekly, or monthly schedule, over short or long periods of time, e.g., over several months to several years. The dosing range for the PBA can be 0.01 to 100 mg / kg, including all values ​​above 0.01 mg / kg and ranges therebetween. The appropriate ratio of ADC to PBA can be determined by one skilled in the art. For example, the molar ratio can be 1:1 to 1:100 ADC:PBA.

[0053] The amount of the ADC and anti-payload antibody can be administered to an individual in need of treatment in a dose effective to treat solid tumors. Generally, suitable dosages of the antibody or fragment thereof can range from about 0.1 mg / kg to 100 mg / kg (including all values ​​above 0.1 mg / kg and ranges therebetween) for both the ADC and the anti-payload antibody. Exemplary dosages include 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg / kg. Various dosing regimens are contemplated, including dosing regimens (e.g., maintenance therapy) in which the ADC and anti-payload antibody can be repeatedly administered, for example, on a daily, weekly, or monthly schedule, over short or long periods of time, e.g., over several months to several years. The dosage range for the anti-payload antibody can be 0.01 to 100 mg / kg, including all 0.01 mg / kg values ​​and ranges therebetween. The appropriate ratio of ADC to anti-drug antibody can be determined by one of skill in the art. In one embodiment, the molar ratio can be 1:1 to 1:100 ADC:anti-drug antibody.

[0054] As described above, in embodiments, half-life extension strategies can be used to increase the plasma half-life of anti-payload antibodies, including fusion of a moiety to an sdAb or Fab that binds to blood components such as albumin, red blood cells (e.g., band 3 on RBCs), or endogenous IgG, as well as PASylation and PEGylation. Thus, in embodiments, an anti-payload antibody may be fused to a moiety that binds to albumin, red blood cells, or endogenous IgG, or a fragment thereof, or may be PASylated and / or PEGylated. As an example, a bispecific antibody may have an arm that binds to the payload and another arm that binds to albumin or red blood cells (e.g., band 3 on RBCs). In one embodiment, the antibody or fragment does not comprise a polyhistidine tag. Thus, sdAb-sdAb fusion proteins that combine anti-payload binding activity with anti-albumin or anti-erythrocyte binding activity may exhibit desirable pharmacokinetic attributes (restricted distribution in tissues and tumors relative to distribution in the blood, low molecular weight leading to clearance by renal filtration, long half-life) and may provide optimal enhancement of ADC therapeutic selectivity (increasing the ratio of efficacy to off-site toxicity). sdAb-peptide or Fab-peptide fusion proteins that combine anti-payload binding affinity (via sdAb or Fab) and albumin binding affinity (via peptide) may also exhibit desirable pharmacokinetic attributes (restricted distribution in tissues and tumors relative to distribution in the blood, low molecular weight leading to clearance by renal filtration, long half-life) and may provide optimal enhancement of ADC therapeutic selectivity (increasing the ratio of efficacy to off-site toxicity).

[0055] Representative examples of single domain antibodies that have been demonstrated to bind to red blood cells via band 3 are:

[0056] >RMC1 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 10) >RA8 QVQLVQSGGGLVQAGGSLRLSCAASERTFSTYAMGWFRQIPGKERLFVAAVNWNGKTIRYADSVKGRFTISRDNAKNTIALQMNSLKPEDTAVYYCALRSTPMYFTNLASQESYNYWGPGTQVTVSS (SEQ ID NO: 11) >RB12 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYEYRTYDYWGQGTQVTVSS (SEQ ID NO: 12) >RD1 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYEYRTYDYWGQGTQVTVSS (SEQ ID NO: 13) >RD11 EVQLVESGGGLVQPGGSLRLSCAASGRIFSISNMGWYRQAPGKQRELVATITSGGSTNYGDSVKGRFTISMANAKNAVYLQMNSLKPEDTAVYYCNAGISRRTGTYSGGRYSDYWAQGTQVTVSS (SEQ ID NO: 14) >RE8 QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTMGWYRQAPGKQRELVALITSTSSTMYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARQTKWYAAGYEYRTYDYWGQGTQVTVSS (SEQ ID NO: 15) >RG10 QVQLQESGGGLVQAGGSLRLSCAASERTFSTYAMGWFRQTPGKERLFVAAVNWNGKTIRYADSVKGRFTISRDNAKNTMSLQMNSLKPEDTAVYYCALRSTPMYFTNLASQESYNYWGPGTQVTVSS (SEQ ID NO: 16) >RH5 QVQLVQSGGGLVQPGGSLRLSCAASGRIFSISNMGWYRQAPGKQRELVATITSGGSTNYGDSVKGRFTISMVNAKNAVYLQMNSLKPEDTAVYYCNAGISRRTGTYSGGRYSDYWGQGTQVTVSS (SEQ ID NO: 17) >RMA1 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYTDSVKGRFTISRDKAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYVYRTYDYWGQGTQVTVSS (SEQ ID NO: 18) >RMD1 QVQLVQSGGGLVQPGGSLRLGCAASGRVSEINTMGWYRQAPGKQRGLVALITSTSSTMYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARLTRWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 19) >RMF1 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVNGRFTISRDNAKNTVYLQMTSLEPEDTAVYYCHARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 20) >RMG1 QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTMGWYRLAPGKQRELVALITSTSSTMYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 21) >RMC2 QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTMGWYRQAPGKQRELVALITSTSSTMYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARQTIWYAAGYKYRTYDYWGLGTQVTVSS (SEQ ID NO: 22) >RME2 QVQLVQSGGGLVQSGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYEYRTYDYWGQGTQVTVSS (SEQ ID NO: 23) >RMF2 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNNDTTNYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 24) >RMG2 QVQLVQSGGGQVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 25) >RMH2 QVQLVQSGGGLAQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 26) >RMB3 QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTMGWFRQAPGKQRELVALITSTSSTMYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 27) >RMD3 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTRWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 28) >RME3 QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTVGWYRQAPGKQRELVALFTSTSSTMYSDSVKGRFTVSRDVAKNMVYLQMNSLRPEDTAVYYCNARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 29) >RMG3 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTNYIDSVKGRFTISRDNAKNTVYLRMASLEPEDTAVYYCNARQTKWYAAGYKYRTYDYWGQGTQVTVSS (SEQ ID NO: 30)

[0057] The composition(s) of the present invention can be administered alone or in combination with other types of treatment (e.g., surgical resection, radiation therapy, chemotherapy, hormone therapy, immunotherapy, or other anti-tumor agents).

[0058] The compositions of the present invention can be used for any type of cancer, including carcinoma, lymphoma, sarcoma, melanoma and leukemia.Non-limiting examples include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, myeloma (including multiple myeloma), hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma / glioma (for example, anaplastic astrocytoma, glioblastoma multiforme, anaplastic oligodendroglioma, anaplastic oligoastrocytoma), cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, brain cancer, colon cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma and various types of head and neck cancer.

[0059] In one aspect, the present disclosure provides a method for generating and identifying anti-payload antibodies suitable for use in combination with ADC therapy to reduce non-target cytotoxicity. The method includes generating or obtaining a library of antibodies, identifying specific antibodies based on positive binding to the payload molecule by ELISA and / or surface plasmon resonance techniques, identifying antibodies with desired affinity (e.g., a KD of 50 nM or less), determining binding kinetic parameters, and determining in vivo efficacy. Any of the auristatins described herein may be monomethyl auristatins.

[0060] In one embodiment, the present disclosure provides compositions and methods for treating cancer using an ADC, wherein the drug moiety of the ADC is auristatin E (MMAE) or an auristatin E derivative, analog, or metabolite, or auristatin F or an auristatin F derivative, analog, or metabolite, or a related auristatin derivative. The method comprises administering to an individual in need of treatment an ADC whose drug moiety is a previously described auristatin and a PBA directed against the described auristatin moiety of the ADC. The ADC and PBA may be administered in the same composition as described elsewhere in this disclosure or in separate compositions. An example of an ADC whose drug moiety is auristatin E is brentuximab vedotin. Another example of an ADC whose drug moiety is auristatin E is polatuzumab vedotin. When the drug moiety of an ADC is auristatin E, examples of PBAs that may be used are IgMD9, sdAbMA3, MB2, and MC7. Also provided are methods for treating cancer (such as a solid tumor), comprising administering to an individual in need of treatment an ADC, where the drug is auristatin E, and an antibody, which can be IgMD9, sdAbMA3, MB2, and MC7.

[0061] When the drug moiety of the ADC is an auristatin, examples of PBAs that may be used are described herein and in the drawings. In embodiments, the PBA is any one or combination of ABC3320, ABC3319, ABC3317, ABC3315, 1B3, 1H23B8, 2E8, or 2C2.

[0062] In a non-limiting embodiment, the present disclosure is used with an ADC that is polatuzumab vedotin (PV).

[0063] Some non-limiting examples of PBA sequences provided by this disclosure are as follows:

[0064] Sequences of clones identified from immune library screening

[0065] 1B3

[0066] DIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKIEESGGGLVKAGGSLKLSCAASGFTFSRYDMSWVRQTPEKRLEWVATISSGGRHTYYPDSVKGRFTISRDNVKNTLYLQMNSLRSVDTAMFYCLASMLTTDYFEYWGQGTSLTVSS (SEQ ID NO: 31)

[0067] 1H2

[0068] DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 32)

[0069] 3B8

[0070] DVVMTQTQKFMSTSVGDRVSITCKASQNVGTAVAWYQQKPGQSPKLLIYSASNRYTGVPDRFTGSGSGTDFTLTISNMQSEDLADYFCQQYSSYPYTSGGGTKLEIKRGGGGSGGGGSGGGGSSGGGSQVQLVETGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQTPEKRLEWVATISSGGSYTYYPDSVKGRFTSSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVL (SEQ ID NO: 33)

[0071] Sequence from mutagenesis library m = mutagenesis, A / B = plate, 3 / 24 = dissociation time, Letter# = Well (see examples)

[0072] MA24G1

[0073] MDIVMTQSHKFMSTSVGDRVSITCKASQDVDTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 34)

[0074] MA24E2

[0075] MDVVMTQTQKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRCGGGSGGGGSGGGGSGGGGSQVQLVETGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 35)

[0076] MA24C5

[0077] MDVVMTQTQKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPVRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSQVQLVETGGGLVKPGGSLKLSCAASSSTFSGYAMSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 36)

[0078] MA24B5

[0079] MDIVMTQSHKFMSTSVGDRVSITCKASQDVDTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 37)

[0080] MA24H7

[0081] MDIVMTQSQKFMSTSVGDRASVTCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISEVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 38)

[0082] MA24G6

[0083] MDIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTPHTGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSYPYTFGGGTKLEIKRGGGGSGGGGSGGGDSGGGGSEVKLVESGGGLVIPGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDIAKNTLYLQMSSLRSEDTAMYYCLASLFTTDYFEYWGQGTTVTVPL (SEQ ID NO: 39)

[0084] MA24B10

[0085] MDIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAARGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 40)

[0086] MA24B2

[0087] MDIVMTQSQKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLQIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPENRLEWVATISSGGSYTYYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 41)

[0088] MB24E2

[0089] MDIVMTQSHKFMSTSIGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSQVQLVETGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 42)

[0090] MB24D9

[0091] MDIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTLNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRNEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 43)

[0092] MB24E4

[0093] MDIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKIEESGGGLVKAGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 44)

[0094] MB24E3

[0095] MDVVMTQTQKFMSTSVGDRVSITCKASQNVGTAVAWYQQKPGQSPKLLIYSASNRYTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPENRLEWVATISSGGSYTYYPDSVKGRFTSSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 45)

[0096] MB24D10

[0097] MDIVMTQSHKFVSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTLHTGVPDRFTGSGSGTDFTLTISNVQNEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYSEYWGQGTTVTVLP (SEQ ID NO: 46)

[0098] MA3B10

[0099] MDVVMTQTQKFMSTSVGDRVSITCKASQNVGTAVAWYQQKPGQSPKLLIYSASNRYTGVPDRYTGSGSGTDFTLTISNMQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTFYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASMLTTDYFEYWGQGTTVTVLL (SEQ ID NO: 47)

[0100] MA3B11

[0101] MDIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVKLVESGGGLVKPGGSLKLSCAASGFTFNRYALSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 48)

[0102] MB3G6

[0103] MDIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSQVQLVETGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQTPEKRLEWVATISSGGSYSYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYYCLASLITTDYFEYWGQGTTVTVLL (SEQ ID NO: 49)

[0104] MB3E8

[0105] MDVVMTQTQKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSQVQLVETGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTVSRDNAKNTLYLQMSSLRSEDTAKYYCLASLFTTDYFEYWGQGTTVTVLL (SEQ ID NO: 50)

[0106] ABC3315 humanized Fab sequence (predicted CDR sequences shown in bold)

[0107] Light chain

[0108] TIFF2025528390000006.tif35155

[0109] heavy chain

[0110] TIFF2025528390000007.tif36154

[0111] The present disclosure includes antibodies and antigen-binding fragments thereof with all amino acid substitutions as shown in Figure 4, individually and in all combinations, including but not necessarily limited to the amino acid substitutions designated in the boxes.

[0112] In one aspect, the present disclosure provides a kit comprising an ADC and components for reducing the non-target toxicity of the ADC. The kit may comprise, in the same or different compositions, i) the ADC and ii) an anti-payload antibody, where the anti-payload antibody is specific for the drug moiety of the ADC. The ADC and anti-payload antibody may be provided in powdered, lyophilized form together with a reconstitution medium, and the antibody and ADC may be reconstituted prior to use. The kit may also include instructions for administering the composition comprising the ADC and the composition comprising the anti-payload antibody, which may be administered via different routes, if desired.

[0113] Some non-limiting examples are provided in the following paragraphs.

[0114] Example 1. A method for reducing non-target toxicity of an antibody-drug conjugate (ADC), comprising administering to an individual in need of treatment the ADC and a payload binding agent (PBA) directed against the drug moiety of the ADC. In various examples, the drug moiety is a cleaved payload from the ADC.

[0115] Example 1a. The method of Example 1, wherein the PBA is an antibody or modification thereof (anti-drug antibody), a fragment of which is directed against the drug moiety of the ADC.

[0116] Example 1b. The method of Example 1, wherein the PBA is a peptide.

[0117] Example 2. The method of Example 1, wherein the ADC and PBA are administered in the same composition.

[0118] Example 3. The method of Example 1, wherein the ADC and PBA are administered in different compositions.

[0119] Example 4. The method of Example 3, wherein the ADC and PBA are administered via different routes.

[0120] Example 4a. The method described in Example 4, wherein the ADC is administered by the intraperitoneal route and the PBA is administered by the intravenous route.

[0121] Example 5. The method of Example 1, wherein the drug is auristatin E or auristatin F.

[0122] Example 6. The method described in Example 1, wherein the KD of PBA is 50 nM or less.

[0123] Example 6a. The method of Example 1, wherein the KD of the anti-drug antibody is 50 nM or less.

[0124] Example 7. The method of Example 6 or 6a, wherein the KD of the PBA (Example 6) or anti-drug antibody (Example 6a) is less than 1 nM.

[0125] Example 8. The method of Example 7, wherein the KD of the PBA or anti-drug antibody is 1 pM to 100 pM.

[0126] Example 9. A composition comprising an ADC and a PBA directed against the drug moiety of the ADC.

[0127] Example 9a. The composition described in Example 9, wherein the PBA is an antibody or modification thereof (anti-drug antibody), a fragment of which is directed against the drug moiety of the ADC.

[0128] Example 10. A kit comprising: i) a composition comprising an ADC; ii) a composition comprising an anti-drug antibody that is specific for the drug in the ADC; and iii) optionally, instructions for use, e.g., instructions for administration of (i) and ii).

[0129] The invention is further demonstrated by the figures and data presented herein, whether provided in the detailed description or drawings.

[0130] [Example 1] This example provides a description of the compositions and methods used in the present disclosure, particularly for the identification of murine antibodies against MMAE.

[0131] method

[0132] immunity

[0133] Monomethyl auristatin F (MMAF) was conjugated to keyhole limpet hemocyanin (KLH) or BSA via an EDC linker. Briefly, 0.5 mg of MMAF was dissolved in MES buffer (0.1% MMES, pH 4.7) / 30% DMF and mixed with 2 mg of KLH or BSA in MES buffer, followed by the addition of 0.5 mg of EDC dissolved in water. The solution was incubated overnight at room temperature. Approximately 50 μg of KLH-MMAF immunogen emulsified in Freund's incomplete adjuvant was used for single-animal immunization. Female Balb / c mice were injected subcutaneously with 200 μL of the emulsion and given booster doses every 3 weeks. Anti-MMAF-BSA plasma titers were assessed by ELISA using an anti-mouse Fc secondary antibody conjugated to alkaline phosphatase.

[0134] RNA isolation

[0135] Spleens were surgically removed from immunized mice and torn apart with forceps and a needle. Released splenocytes were collected in a 15-ml conical tube. Lymphocyte samples were lysed and homogenized in 5 ml of TRIzol reagent. After 5 minutes of incubation, 1 ml of chloroform was added. The mixture was vortexed for 30 seconds, incubated for 3 minutes, and centrifuged at 12,000 × g for 15 minutes at 4 °C. The mixture separated into three layers: a lower red phenol-chloroform interface, a colorless upper aqueous phase, and a colorless aqueous phase. The aqueous phase containing RNA was transferred to a new tube, and 2.5 ml of isopropanol was added and incubated for 10 minutes. The sample was centrifuged at 12,000 × g for 10 minutes at 4 °C, and the total RNA precipitated to form a white gel-like pellet. The supernatant was discarded, and the pellet was resuspended in 5 ml of 75% ethanol. The sample was vortexed briefly and then centrifuged at 10,000 × g for 5 minutes at 4 °C. The supernatant was discarded, and the pellet was air-dried for 15 minutes. The pellet was resuspended in 200 μL of RNAse-free water and incubated at 60°C for 10 minutes to ensure complete solubilization of total RNA. The RNA sample was stored at -80°C for further procedures.

[0136] cDNA synthesis

[0137] The following reagents were mixed and heated at 65°C for 5 minutes, then incubated on ice for at least 1 minute: 1 μl of 50 μM oligo d(T)20 primer, 1 μl of 10 mM dNTP mix (10 mM each), 2.5 μl of template RNA, and 9.5 μl of nuclease-free water. The following reagents were added to the RNA-primer mixture: 4 μl of 5x SSIV buffer, 1 μl of 100 mM DTT, 1 μl of RNaseOUT™ recombinant RNase inhibitor, and 1 μl of SuperScript® IV reverse transcriptase (200 U / μL). The combined reaction mixture was incubated at 50–55°C for 15 minutes, then inactivated at 80°C for 10 minutes.

[0138] DNA amplification and scFv

[0139] Mouse variable heavy (VH) and light (VL) chains were amplified by polymerase chain reaction (PCR) using the following reagents: 25 μl OneTaqGC2X Master Mix, 2 μl cDNA, 0.5 μl forward primer, 0.5 μl reverse primer, and 22 μl nuclease-free water. PCR products were obtained after 30 cycles of denaturation at 94°C for 30 seconds, annealing at 55°C for 30 seconds, and extension at 68°C for 45 seconds, with a final extension of 5 minutes. The amplified VH and VL products (approximately 400 bp) were size-selected and purified on a 1% agarose gel, and an SfiI cloning site was added to assemble the mouse scFv by overlap-extension PCR using the following reagents: 25 μl of OneTaqGC2X Master Mix, 10 ng each of purified VH and VL, 1 μl each of forward and reverse primers, 5 μl of GC enhancer, and 50 μl of water. PCR was performed under the following conditions: denaturation at 95°C for 1 minute, 5 cycles of annealing at 63°C for 1 minute, and extension at 72°C for 1 minute. This was followed by 5 cycles of denaturation at 95°C for 1 minute, annealing at 56°C for 30 seconds, and extension at 72°C for 1 minute. This was followed by 25 cycles of denaturation at 95°C for 1 minute, combined annealing and extension at 72°C for 90 seconds, and a final extension for 5 minutes. The amplified scFv product (approximately 850 bp) was size-selected on a 1% agarose gel and purified.

[0140] Construction of immunized phage display library

[0141] For construction of the test library, the amplified PCR product (1 μg / replicate) and pADL-10b phagemid vector (2 μg / replicate) were triple-digested with SfiI restriction enzyme according to the manufacturer's recommendations. The reaction was incubated at 50°C for 16 hours. The cleavage products were recovered by DNA gel electrophoresis using a 1% agarose gel. The test library was developed by first ligating the digested DNA into the phagemid vector. The ligated vector was purified using the EZNA Cycle Pure Kit. Electrocompetent TG-1 cells were transformed by electroporation with 2 μL of DNA using the following conditions: 1.0 mm cuvette, 10 μF, 600 ohms, 1800 volts, and a time constant of 3.5–4.5 msec. Immediately after pulsing, 975 μL of recovery medium was added to the cells. The cell suspension was then transferred to a 3 mL tube and incubated at 250 rpm at 37°C for 1 hour. The cell suspension was then serially diluted 1:1000 onto LB agar plates containing 100 μg / ml ampicillin and 2% (wt / v) glucose and grown overnight at 37°C. Electroporation efficiency was determined by counting colonies and multiplying by the corresponding dilution factor. Approximately 10–20 clones were isolated, resuspended in water, and incubated at 95°C for 5 minutes, followed by centrifugation at 4°C for 5 minutes. DNA in the supernatant was amplified as previously described using 5' and 3' sequencing primers. PCR products were purified and sequenced to assess library functionality and size.

[0142] To construct the complete library, sufficient DNA was ligated into pADL-10b to obtain a library of at least 107 individual transformants. Several separate electroporations were performed using 3 μL of ligated DNA and 25 μL of TG1 cells. All electroporations were combined in a 50 mL conical tube. Transformed bacteria were serially diluted 1:10,000 onto LB agar plates containing 100 μg / ml ampicillin and 2% (wt / v) glucose and grown overnight at 37°C. Library size was assessed by colony counting. Fragmentation PCR and sequencing were performed as described above. The remaining bacterial suspension was plated onto four 245 mm square LB agar plates containing 100 μg / ml ampicillin and 2% (wt / v) glucose and grown overnight at 37°C. This process was repeated until the library size reached ≥107. The library was first harvested by scraping bacteria from a 245 mm dish into 8 mL of LB medium and combining them in a 50 mL conical. The collected cell suspension was mixed with sterile glycerol (20%, v / v). Cell library aliquots were stored at -80°C.

[0143] A thawed library aliquot was used to inoculate 60 mL of 2xYT medium supplemented with 100 μg / mL ampicillin and 2% (wt / v) glucose in a baffled 250 mL Erlenmeyer flask. The inoculated medium was grown at 37°C until the OD600 reached approximately 0.5. To rescue the phage, 10 mL of broth was transferred to a 50 mL conical tube, where 1 μL of CM13 helper phage was added and incubated at 250 rpm and 37°C for 1 hour. Infected cells were then isolated by centrifugation at 2,800 × g for 10 minutes at room temperature. The cells were resuspended in 50 mL of 2xYT supplemented with 100 μg / mL ampicillin and 50 μg / mL kanamycin and placed in a baffled 250 mL Erlenmeyer flask, which was incubated overnight at 30°C and 200 rpm. The bacterial culture was transferred to two 50 ml conical tubes and centrifuged at 3,200 × g and 4°C for 15 minutes to pellet the cells. The supernatant was isolated in a new 50 ml conical tube, to which 6 ml of 20% (wt / v) PEG6000 / 2.5 M NaCl solution was added, mixed by inversion, and chilled on ice for 30 minutes. The phage particles were pelleted by centrifugation at 3,200 × g and 4°C for 10 minutes. The precipitated phage particles were resuspended in 1 ml of ice-cold PBS and transferred to a microcentrifuge tube. The phage particle suspension was centrifuged at 16,000 × g and 4°C for 90 seconds to pellet any remaining bacteria. The phage particles from the supernatant were reprecipitated by adding 250 μl of ice-cold 20% (wt / v) PEG6000 / 2.5 M NaCl solution, mixed by inversion, and incubated on ice for 10 minutes. Phage particles were pelleted by centrifugation at 16,000 × g for 20 minutes at 4°C and resuspended in 0.5 mL of ice-cold PBS. Remaining bacterial debris was removed by centrifugation at 16,000 × g for 90 seconds at 4°C. Prior to panning, phage concentrations were determined by titration. Briefly, phage were serially diluted 10-fold in PBS. 10 μL of each dilution was added to a single well of a low-binding 96-well round-bottom culture plate containing 90 μL of TG1 cells (pre-growth suspension). The plate was incubated at 37°C for 15 minutes to allow infection of the TG1 cells.Approximately 5 μL of infected TG1 cells from each dilution were transferred to solid selective medium (LB + 100 μg / mL ampicillin + 2% glucose) and grown overnight at 37° C. Phage concentration was determined by counting colonies on the highest dilution plate that showed growth.

[0144] Biopanning and screening of mouse scFv

[0145] MMAF was conjugated to biotin-PEG2-amine and used for biopanning and screening of anti-MMAE scFv. 0.5 mg of MMAF was dissolved in MES buffer (0.1 M MES, pH 4.7) / 30% DMF and mixed with 100 μg of biotin-PEG2-amine in MES buffer, followed by the addition of 1.5 mg of EDC dissolved in water. The reaction was incubated overnight at room temperature and stored at 4°C. Streptavidin magnetic beads were washed three times with PBST (PBS + 0.05% Tween® 20) and blocked for 2 hours with MPBS (PBS + 5% nonfat dry milk). After the blocking step, the streptavidin beads were incubated with 1 mL of 1 μM biotin-MMAF for 15 minutes and then washed three times with PBST. For the first round of panning, stock phage was diluted to 10 cfu (colony-forming units) / mL in blocking buffer (2% milk in PBS), and 1 mL of diluted phage was added to MMAF biotin-coated streptavidin beads and incubated for 2 hours. For subsequent pannings, stock phage was diluted 1:1 with blocking buffer. After incubation, the beads were washed with PBST five times for the first round, 10 times for the second round, 15 times for the third round, and 15 times for the fourth round. Bound phage was then eluted by incubation with free MMAE in PBS at concentrations of 1 μM, 100 nM, 10 nM, and 1 nM for 1 hour for the first, second, third, and fourth rounds of panning. Output phage was titrated and reinfected into TG-1 cells for phage production in the next round of panning.

[0146] Fourth-round panning phage-infected TG1 cells were grown overnight, serially diluted in 2xYT medium, and spread onto individual culture plates containing selective medium (LB agar + 100 μg / mL ampicillin + 2% wt / v glucose) and incubated overnight at 37°C. Master plates were generated by inoculating single colonies into wells of a 96-well round-bottom culture plate filled with 100 μL of 2xTY medium supplemented with 100 μg / mL ampicillin, 2% (wt / vol) glucose, and 15% (vol / vol) glycerol and grown overnight at 37°C and 300 rpm. These wells were then used to inoculate wells of a 96-well deep plate containing 1 mL of 2xTY medium (100 μg / mL ampicillin per well). The plates were incubated at 37°C and 300 rpm for 4 hours until the OD600 reached approximately 0.5, after which 1 μL of stock helper phage was added to each well and incubated for an additional hour. Kanamycin was added to a final concentration of 50 μg / mL and the plates were incubated overnight at 30° C. and 250 rpm.

[0147] Nunc Maxisorp 96-well ELISA plates were coated with 4 μg / ml neutravidin overnight at 4°C. The plates were washed five times with PBST, blocked with MPBS for 2 hours at room temperature, and 100 μL of 1 μM biotin-MMAF was added for 30 minutes. The plates were then washed five times with PBST and incubated with 100 nM MMAE-ADC for 2 hours with 4-fold diluted phage supernatants, with or without preincubation with free MMAE at concentrations of 10 nM and 100 nM. The plates were then washed five times with PBST, and bound scFv-displaying phage was detected for 1 hour using an anti-M13 phage HRP-conjugated antibody (Antibody Design Labs, San Diego, CA) diluted 1:1000 in MPBST. After washing five times with PBST, 100 μL of 1-StepTurboTMB-ELISA solution was added to each well and incubated for 15 minutes. The reaction was stopped by adding 100 μL of stop solution to each well, and the absorbance was measured at 450 nm. DNA isolated from positive clones was sent to the Roswell Park Sequencing Core Facility (Buffalo, NY) for sequencing.

[0148] Mutagenesis library

[0149] The genes for scFv clones 3B8, 1H2, and 1B3 were codon-optimized for E. coli and synthesized by GeneArt. The heavy and light chains of each clone were amplified by PCR and then mutated using PCR-based random mutagenesis. The purified mutagenesis products were combined, and the heavy and light chains were ligated using overlap-extension PCR. The complete library was constructed following the same method used to construct the immune phage library, using the phagemid vector pComb3XSS instead of the pADL-10b phagemid vector.

[0150] Panning and screening of mutagenesis libraries

[0151] Phages were panned three times against MMAF-PEG11-biotin-streptavidin-coated beads with increasing stringency. After the third panning, phage displaying scFvs were dissociated with 1 μM MMAE for 3 hours, the supernatant was removed, and the remaining phage was eluted with 1 μM MMAE for 24 hours. Two 96-well deep plates were inoculated with single colonies from the 24-hour elution, and phage were expressed in deep well plates according to the protocol described above. The next day, phage-containing supernatants were diluted 1:10 with 2% milk-PBS in individual wells of a 96-well plate with or without 1 nM free MMAE for 1 hour. The phage-containing solution was then transferred to wells of a Nunc Maxisorb plate containing immobilized MMAF-PEG11-biotin-neutravidin and incubated at room temperature for 2 hours in a shaking incubator. The plate was washed, and bound phage was detected. Colonies with greater than 70% signal knockdown were sent for DNA sequencing.

[0152] Humanization

[0153] The amino acid sequences of the variable heavy and variable light chains of clone MA24E2 were input into Abysis. Mouse framework residues that occur infrequently in human antibodies were conservatively mutated to frequently occurring amino acids. The mouse and humanized sequences were input into Abodybuilder to generate structural model predictions for the human and mouse sequences. To ensure that the human sequence was predicted to have a similar structure to the mouse sequence, the predicted structures were superimposed on ChimeraX. The humanized sequence was expressed as a fab fragment (ABC3315) in ExpiCHO-S cells and purified using CaptureSelect™ CH1-XL affinity resin according to the manufacturer's recommendations.

[0154] Competitive ELISA

[0155] Anti-MMAE Fab was diluted to 1 nM and incubated with a range of concentrations of MMAE, MMAF, and trastuzumab-vc-MMAE. The solution was added in triplicate to individual wells of an ELISA plate containing immobilized MMAF-PEG11-biotin-streptavidin. The plate was incubated for 2 hours at room temperature on a shaking platform set at 300 rpm. The wells were washed four times with PBST, and 250 μL of a 1:1,000 dilution of the secondary anti-human AP dilution was added to each well and incubated for 1.5 hours. The wells were washed twice with PBST and twice with distilled water. 250 μL of 4 mg / ml PnPP in diethanolamine was added to each well, and the change in absorbance at 405 nm over time was assessed for 10 minutes. The change in absorbance over time for MMAE / MMAF and trastuzumab-vc-MMAE wells was normalized to wells treated with anti-MMAE fab alone to determine the fraction of anti-MMAE fab bound.

[0156] Surface plasmon resonance

[0157] SR7500DC surface plasmon resonance was used to evaluate the binding of anti-MMAE Fab. MMAF-PEG11-biotin was flowed onto the left channel of a neutravidin-immobilized SPR chip. Unbound sites on both channels were then blocked by injection of free biotin. ABC3315 Fab was injected sequentially at concentrations of 1.23 nM, 3.70 nM, 11.11 nM, 33.33 nM, and 100 nM for 3 min, with a 3-h dissociation step following the final 100 nM injection. To evaluate ABC3315 binding to free MMAE and PV, ABC3315 was conjugated to nhs-PEG12-biotin and injected onto the left channel of a streptavidin SPR chip. Unbound sites on both channels were then blocked by injection of free biotin. MMAE was injected sequentially at concentrations of 0.37 nM, 1.11 nM, 3.33 nM, 10 nM, and 30 nM for 3 min, with a 3-h dissociation step following the final 30 nM injection. A second kinetic titration was completed by injecting PV at conjugated MMAE concentrations of 1.23, 3.70, 11.11, 33.33, and 100 nM, with a 3-h dissociation step following the final 100 nM injection. The observed sensorgrams were fitted using the kinetic titration module in ClampXP to obtain association, dissociation, and equilibrium dissociation rate constants.

[0158] Cell viability assay

[0159] Ramos cells at a density of 50,000 cells / mL were split into individual wells of a 96-well flat-bottom culture plate. Medium containing dilutions of MMAE or PV, with or without 500 nM anti-MMAE Fab, was added to each well, and the cells were incubated at 37°C in a humidified incubator with 5% CO2 for 4 days. On day 4, 25 μL of 4 mg / mL MTT was added to each well, and the plate was incubated for 2 hours. The MTT was then solubilized overnight after the addition of 100 μL of 10% SDS, 0.1 M HCl. The absorbance of each well was read at wavelengths of 550 nm and 690 nm. A similar protocol was followed to evaluate the effect of anti-MMAE Fab on the efficacy of trastuzumab-vc-MMAE and MMAE in SKBR3 cells. SKBR3 cells were trypsinized and diluted to a concentration of 40,000 cells / mL. 100 μL of cell suspension was added to individual wells of a 96-well U-bottom culture plate, and cells were allowed to attach overnight. The following day, the culture medium was aspirated and replaced with fresh medium containing MMAE or trastuzumab-vc-MMAE with or without 500 nM anti-MMAE Fab. Cells were incubated with fresh medium for 6 days, and drug dilutions were added on days 3 and 5. Cell viability was assessed using the same MTT protocol as described for RAMOS cells. Cell viability was determined as the difference in absorbance at 550 nm and 690 nm for treated wells divided by the difference for untreated wells. The observed cell viability for each group was fitted to a four-parameter inhibitor-response equation in GraphPad Prism 7.

[0160] Xenograft efficacy studies

[0161] Male and female Nu / J mice (The Jackson Laboratory) were injected with 100 μL of DPBS containing 5 × 10 Ramos cells into the right hind limb. Xenograft growth was monitored using digital calipers, and tumor volume was calculated as W × L / 2, where L is the longest tumor diameter and W is the tumor diameter perpendicular to L. At tumor volumes of 200–300 mm (average approximately 250 mm), mice were randomized into groups of eight and administered: (i) PBS + PBS control; (ii) 1 mg / kg PV + PBS; (iii) 1 mg / kg + 12 × ABC3315; (iv) 3 mg / kg PV + PBS; and (v) 3 mg / kg + 12 × ABC3315. PV was administered via injection into the retro-orbital sinus. ABC3315 was administered by intraperitoneal injection, divided into five injections: 30% of the dose was administered immediately after PV injection, 25% was administered 8 hours after PV, and 15% was administered at 24, 32, and 48 hours. Tumor volume and body weight were monitored daily, and mice were sacrificed when tumor volume reached 2000 mm3. Kaplan-Meier survival curves were generated using GraphPad Prism 7 and compared using the log-rank test with a significance level of p ≤ 0.05.

[0162] Toxicity testing

[0163] Toxicity evaluation of PV after a 120 mg / kg dose with and without 3x ABC3315 coadministration was submitted to Champions Oncology (Rockville, MD). Swiss-Webster mice (n=5 / group) were injected with PV via tail vein injection. ABC3315 was administered via intraperitoneal injection, following the same administration protocol outlined in the xenograft study methods. Control mice received an equal volume of PBS at each time point. Mouse weights were measured daily for 14 days after PV injection. Mice with weight loss greater than 10% were given food gel ad libitum.

[0164] [Example 2] This example provides a description of the results obtained using the materials and methods of Example 1.

[0165] An scFv phage library was developed from spleen cells obtained from immunized mice, and this library was screened to identify scFvs with selective binding to free MMAE (compared to vc-MMAE conjugates). Figure 1 shows the top five hits that demonstrated binding to free MMAE with negligible binding to trastuzumab-vc-MMAE (T-vc-MMAE). The bars represent the fraction of phage displaying scFvs bound to MMAF-peg11-biotin-streptavidin with spiked MMAE or T-vc-MMAE compared to control wells. The amino acid sequences of the clones are shown in Figure 2.

[0166] A randomly mutagenized phage library was developed from clones 1H2, 1B3, and 3B8, and then panned and screened to identify clones with increased MMAE affinity. Figure 3 shows the fractional binding signals observed for individual clones from four 96-well plates with or without incubation with 10 nM or 1 nM free MMAE. Clones were sequenced, and the amino acid sequences were aligned (Figure 4).

[0167] A humanized anti-MMAE Fab (ABC3315) was generated by a resurfacing protocol, increasing the z-score of the variable domains after humanization from -0.624 to 0.872 for the heavy chain and from 0.120 to 0.989 for the light chain. ABC3315 was characterized using a competition ELISA with increasing concentrations of free MMAE / MMAF and T-vc-MMAE (Figure 5). ABC3315 binding decreased by approximately 1 nM in IC50 with the addition of free MMAE and MMAF, but no knockdown of the binding signal was observed with the addition of T-vc-MMAE. For high-affinity interactions, the IC50 values ​​observed in competition ELISA experiments are often greater than the equilibrium dissociation constant. To more fully characterize the binding affinity of ABC3315, a series of kinetic titration surface plasmon resonance (SPR) analyses were performed. The rate constant for ABC3315 binding to MMAF-PEG11-biotin bound to a neutravidin SPR chip was estimated. The observed sensorgram is shown in the left panel of Figure 6. The estimated equilibrium dissociation constant for ABC3315 binding to MMAF-PEG11-biotin-neutravidin was 44.2 pM. Follow-up SPR experiments were completed using biotinylated ABC3315 immobilized on a streptavidin chip. The center panel of Figure 6 shows the observed sensorgram for free MMAE injected over immobilized ABC3315. The fitted equilibrium dissociation constant for free MMAE binding to ABC3315 is 7.7 pM. The higher affinity for free MMAE is a result of the faster association rate constant of ABC3315 for free MMAE (2.67 x 105 M-1 sec-1) compared to immobilized MMAF-PEG11-biotin (4.11 x 104 M-1 sec-1). The right panel of Figure 6 shows the sensorgram observed after kinetic titration of polatuzumab vedotin (PV) against immobilized ABC3315. Consistent with ABC3315 selectively binding to free MMAE, no binding signal was observed and there was minimal change in response units (±2 μRU) during the binding analysis.

[0168] Burkitt's lymphoma cell line (Ramos) was incubated with free MMAE or PV with or without 500 nM ABC3315. The cell viability fraction was determined after 4 days of incubation and calculated as the MTT signal of the treated wells divided by the control wells. Addition of ABC3315 increased the observed IC50 of free MMAE in RAMOS cells from 0.12 nM to 95.96 nM. The IC50 of cells treated with PV was 0.12 nM, and the IC50 of PV + ABC3315 was 0.13 nM. Comparable results were obtained in the HER2+ SKBR3 cell line after treatment with free MMAE or trastuzumab-vc-MMAE. The IC50 of free MMAE increased from 0.09 nM to 46.24 nM with ABC3315, while the IC50 of T-vc-MMAE was 0.04 nM with and without co-incubation with ABC3315 and 0.03 nM, respectively. ABC3315 increased the ADC potency / payload potency ratio by 738-fold for PV in Ramos cells and 385-fold for T-vc-MMAE in SKBR3 cells. The cell viability curves observed for free MMAE, PV, and T-vc-MMAE are shown in Figure 7.

[0169] To evaluate the effect of ABC3315 on the efficacy of PV in vivo, RAMOS xenograft-bearing NU / J mice were injected with a single dose of PV alone or with co-administration of ABC3315 at a 12-fold molar ratio (relative to conjugated MMAE). Tumor growth curves for each group are shown in Figure 8A, and survival curves for each group are shown in Figure 8B. Using the log-rank test, co-treatment with ABC3315 did not significantly alter the survival of PV-treated mice at doses of 1 mg / kg (p=0.075) or 3 mg / kg (p=0.89).

[0170] To evaluate the effect of ABC3315 on PV toxicity, Swiss-Webster mice were intravenously injected with 120 mg / kg PV with PBS vehicle or a co-administered dose of ABC3315 at a 3-fold molar ratio compared to conjugated MMAE. Mouse weights were measured daily for 14 days after administration. The observed mean body weight over time for each group is shown in Figure 9A, and the nadir weights for each group are shown in Figure 9B. Administration of ABC3315 with 120 mg / kg PV reduced nadir weight loss in mice from 11.9% (mice treated with ADC co-administered with PBS) (standard deviation ±7.0%) to 4.1 ±2.1% (mice treated with ADC co-administered with ABC3315, p=0.045).

[0171] [Example 3]

[0172] method

[0173] Albumin-conjugated anti-MMAE Fab

[0174] The gene sequence of a previously reported albumin-binding peptide (published in an abandoned Genentech patent application: U.S. Patent Application Publication No. 20050287153(A1)) was added to the C-terminus of the heavy chain of ABC3315. The variants were expressed in ExpiCho-S cells according to the manufacturer's recommendations. Human serum albumin binding affinity was assessed using surface plasmon resonance (SPR). For SPR assessment, human serum albumin (HSA) was immobilized on a carboxymethyl dextran chip. ABC3315-WEDD was injected onto the HSA chip at concentrations ranging from 61.2 nM to 11.4 μM for 2 minutes and allowed to dissociate for 1 minute. ABC3315-WE was injected onto the HSA chip at concentrations ranging from 637 nM to 30 μM for 2 minutes and allowed to dissociate for 1 minute. The observed sensorgrams were fitted to obtain the association, dissociation, and equilibrium dissociation rate constants for HSA binding.

[0175] Albumin-binding variant sequences

[0176] *Albumin binding peptide is underlined. The light chain sequence of ABC3315 is not modified for the albumin binding variant.

[0177] ABC3315-WEDD

[0178] TIFF2025528390000008.tif36155

[0179] ABC3315-WE

[0180] TIFF2025528390000009.tif36155

[0181] ABC3315 mutant

[0182] ABC3315 variants with improved affinity or humanization have been generated. To identify ABC3315 variants with increased affinity compared to ABC3315, error-prone PCR was used to generate a mutant scFv phage library based on the ABC3315 scFv sequence. Phage displaying the scFv variants were bound to MMAF-PEG11-biotin-streptavidin magnetic beads for 1 hour. The scFv-displaying phage were then dissociated from the beads for 24 hours for the first panning round, 72 hours for the second panning round, and 120 hours for the third panning round. 1 μM free ABC3315 was included in the dissociation buffer to prevent rebinding of the scFv phage during dissociation. After each round of dissociation, the remaining scFv-displaying phage were eluted with 10 mg / mL trypsin for 20 minutes. The eluted phage were amplified after each round, and the amplified phage were used as input titers for the next panning round. After the third round of panning, a small amount of phage eluate was titrated, and the remaining phage were amplified. Two 96-well master plates were generated from the titrated phage, and the phage were screened using a dissociation ELISA. Briefly, 10 μg / ml streptavidin was immobilized onto the wells of a Nunc® Immobilizer™ Amino (Thermo Scientific) plate overnight. The next day, unreacted sites were blocked with 10 mM ethanolamine in pH 9.5 sodium bicarbonate buffer, and then MMAF-PEG11-biotin was bound to the immobilized streptavidin. Amplified phage from individual wells of the two master plates were diluted 4-fold in PBS, added twice to the plate, and incubated for 1 hour in a shaking incubator. The plate was washed three times, and either PBS or PBS containing 1 μM MMAF was added to the wells. The plate was incubated for 24 hours, washed three times, and anti-CM13 phage secondary was added to the wells. Phage binding with 1 μM MMAF was normalized to the phage binding for each clone with PBS-only treatment. Wells observed to have minimal change with MMAF incubation were predicted to have slow dissociation rates and were sequenced.Phagemid DNA was isolated from phages amplified after the third round of panning, digested with NdeI and XhoI restriction enzymes, and scFv DNA was isolated using agarose gel electrophoresis, ligated to pet22b, and transformed into SHuffle E. coli cells. The following day, individual transformants were inoculated into the inner wells of an ELISA plate and grown overnight. The following day, 10 μL of medium from each well was transferred to a 96-well deep-well plate and placed in a shaker incubator at 30°C for 4 hours. 1 mM IPTG was added to each well, and the cells were incubated overnight in a shaker incubator at 16°C. The following day, the cells were lysed and diluted with PBS containing HRP-labeled ABC3315. The solution was transferred to a MMAF-PEG11-biotin neutravidin-coated plate preblocked with 2% milk. The plate was incubated for 2 hours, washed, and bound ABC3315-HRP was assessed after the addition of Turbo TMB substrate. Clones with reduced ABC3315-HRP signal were sequenced to identify scFv clones that efficiently competed with ABC3315 for substrate binding. To generate more humanized variants, murine residues from the variable heavy chain of ABC3315 that were retained during the humanization process (because they were located in positions that could affect MMAE binding) were mutated to amino acid residues frequently represented in the human sequence using the Q5® Site-Directed Mutagenesis Kit (New England BioLabs). The variants were expressed in ExpiCho-S cells according to the manufacturer's recommendations. The variants were compared to ABC3315 for binding activity using an indirect ELISA with MMAF-peg11-biotin-neutravidin as the capture substrate and anti-human Fab alkaline phosphatase as the detection antibody.

[0183] result

[0184] Human serum albumin binding

[0185] Both ABC3315-WEDD and ABC3315-WE were observed to bind to immobilized human serum albumin. The observed sensorgrams for ABC3315-WEDD and ABC3315-WE are shown in Figures 10 and 11, respectively. The best-fit association, dissociation, and equilibrium dissociation rate constants are shown in the insets of each figure. The estimated equilibrium dissociation rate constant for ABC3315-WEDD toward human serum albumin is 2.34 μM. The estimated equilibrium dissociation rate constant for ABC3315-WE toward human serum albumin is 10.50 μM. As shown in the bottom panels of both Figures 10 and 11, the maximum signal observed at each concentration was used to obtain similar equilibrium dissociation rate constants.

[0186] ABC3315 mutant

[0187] Unique ABC3315 mutants were identified after panning and screening of a mutant scFv phage display library (shown in Figure 12). Several clones with CDR mutations of interest for the development of ABC3315 derivatives with increased MMAE binding affinity were identified. Four clones with a phenylalanine (F) to leucine (L) mutation at position 27 of the heavy chain were identified, and this substitution was therefore selected for further characterization. Mutant ABC3315 Fabs with increased humanization (VH_E42G, VH_R44G, VH_L61A, VH_F37V) or potentially increased MMAE affinity (VH_F27L) were compared using an indirect ELISA. Most of the ABC3315 mutants exhibited binding signals to immobilized MMAF-PEG11-biotin similar to ABC3315, indicating that binding function was retained after mutagenesis. The VH_F37V clone showed a significantly reduced binding signal compared to ABC3315, demonstrating that the phenylalanine residue at position 37 of the heavy chain is required for high-affinity binding. ABC3315 and VH_F27L were compared in a competitive SKBR3 cell cytotoxicity assay as described, except that the Fab concentration was maintained at a 5-fold excess over MMAE for all MMAE dilutions, instead of a constant 500 nM Fab concentration. SKBR3 cells treated with MMAE and VH_F27L were observed to have a higher cell survival fraction compared to cells treated with MMAE and ABC3315 (Figure 14). The observed results are consistent with VH-F27L having a higher affinity for free MMAE than ABC3315.

[0188] Mutant heavy chain sequence

[0189] VH_E42G (humanized)

[0190] EVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPGKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 53)

[0191] VH_R44G (humanized)

[0192] EVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKGLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 54)

[0193] VH_L61A (humanized)

[0194] EVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYADSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 55)

[0195] VH_F37V (humanized)

[0196] EVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWVRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 56)

[0197] VH_F27L (affinity)

[0198] EVQLVESGGGLVKPGGSLKLSCAASGLTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 4)

[0199] Mutant scFv sequence

[0200] >C1B11

[0201] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYRASTRHTGVPDRFSGNGSGTDLTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFSFSGYAMSWFRQAPDKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 57)

[0202] >C1C8

[0203] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRPEWVATISSGGSYTYYYLDSVKGRFTISRDNNKNTLFLQMSSLRSEDTAVYYCLASMITTDYFEYWGQGTLVTVSS (SEQ ID NO: 58)

[0204] >C1D7

[0205] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTELEIKRGGSGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLVTTDYFEYWGQGTLVTVSS (SEQ ID NO: 59)

[0206] >C1D10

[0207] MDIVMTQSTSSMRASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 60)

[0208] >C1E2

[0209] MDIVMTQSPSSLSASVGDRVIFTCRTSQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTELEVKRSGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSSGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLMTTDYFEYWGQGTLVTVSS (SEQ ID NO: 61)

[0210] >C1G3

[0211] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQFSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGLTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKKTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 62)

[0212] >C2C2

[0213] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSGVQLVESGGGLVKPGGSLKLSCAASGFTISGYAMSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTTSRDNSINTLYLQMSSLRSEDTAVYYCLASLFTTDYFEYWGQGTLVTVNS (SEQ ID NO: 63)

[0214] >C2C4 MDIVMTQSPSSLSASVGDRVTISCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGSKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQTPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 64)

[0215] >C2D11

[0216] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVQDRFSGSGSGTVFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPGKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 65)

[0217] >C2F5

[0218] MDIVMTQSPSSLGASVGDRVTITCRASQDIGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGAGTKLEIRRGGGGSGGGGSGGGGSGGGGSEVQLDESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPDKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 66)

[0219] >DBG6

[0220] MDIVMTQSPSSLSTSVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPGRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEINRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTVSRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 67)

[0221] >DAD3

[0222] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVERGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLLTTDYFEYWGQGTLVTVSS (SEQ ID NO: 68)

[0223] >DAD4

[0224] MDIVMTQSPSSLNASVGGRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGLTFSGYAMSWFRQAPEKRLEWVGTISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 69)

[0225] >DAG4

[0226] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYLEYWGQGTLVTVSS (SEQ ID NO: 70)

[0227] >DAC2

[0228] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTHYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 71)

[0229] >DBF5

[0230] MDIVMTQSPSSQSASIGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIERGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQTSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 72)

[0231] >DAD10

[0232] MDIVMTQSPSGLSASVGDRVTITCHASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGSDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLFESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRPEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 73)

[0233] >AC10

[0234] MDIVMTQSPSSLSASVGDRVTITCSASQDVGTAGAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGDSGSGGSEVQLVESGGGLVKRGGSLKLSCAASGFTLSGYAMSWFRQAPGKRPEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 74)

[0235] >DBB10

[0236] MDIVMTQSPSSLSASVGDRVTFTCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 75)

[0237] >DBD2

[0238] MDIVMTQSPSSLSASVGDRVTITCHASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFNLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPDKRLEWVATISSGGGYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGALVTVSS (SEQ ID NO: 76)

[0239] >DBG2

[0240] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRYTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSKVQLVESGGGLVKRGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQLSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 77)

[0241] >DAD5

[0242] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRYTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGLTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 78)

[0243] >DAG2

[0244] MDIVMTQSPSSLSASVGDRVTITCRTSQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGAGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGLTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 79)

[0245] >DAG7

[0246] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYRQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKGGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 80)

[0247] [Example 4]

[0248] This example includes the sequence of further described antibodies and characterization of the antibody designated herein as ABC3315.

[0249] >DAB6

[0250] MDIVMTQSPSSLSASVGDRVTIACRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEVKRGGGGSGGGGSGSGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGSTFSGYAMSWFRQAPDKRLEWVATISSGGSYTYYLDSVKGRYTISRDNSKNTLYLQMSSLRSEDTAVYYCLASRITTDYFEYWGQGTLVTVSS (SEQ ID NO: 81)

[0251] >DAC3

[0252] MDIVMTQSPSSLSASVGDRVTITCRASQDVGAAVAWYKKKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 82)

[0253] >DAC4

[0254] MDIVMTQSPSSLSASVGDRVTITCHASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYSCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGRVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 83)

[0255] >DAC9

[0256] MDIVMTQSPSSLSASVGDRVTITCHASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPDKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 84)

[0257] >DAD9

[0258] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPGRFSGSGSGTDFTLTIRGLQSEDEADYFCQQYSNYPYTFGGGTKLDIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPDKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLFTTDYFEYWGQGTLVTVSS (SEQ ID NO: 85)

[0259] >DAE2

[0260] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIHWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKMEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPGKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 86)

[0261] >DAG5

[0262] MDIVMTQSPSSLSASVGGRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRYTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGLTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYLDSVKGRLTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 87)

[0263] >DAG10

[0264] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 88)

[0265] >DBC8

[0266] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGADFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMNSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 89)

[0267] >DBD5

[0268] MDIVMTQSPGSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRLSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGSTFSGYAMSWFRQAPEKRPEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 90)

[0269] >DBD9

[0270] MDIVMTQSPSSLRASVGGRVTITCRASQDVGTAVAWYQQKPGQSPKLLIHWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGSTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSINTLYLQMSSLRSEDTAVYYCLASQFTTDYFEYWGQGNLVTVSS (SEQ ID NO: 91)

[0271] >DBD11

[0272] MDNVMTQSPSSLSASVGDRVTITCHASQDVGTAVAWYQQKPGRSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSVDGADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 92)

[0273] >DBG3

[0274] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEINRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTLSGYAMSWFRQAREKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTPVTVSS (SEQ ID NO: 93)

[0275] >DBG4

[0276] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLTYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYSCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSDGGGTGGGGSEVQLVESGGGLIKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGSYTYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 94)

[0277] >DBG8

[0278] MDIVMTQSLSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYAMSWFRQAPEKRLEWVATISSGGNYTYYLDSVKGRFTISRDNSKNILYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 95)

[0279] >DBG11

[0280] MDIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQNPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFTFSGYTMSWFRQAPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKKTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 96)

[0281] ABC3317 sequence

[0282] Light chain

[0283] DIVMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1)

[0284] Heavy chain (italics, albumin binding sequence)

[0285] TIFF2025528390000010.tif36155

[0286] ABC3320 sequence

[0287] Light chain (bold, H55Y mutation) TIFF2025528390000011.tif30157

[0288] Heavy chain (bold, F27L mutation; italic, albumin binding sequence) TIFF2025528390000012.tif37155

[0289] Newly identified sequences from a naive human Fab library

[0290] Human Fab (VL and VH listed)

[0291] >hFM1

[0292] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAYYVHWYQQVPGTAPRLLIFDNDNRPSGVPDRFSASKSGTSASLAIIGLQAEDEAEYYCQSVDYSLGDGVVFGGGTKLTVL (SEQ ID NO: 177)

[0293] QVQLVESGPGLVKPSETLSLTCAVSGGSISSNNWWSWVRQTPGKGLEWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCANLRGQWGQGTLVTVSS (SEQ ID NO: 100)

[0294] >hFM2

[0295] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPRLLISGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGHVVFGGGTKLTVL (SEQ ID NO: 101)

[0296] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGKRGNFDYWGQGTLVTVSS (SEQ ID NO: 102)

[0297] >hFM3

[0298] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0299] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0300] >hFM4

[0301] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0302] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0303] >hFM5

[0304] QSVLTQPPSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128)

[0305] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111)

[0306] >hFM6

[0307] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLSVFGTGTKVTVL (SEQ ID NO: 129)

[0308] QLQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSLASRVTISIDRSQNQFSLKLTSVTAADTAVYYCARGGGRFDFWGQGTLVTVSS (SEQ ID NO: 130)

[0309] >hFM7

[0310] QAVLTQPSSVSGAPGQRVTISCTGTNSNIGAGYDVHWYQQFPGAAPKVLIYGNTNRPSGVPGRFSASKSGTSASLAITGLQAEDEADYYCQTYDSSLSGTWVFGGGTKLTVL (SEQ ID NO: 137)

[0311] QVQLQQWGPGLVKPSGTLSLTCAVSGVSISSSNWWSWVRQTPGKGLEWIGEISHSGSPNYNPSLKSRVTISVDTSKNQFSLKLTSVTAADSAVYYCARGGGPIPHIWGQGTTVTVSS (SEQ ID NO: 138)

[0312] >hFM8

[0313] QAVLTQPSSVSGAPGQRVTISCTGSSTNIGADFDVHWYQQLPGTAPKLLIHGDNNRPSGVPDRFSGSKSGTSAYLAISGLQAEDEADYYCQTYDSRSSGSRVFGGGTKVTVL (SEQ ID NO: 139)

[0314] QLQLQESGPGLVKPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNAGDIWGQGTMVTVSS (SEQ ID NO: 107)

[0315] >hFM9

[0316] QSVLTQPPSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128)

[0317] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111)

[0318] >hFM11

[0319] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131)

[0320] QVQLQQSGPGLVKPSGTLSLTCDVSGGSISSRNWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLESRVAMSVDKSRYQFSLRLSSVTAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 132)

[0321] >hFM12

[0322] QAVLTQPSSVSGAPGQRVAISCTGSSSNIAAGYDVQWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSVLYVFGTGTKVTVL (SEQ ID NO: 156)

[0323] QLQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCAKRPRNSGYLGAFDIWGQGTMVTVSS (SEQ ID NO: 157)

[0324] >hFM13

[0325] DVVMTQSPLSLAVTLGQPASISCRSSQSLLHSSGYKFLNWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQSPTFGGGTKVEIK (SEQ ID NO: 158)

[0326] EVQLVESGGGLVQPGGSLRLSCTASGFTFSSFSMNWVRQAPGKGPEWVSAISGSGGGTYYADSVKGRFTISRDNAKNSLYLQMSSLRAEDTAVYYCARVRVPQAFDIWGQGTMVTVSS (SEQ ID NO: 159)

[0327] >hFM14

[0328] QSVLTQPPSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128)

[0329] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111)

[0330] >hFM15

[0331] QAVLTQPSSVSGAPGQRVTISCTGSSTNIGADFDVHWYQQLPGTAPKLLIHGDNNRPSGVPDRFSGSKSGTSAYLAISGLQAEDEADYYCQTYDSRSSGSRVFGGGTKVTVL (SEQ ID NO: 139)

[0332] QLQLQESGPGLVKPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNAGDIWGQGTMVTVSS (SEQ ID NO: 107)

[0333] >hFM16

[0334] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGDTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 177)

[0335] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARVGEGAFKDLGQGTLVTVSS (SEQ ID NO: 178)

[0336] >hFM18

[0337] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0338] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0339] >hFM19

[0340] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117)

[0341] QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDKSKNHFSLNLSSVTAADTAVYYCANADYYTHHYWGQGTLVTVSS (SEQ ID NO: 118)

[0342] >hFM20

[0343] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGRAPKLLIYGNNQRPSGVPDRFSGSTSGTSASLAITGPQAEDEADYYCQSYDSSLNGIWVFGGGTKLTVL (SEQ ID NO: 119)

[0344] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEINPSGSTNYNPSLKSRVTMSLDTSKNQFSLKLRSVTAADTALYYCATRDYWGQGTLVTVSS (SEQ ID NO: 120)

[0345] >hFM21

[0346] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0347] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0348] >hFM23

[0349] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0350] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0351] >hFM24

[0352] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131)

[0353] QVQLQQSGPGLVKPSGTLSLTCDVSGGSISSRNWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLESRVAMSVDKSRYQFSLRLSSVTAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 132)

[0354] >hFM28

[0355] QSVLTQPPSVSAAPGQKVTISCSGSSSDIGNNFVSWYQQLPGTAPKRLIYDNSKRPSGIPERFSGSKSGTSATLGITGLQTGDEADYYCGAWDTSLSAYVFGTGTKVTVL (SEQ ID NO: 108)

[0356] QVQLQQWGPGLVKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYSNYRHYYYGMDVWGQGTLVTVSS

[0357] >hFM29

[0358] QSVLTQPPSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128)

[0359] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111)

[0360] >hFM30

[0361] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0362] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0363] >hFM31

[0364] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0365] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0366] >hFM32

[0367] QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155)

[0368] QVQLQESGPGLVKPSETLSLTCAVSGVSISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127)

[0369] >hFM33

[0370] QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNYHVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLDITGLQTGDEADYYCGTWDSSLSAVLFGRGTKLTVL (SEQ ID NO: 169)

[0371] QLQLQESGPGLVKPSGTLSLTCAVSGGSISSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARLRGSGRWGQGTLVTVSS (SEQ ID NO: 170)

[0372] >hFM34

[0373] QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNYHVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLDITGLQTGDEADYYCGTWDSSLSAVLFGRGTKLTVL (SEQ ID NO: 169)

[0374] QLQLQESGPGLVKPSGTLSLTCAVSGGSISSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARLRGSGRWGQGTLVTVSS (SEQ ID NO: 170)

[0375] >hFM36

[0376] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0377] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0378] >hFM39

[0379] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLYVFGTGTKVTVL (SEQ ID NO: 145)

[0380] QVQLQESGPGLVKPSETLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLKSRVTISVDKAKNQFSLMLNSVTAADTAVYYCARGYGMDVWGQGTMVTVSS (SEQ ID NO: 146)

[0381] >hFM40

[0382] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117)

[0383] QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDKSKNHFSLNLSSVTAADTAVYYCANADYYTHHYWGQGTLVTVSS (SEQ ID NO: 118)

[0384] >hFM41

[0385] QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155)

[0386] QVQLQESGPGLVKPSETLSLTCAVSGVSISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127)

[0387] >hFM42

[0388] QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155)

[0389] QVQLQESGPGLVKPSETLSLTCAVSGVSISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127)

[0390] >hFM43

[0391] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117)

[0392] QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDKSKNHFSLNLSSVTAADTAVYYCANADYYTHHYWGQGTLVTVSS (SEQ ID NO: 118)

[0393] >hFM44

[0394] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0395] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0396] >hFM45

[0397] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAYYVHWYQQVPGTAPRLLIFDNDNRPSGVPDRFSASKSGTSASLAIIGLQAEDEAEYYCQSVDYSLGDGVVFGGGTKLTVL (SEQ ID NO: 99)

[0398] QVQLVESGPGLVKPSETLSLTCAVSGGSISSNNWWSWVRQTPGKGLEWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCANLRGQWGQGTLVTVSS (SEQ ID NO: 100)

[0399] >hFM46

[0400] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKVLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 148)

[0401] QVQLQQWGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQFPGKGLEWIGEMSHTGSTNYNPSFKSRVTISVDKSKNQFSLKLSPVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 147)

[0402] >hFM47

[0403] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNRNRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVL (SEQ ID NO: 134)

[0404] QLQLQESGPGLVKPSETLSLTCTVSGGSISSGNYWSWVRQSPEKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCVGTLRTWFDYWGQGTLVTVSS (SEQ ID NO: 105)

[0405] >hFM48

[0406] QSVLTQPPSVSAAPGQKVTISSCSGSSSNIGNYYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGVTGLQTGDEADYYCGTWDSSLSAYVFGTGTKVTVQ

[0407] QVQLQESGPGLVKSSETLSLICAVSGGSISSNNWWSWVRQPPGKGLEWIGEIHHSGTTINYNPSLKSRVTISVDKSKNQFSLQLNSVTPEDTAVYFCARSASGAFDIWGQGTMVTVSS (SEQ ID NO: 142)

[0408] >hFM49

[0409] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADNNRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVP (SEQ ID NO: 143)

[0410] QVQLQESGPGLVELSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSFVSRVTISIDRSQNQFSLKLTSMTAADTAVYYCARLYSGYGHGMDVWGQGTTVTVSS (SEQ ID NO: 144)

[0411] >hFM51

[0412] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLYVFGTGTKVTVL (SEQ ID NO: 145)

[0413] QLQLQESGPGLVKPSGTLSLNCAVSGVSISSTNWWSWVRQFPGKGLEWIGEINHSGTTNYNPSLKSRVTISVDTSKNQFSLQLNSVTPEDTAVYFCAQHLTVWGQGTLVTVSS (SEQ ID NO: 179)

[0414] >hFM52

[0415] QAVLTQPSSLSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLISGNRNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSFVFGTGTKVTVL (SEQ ID NO: 164)

[0416] QLQLQESGPGLVEPSGTLSLTCAVSGVSISTRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSFVSRVTISVDASKNQLSLKLTSVTVADTAVYYCSRKGVDAFDIWGQGTMVTVSS (SEQ ID NO: 165)

[0417] >hFM53

[0418] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0419] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0420] >hFM57

[0421] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0422] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0423] >hFM58

[0424] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADNNRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVP (SEQ ID NO: 143)

[0425] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSFVSRVTISIDRSQNQFSLKLTSMTAADTAVYYCARLYSGYGHGMDVWGQGTTVTVSS

[0426] >hFM59

[0427] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0428] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0429] >hFM60

[0430] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGARYDVHWYQQLPGGAPKLLIHSNSNRPSGVPDRFSGSKSGTSATLDITGLQTGDEADYYCGTWDSSLNSYVFGTGTKVTVL

[0431] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLRRGYWGQGTLVTVSS

[0432] >hFM62

[0433] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0434] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0435] >hFM64

[0436] QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNYYVAWYQQVPGAAPKLLIYDTNKRPSGIPDRFSGSKSGTSATLDITGLRTGDEADYYCGTWDSSLDTDVVFGGGTKLTVL (SEQ ID NO: 167)

[0437] QVQLQESGPGLVKPSETLSLTCAVSGGSISSGSWWSWVRQAPGKGLEWIGEISHSGTTTYNPSLKSRVTISLDKSTSHLSLSLKSVTAADTAVYYCARELGGGAYDIWGQGTIVTVSS (SEQ ID NO: 168)

[0438] >hFM65

[0439] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131)

[0440] QVQLQQSGPGLVKPSGTLSLTCDVSGGSISSRNWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLESRVAMSVDKSRYQFSLRLSSVTAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 132)

[0441] >hFM66

[0442] QSVLTQPPSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128)

[0443] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111)

[0444] >hFM68

[0445] QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155)

[0446] QVQLQESGPGLVKPSETLSLTCAVSGVSISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127)

[0447] >hFM69

[0448] QAVLTQPSSVSGAPGQRVTISCTGTNSNIGAGYDVHWYQQFPGAAPKVLIYGNTNRPSGVPGRFSASKSGTSASLAITGLQAEDEADYYCQTYDSSLSGTWVFGGGTKLTVL (SEQ ID NO: 137)

[0449] QVQLQQWGPGLVKPSGTLSLTCAVSGVSISSSNWWSWVRQTPGKGLEWIGEISHSGSPNYNPSLKSRVTISVDTSKNQFSLKLTSVTAADSAVYYCARGGGPIPHIWGQGTTVTVSS (SEQ ID NO: 140)

[0450] >hFM70

[0451] QAVLTQPSSVSGAPGQRVTISCTGTNSNIGAGYDVHWYQQFPGAAPKVLIYGNTNRPSGVPGRFSASKSGTSASLAITGLQAEDEADYYCQTYDSSLSGTWVFGGGTKLTVL (SEQ ID NO: 137)

[0452] QVQLQQWGPGLVKPSGTLSLTCAVSGVSISSSNWWSWVRQTPGKGLEWIGEISHSGSPNYNPSLKSRVTISVDTSKNQFSLKLTSVTAADSAVYYCARGGGPIPHIWGQGTTVTVSS (SEQ ID NO: 140)

[0453] >hFM71

[0454] QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNYYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGVTGLQTGDEADYYCGTWDSSLSAYVFGTGTK VTVQ (SEQ ID NO: 141)

[0455] QVQLQESGPGLVKSSETLSLICAVSGGSISSNNWWSWVRQPPGKGLEWIGEIHHSGTTINYNPSLKSRVTISVDKSKNQFSLQLNSVTPEDTAVYFCARSASGAFDIWGQGTMVTVSS (SEQ ID NO: 142)

[0456] >hFM72

[0457] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0458] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0459] >hFM73

[0460] QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155)

[0461] QVQLQESGPGLVKPSETLSLTCAVSGVSISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127)

[0462] >hFM74

[0463] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0464] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0465] >hFM75

[0466] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVNWHQQFPGTAPKVLIFGDNARPSGVPDRFYASKSGTSASLTIIGVQSDDEADYYCSTWDDSLNAVVFGGGTTLTVL (SEQ ID NO: 149)

[0467] QLQESGPGLVKPSGTLSLTCAVSGGSISSGNWWSWVRQPPGRGLEWIGEISHSGTINYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRADGYFQPWGQGTLVTVSS

[0468] >hFM76

[0469] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0470] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0471] >hFM77

[0472] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLSVFGTGTKVTVL (SEQ ID NO: 129)

[0473] QLQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSLASRVTISIDRSQNQFSLKLTSVTAADTAVYYCARGGGRFDFWGQGTLVTVSS (SEQ ID NO: 130)

[0474] >hFM78 QAVLTQPSSVSGAPGQRVAISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLRVFGGGTKLTVL (SEQ ID NO: 162)

[0475] QLQLQESGPGLVKPSQTLSLTCTVSGASISSSNWWSWVRQTPGKGLEWIGEISHSGSPNYNPSLKSRVTISVDTSKNQFSLKVSSVTAADTAVYYCAREPRYWGQGTLVTVSS (SEQ ID NO: 163)

[0476] >hFM80

[0477] QAVLTQPSSLSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLISGNRNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSFVFGTGTKVTVL (SEQ ID NO: 164)

[0478] QLQLQESGPGLVEPSGTLSLTCAVSGVSISTRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSFVSRVTISVDASKNQLSLKLTSVTVADTAVYYCSRKGVDAFDIWGQGTMVTVSS (SEQ ID NO: 165)

[0479] >hFM81 QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNYYVAWYQQVPGAAPKLLIYDTNKRPSGIPDRFSGSKSGTSATLDITGLRTGDEADYYCGTWDSSLDTDVVFGGGTKLTVL (SEQ ID NO: 167)

[0480] QVQLQESGPGLVKPSETLSLTCAVSGGSISSGSWWSWVRQAPGKGLEWIGEISHSGTTTYNPSLKSRVTISLDKSTSHLSLSLKSVTAADTAVYYCARELGGGAYDIWGQGTIVTVSS (SEQ ID NO: 168)

[0481] >hFM82

[0482] QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNYHVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLDITGLQTGDEADYYCGTWDSSLSAVLFGRGTKLTVL (SEQ ID NO: 169)

[0483] QLQLQESGPGLVKPSGTLSLTCAVSGGSISSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARLRGSGRWGQGTLVTVSS (SEQ ID NO: 170)

[0484] >hFM84

[0485] QAVLTQPSSVSGAPGQRLTISCTGSTSNIGAGYDVQWYQKLPGAAPKLLVYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEGHYYCQSYDSSLSGWVVFGGGTKLTVL (SEQ ID NO: 171)

[0486] QLVQSGPGLVKPSGILSLTCAVSGGSITSSNWWSWVRQPPGKGLEWIGEISHSGSTNYNPSLKSRVTMSVDKSKNQLSLKLSSLTAADTAVYYCARGGSSLPIWGQGTTVTVSS (SEQ ID NO: 172)

[0487] >hFM85 QAVLTQPSSVSGAPGQTVTISCTGSSSNIGADYDVHWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSGASASLAITGLQADDEADYYCHSYDSTRSGLYIFGTGTRVIV (SEQ ID NO: 173)

[0488] QLQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTISVDKSKNQFSLKLSSVTAEDTAVYYCTTGSSGYWGQGTLVTVSS (SEQ ID NO: 174)

[0489] >hFM87

[0490] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGADYDVQWYQQLPGTAPKLLIYANNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLRVFGGGTKLTVL (SEQ ID NO: 175)

[0491] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARSGRRSSWIDYWGQGTLVTVSS (SEQ ID NO: 176)

[0492] >hFM88 QAVLTQPSSVSAAPGQKVTISCSGSDSNIGNYYVWWYQQLPGAAPKLLIYDNHRRPSGVPDRFSGSKSGTSATLDITGLQTGDEADYYCGTWDGSLTGYVFGPGTKVTVL (SEQ ID NO: 125)

[0493] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCARGRVRGRWLPYYWGQGTLVTVSS (SEQ ID NO: 126)

[0494] >hFM90

[0495] QAVLTQPSSVSGAPGQRVTISCTGTNSNIGAGYDVHWYQQFPGAAPKVLIYGNTNRPSGVPGRFSASKSGTSASLAITGLQAEDEADYYCQTYDSSLSGTWVFGGGTKLTVL (SEQ ID NO: 137)

[0496] QVQLQQWGPGLVKPSGTLSLTCAVSGVSISSSNWWSWVRQTPGKGLEWIGEISHSGSPNYNPSLKSRVTISVDTSKNQFSLKLTSVTAADSAVYYCARGGGPIPHIWGQGTTVTVSS (SEQ ID NO: 140)

[0497] >hFM91

[0498] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0499] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0500] >hFM92

[0501] DIQLTQSPSSLSASVGDRVTITCRASQNINNFLNWYQQKPGNVPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSPLSTFGQGTKVEIK (SEQ ID NO: 160)

[0502] QVQLVQSGAEVKKPGSSVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSVSVVTDAFDIWGQGTTVTVSS (SEQ ID NO: 161)

[0503] >hFM93

[0504] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0505] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0506] >hFM94

[0507] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVL (SEQ ID NO: 153)

[0508] QVQLQESGPGLVKPSGTLSLTCDVSGGSISSNNWWSWVRQSPGKGLEWIGEIIHTGRTNYNPSLTSRVTILIDKSKNQFSLKLTSVTPEDTALYYCARLRGPFDIWGQGTMVTVSS (SEQ ID NO: 154)

[0509] >hFM96

[0510] QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155)

[0511] QVQLQESGPGLVKPSETLSLTCAVSGVSISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127)

[0512] >hFM97

[0513] QAVLTQPSSVSGAPGQRVTISCTGSSTNIGADFDVHWYQQLPGTAPKLLIHGDNNRPSGVPDRFSGSKSGTSAYLAISGLQAEDEADYYCQTYDSRSSGSRVFGGGTKVTVL (SEQ ID NO: 139)

[0514] QLQLQESGPGLVKPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNAGDIWGQGTMVTVSS (SEQ ID NO: 107)

[0515] >hFM98 DVVMTQSPLSLAVTLGQPASISCRSSQSLLHSSGYKFLNWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQSPTFGGGTKVEIK (SEQ ID NO: 158)

[0516] EVQLVESGGGLVQPGGSLRLSCTASGFTFSSFSMNWVRQAPGKGPEWVSAISGSGGGTYYADSVKGRFTISRDNAKNSLYLQMSSLRAEDTAVYYCARVRVPQAFDIWGQGTMVTVSS (SEQ ID NO: 159)

[0517] >hFM99

[0518] QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121)

[0519] QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122)

[0520] >hFM100

[0521] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYEVHWYQQLPGRAPRLLIFDNNNRPSGVPDRFSASKSGTSASLAITGLRAEDEGDYYCQSYDSKRTPPYVFGTGTRVTVL (SEQ ID NO: 123)

[0522] QVQLQQSGAEVKKPGASVKVSCKASGYSFSKYGMSWVRQAPGQGLEWMGWINAGNGDTKYSQKFQGRVTITRDTSASTAYMELSSLKYEDTAIYYCARRLSYYGMDVWGQGTTVTVSS (SEQ ID NO: 124)

[0523] >hFM101 QAVLTQPSSVSAAPGQKVTISCSGSDSNIGNYYVWWYQQLPGAAPKLLIYDNHRRPSGVPDRFSGSKSGTSATLDITGLQTGDEADYYCGTWDGSLTGYVFGPGTKVTVL (SEQ ID NO: 125)

[0524] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCARGRVRGRWLPYYWGQGTLVTVSS (SEQ ID NO: 126)

[0525] >hFM102

[0526] QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155)

[0527] QVQLQESGPGLVKPSETLSLTCAVSGVSISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127)

[0528] >hFM103

[0529] QSVLTQPPSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128)

[0530] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111)

[0531] >hFM104

[0532] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGFWVFGGGTKLTVL (SEQ ID NO: 112)

[0533] QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDNSKNQFSLQLSSVTAADTAVYYCVSNASGRRGFAWGQGTLVTVSS (SEQ ID NO: 113)

[0534] >hFM105 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVNWHQQFPGTAPKVLIFGDNARPSGVPDRFYASKSGTSASLTIIGVQSDDEADYYCSTWDDSLNAVVFGGGTTLTVL (SEQ ID NO: 149)

[0535] VQLQESGPGLVKPSGTLSLTCAVSGGSISSGNWWSWVRQPPGRGLEWIGEISHSGTINYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRADGYFQPWGQGTLVTVSS (SEQ ID NO: 150)

[0536] >hFM106

[0537] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKVLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 148)

[0538] QVQLQQWGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQFPGKGLEWIGEMSHTGSTNYNPSFKSRVTISVDKSKNQFSLKLSPVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 147)

[0539] >hFM107

[0540] QSVLTQPPSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128)

[0541] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111)

[0542] >hFM108

[0543] VLTQPPSVSGAPGQRVTISCTGSDSNIGAGYDVHWYQQYPGIAPKLLIYAHHKRPSGVPDRFSGSTSGTSASLAITGLQAEDEADYYCQSYDSSLSGHYVFGTGTQVSVL (SEQ ID NO: 151)

[0544] QVQLQESGPGLVKPSETLSLTCAVSGGSISSNNWWSWVRQTPGKGLEWIGEIYHSGNTNYNPSLKSRVTISVDKSKNQFSLKLNSVTAADTAVYYCARGRQGAFDPWGQGTLVTVSS (SEQ ID NO: 152)

[0545] >hFM109

[0546] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLSVFGTGTKVTVL (SEQ ID NO: 129)

[0547] QLQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSLASRVTISIDRSQNQFSLKLTSVTAADTAVYYCARGGGRFDFWGQGTLVTVSS (SEQ ID NO: 130)

[0548] >hFM110

[0549] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGFWVFGGGTKLTVL (SEQ ID NO: 112)

[0550] QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDNSKNQFSLQLSSVTAADTAVYYCVSNASGRRGFAWGQGTLVTVSS (SEQ ID NO: 113)

[0551] >hFM112

[0552] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0553] QVQLQESGPGLVELSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 114)

[0554] >hFM113

[0555] QSVLTQPPSVSGAPGQRITISCTGSSSNIGAGYDVQWYQQVPGKAPKHLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYFCQSYDSSLSGYVVFGGGTKLTVL (SEQ ID NO: 115)

[0556] QVQLQESGPGLVKPSETLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEISHTGSPNYNPSLASRVTISMDKSKNQFSLNLRSVTAADTSVYYCARYGRGAFDIWGQGTMVTVSS (SEQ ID NO: 116)

[0557] >hFM114

[0558] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117)

[0559] QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDKSKNHFSLNLSSVTAADTAVYYCANADYYTHHYWGQGTLVTVSS (SEQ ID NO: 118)

[0560] >hFM115

[0561] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0562] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0563] >hFM116

[0564] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVL (SEQ ID NO: 153)

[0565] QVQLQESGPGLVKPSGTLSLTCDVSGGSISSNNWWSWVRQSPGKGLEWIGEIIHTGRTNYNPSLTSRVTILIDKSKNQFSLKLTSVTPEDTALYYCARLRGPFDIWGQGTMVTVSS (SEQ ID NO: 154)

[0566] >hFM117

[0567] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117)

[0568] QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDKSKNHFSLNLSSVTAADTAVYYCANADYYTHHYWGQGTLVTVSS (SEQ ID NO: 118)

[0569] >hFM118

[0570] VLTQPPSVSGAPGQRVTISCTGGSTNIGAGYDVHWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSQSGASASLAITGLQADDEADYYCQSYDSRLDGSKVFGTGTKVTVL (SEQ ID NO: 135)

[0571] QVQLQESGPGLVKPSETLSLTCAVSGVSISSHNWWSWVRQTPGKGLEWIGEMSHSGIPNYNPSLESRVTISLDKSKNQFSLILRSVTAADTAMYYCVGGSGSYSYWGQGTLVTVSS (SEQ ID NO: 136)

[0572] >hFM120

[0573] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGFWVFGGGTKLTVL (SEQ ID NO: 112)

[0574] QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDNSKNQFSLQLSSVTAADTAVYYCVSNASGRRGFAWGQGTLVTVSS (SEQ ID NO: 113)

[0575] >hFM121

[0576] QSVLTQPPSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128)

[0577] QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111)

[0578] >hFM122

[0579] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0580] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0581] >hFM123 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLSVFGTGTKVTVL (SEQ ID NO: 129)

[0582] QLQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSLASRVTISIDRSQNQFSLKLTSVTAADTAVYYCARGGGRFDFWGQGTLVTVSS (SEQ ID NO: 130)

[0583] >hFM124

[0584] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131)

[0585] QVQLQQSGPGLVKPFGRPCPLTCDVSGGSISSRNWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLESRVAMSVDKSRYQFSLRLSSVTAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 133)

[0586] >hFM125

[0587] QSVVTQPPSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131)

[0588] QVQLQQSGPGLVKPSGTLSLTCDVSGGSISSRNWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLESRVAMSVDKSRYQFSLRLSSVTAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 132)

[0589] >hFM126

[0590] QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103)

[0591] QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104)

[0592] >hFM127

[0593] QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNRNRPSGVPDRFSGSSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVL (SEQ ID NO: 134)

[0594] QLQLQESGPGLVKPSETLSLTCTVSGGSISSGNYWSWVRQSPEKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCVGTLRTWFDYWGQGTLVTVSS (SEQ ID NO: 105)

[0595] >hFM128

[0596] QAVLTQPSSVSGAPGQRVTISCTGSSTNIGAGFDVHWYQQLPGTAPKLLIYGDKNRPSGVPDRFSGSKSGTSAYLAITGLQAEDEADYYCQTYDSRLSGSKVFGGGTKVTVL (SEQ ID NO: 106)

[0597] QLQLQESGPGLVKPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNAGDIWGQGTMVTVSS (SEQ ID NO: 107)

[0598] >hFM130

[0599] QSVLTQPPSVSAAPGQKVTISCSGSSSDIGNNFVSWYQQLPGTAPKRLIYDNSKRPSGIPERFSGSKSGTSATLGITGLQTGDEADYYCGAWDTSLSAYVFGTGTKVTVL (SEQ ID NO: 108)

[0600] QVQLQQWGPGLVKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYSNYRHYYYGMDVWGQGTLVTVSS

[0601] While the present invention has been described in terms of illustrative embodiments, routine modifications will be apparent to those skilled in the art and are intended to be within the scope of this disclosure.

Claims

1. A binding partner that specifically binds to a drug used as a drug component of an antibody-drug conjugate (ADC).

2. The binding partner according to claim 1, wherein the binding partner preferentially binds to the drug when the drug is removed from the ADC as compared to the binding of the binding partner to the drug when the drug is present in the ADC.

3. The binding partner according to claim 2, wherein the binding partner comprises an antibody or an antigen-binding fragment thereof, and the antigen-binding fragment may be Fab, Fab’, or F(ab’)2.

4. The binding partner according to claim 3, wherein the drug is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

5. The binding partner according to claim 4, wherein the binding partner has the sequence: DIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRTVAAPSVFIFPPSEDQLKSGTASVVCLNNFYPREAKVQWKVDNA LQSGSQESVT EQDSKDS TYSLSS TLTLSKADYEKH KVYACEVT HQGLSSPV TK SFNRGEC (SEQ ID NO: 1) containing a light chain and the sequence: EVQLVESGGGLVKPGGSLKLSCAA SGF TFSGYAMS WFRQAPEKRLEWVAT ISSGG SYTY YLD SVKG RF TISRDN SKNTL YLQ MSSLRSED TAVYYCLASLITTDYFEYWGQGTVTVSSASTKGPSVFPLAPSSKS TSGGT AAL GCLVK DYFPEPVTVSWN SGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKS C (SEQ ID NO: 2) containing a heavy chain, the sequences of the light chain and / or the heavy chain may comprise at least one amino acid substitution, and the at least one amino acid substitution in the light chain is selected from the group consisting of H55Y, R24H, and L60A. And / or the at least one amino acid substitution in the sequence of the heavy chain is selected from the group consisting of F27L, R44G, E42D, E42G, L61A and I101F, binding partner.

6. The binding partner according to claim 5, wherein the light chain comprises the amino acid substitution of H55Y or the heavy chain comprises the mutation of F27L.

7. The binding partner according to claim 6, wherein the light chain comprises the amino acid substitution of H55Y and the heavy chain comprises the mutation of F27L.

8. The light chain has the sequence: DIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRTVAAPSVIFFPPSEDQLKSGTASVVCLNNFYPREAKVQWKVDNA LQSGNSQESVT EQDSKDS TYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNREG C (SEQ ID NO: 3), The heavy chain has the sequence: EVQLVESGGGLVKPGGSLKLSCAA SGLTFSGYAMS WFRQAPEKRLEWVATISSGGSYYYLD SVKG RF TISR DNSKNTLYLQMSSLRSED TAVYYC LASLITT DYFEYWGQGTVTVSSASTKGPSVFPLAPSSKS TSGGT AALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKS C (SEQ ID NO: 4), The binding partner according to claim 7.

9. The binding partner according to claim 8, wherein the heavy chain or the light chain, or a combination thereof, is adapted to further bind to a substance in the blood of the individual to whom the binding partner is administered but which is not the drug.

10. The binding partner according to claim 9, wherein the binding of the binding partner to the substance in the blood increases the half-life of the binding partner in the circulation of the individual, and optionally, the heavy chain is adapted to bind to the substance.

11. A method for reducing the off-target toxicity of an antibody-drug conjugate (ADC), the method comprising administering to an individual who has received or is receiving the ADC the binding partner according to any one of claims 1 to 10.

12. The method according to claim 11, wherein the binding partner preferentially binds to the drug when the drug is removed from the ADC, as compared to the binding of the binding partner to the drug when the drug is present in the ADC.

13. The method according to claim 12, wherein the binding partner comprises an antibody or an antigen-binding fragment thereof, and the antigen-binding fragment may be Fab, Fab', or F(ab')2.

14. The method according to claim 13, wherein the drug is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

15. The binding partner has the sequence: A light chain comprising the sequence: DIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRTVAAPSVFIFPPSEDQLKSGTASVVCLNNFYPREAKVQWKVDNAQLQSGSQESVTTEQDSKDSSTYSLSSLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNREGEC (SEQ ID NO: 97) and the sequence: A heavy chain comprising the sequence: EVQLVESGGGLVKPGGSLKLSCAAGSFTFSGYAMSWRQAPEKRLEWVATISSGGSYYYLDSSVKGRFTISRDNSKNTLYLQMSSSLRSEDTAVYYCLASLITTTDYFEYWGQGTVTVSSASTKGPSVFPLAPSSKSSTSGGTAAALGCLVKDFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDDKKVEPKS C (SEQ ID NO: 2), wherein the sequence of the light chain and / or the heavy chain may comprise at least one amino acid substitution, and the at least one amino acid substitution in the light chain is selected from the group consisting of H55Y, R24H, and L60A. The method according to claim 14, wherein the at least one amino acid substitution in the sequence of the heavy chain is selected from the group consisting of F27L, R44G, E42D, E42G, L61A and I101F.

16. The method according to claim 15, wherein the light chain comprises the amino acid substitution H55Y or the heavy chain comprises the mutation F27L.

17. The method according to claim 16, wherein the light chain comprises the amino acid substitution H55Y and the heavy chain comprises the mutation F27L.

18. The light chain comprises the sequence DIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRTGVPDRFSGSGSGTDFTLTISGLQSEDDEADYFCQQYSNYPYTFGGGTKLEIKRTVAAPSVIFFPPSEDQLKSGTASVVCLNNFYPREAKVQWKVDNA LQSGSQSESVT EQDSKDS TYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 3), The heavy chain comprises the sequence: EVQLVESGGGLVKPGGSLKLSCAA SGLTFSGYAMSWRQAPEKRL EWVATISSGGSYTYYLDSVKGRFTISRDN SKNTLYLQMSSLRSEDTA VYYCLASLITTDYFEYWGQG TLVTVS SS ASTKGPSVFPLAPSSKS TSGGT AALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LS S VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS C (SEQ ID NO: 4), The method according to claim 17.

19. The method according to claim 18, wherein the heavy chain or the light chain, or a combination thereof, is adapted to further bind to a substance in the individual to which the binding partner is administered but which is not the drug.

20. The method according to claim 19, wherein the binding of the binding partner to the substance increases the half-life of the binding partner in the circulation of the individual, and optionally, the heavy chain is adapted to bind to the substance.

21. A binding partner comprising or consisting of a pair of light and heavy chains, wherein the sequences of the light and heavy chains are selected from the following sequences: VH_E42G (humanized) EVQLVESGGGLVKPGGSLKLSCAAASGFTFSGYAMSWRQAPGKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDDKKVEPKSC (SEQ ID NO: 53) VH_R44G (humanized) EVQLVESGGGLVKPGGSLKLSCAAASGFTFSGYAMSWRQAPEKGLEWVATISSGGSYTYYLDSVKGRFTISRDNSSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDDKKVEPKSC (SEQ ID NO: 54) >VH_L60A (humanized) EVQLVESGGGLVKPGGSLKLSCAAASGFTFSGYAMSWRQAPEKRLEWVATISSGGSYTYYADSVKGRFTISRDNSSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDDKKVEPKSC (SEQ ID NO: 55) >VH_F37V (humanized) EVQLVESGGGLVKPGGSLKLSCAAASGFTFSGYAMSWVRQAPEKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDDKKVEPKSC (SEQ ID NO: 56) VH_F27L (affinity) EVQLVESGGGLVKPGGSLKLSCASGLTFSGYAMSWRQAPEKRLWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDEYEYWGQGTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDDKKVEPKS C (SEQ ID NO: 4) >C1B11 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYRASTRHTGVPDRFSSNGSGT DLTLTISGLQSED EADYFCQQYSNYPYTFGGGTKLEIKRGGGG SGGGGG SGGGGG SGGGGG SEVQLVESGGGLVKPGGSLKLSCASGFSFSGYAMSWRQAPDKRLEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDEYEYWGQGTVTVSS (SEQ ID NO: 57) >C1C8 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSSGSGSGT DFTLTISGLQSED EADYFCQQYSNYPYTFGGGTKLEIKRGGGG SGGGGG SGGGGG SGGGGG SEVQLVESGGGLVKPGGSLKLSCASGFTFSGYAMSWRQAPEKRPEWVATISSGGSYTYYLDSVKGRFTISRDNNKNTLFLQMSSLRSEDTAVYYCLASMITTDEYEYWGQGTVTVSS (SEQ ID NO: 58) >C1D7 MDIVMTQSSPSSSLSSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTEL EIKRGGGSGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAA SGFTSGYAMSWRQAPEKRLEWVATISSSGSYYYLDSVKGRFTISRDN SKNTLYLQMSSLRSEDTAYYCLASLVTTDYFEYWGQGTLVTVSS (SEQ ID NO: 59) >C1D10 MDIVMTQSTSSMRASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAA SGFTSGYAMSWRQAPEKRLEWVATISSSGSYYYLDSVKGRFTISRDN SKNTLYLQMSSLRSEDTAYYCLASLITTTDYFEYWGQGTLVTVSS (SEQ ID NO: 60) >C1E2 MDIVMTQSSPSSSLSSASVGDRVIFTCRTSQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTEL EVKRSGGGGGSGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAA SGFTSGYAMSWRQAPEKRLEWVATISSSGSYYYLDSVKGRFTISRDN SKNTLYLQMSSLRSEDTAYYCLASLMTTDYFEYWGQGTLVTVSS (SEQ ID NO: 61) >C1G3 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDDRFSGSGSGTDFTLTISGLQSEDEADYFCQQFSNYPYTFGGGTKLEIKRGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGLTFSGYAMSWFRQAPEKRLEWVATISSGGSYYYLDSVKGRFTISRDNSSKKTLYLQMSSLRSEDTAVYYCLASLITTDEYFEYWGQGTLVTVSS (SEQ ID NO: 62) >C2C2 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGGSGGGGGSGGGGGSGVQLVESGGGLVKPGGSLKLSCAAGLFTISGYAMSWFRQTPERKLEWVATISSGGSYYYLDSVKGRFTTSRDNSTNTLYLQMSSLRSEDTAVYYCLASLFITTDEYFEYWGQGTLVTVNS (SEQ ID NO: 63) >C2C4 MDIVMTQSPSSLSASVGDRVTISCRASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGSKLEIKRGGGGSGGGGGSGGGGGSGGGGGSGVQLVESGGGLVKPGGSLKLSCAAGLFTFSGYAMSWFRQTPERKLEWVATISSGGSYYYLDSVKGRFTISRDNSSKNTLYLQMSSLRSEDTAVYYCLASLITTDEYFEYWGQGTLVTVSS (SEQ ID NO: 64) >C*2D11 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVQDRFSGSGSGTVFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTFFSGYAMSWFRQAPGKREWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 65) >C2F5 MDIVMTQSPSSLGASVGDRVTITCRASQDIGTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGAGTKEIRRGGGGGSGGGGGSGGGGGSGGGGSEVQLDESGGGLVKPGGSLKLSCAASTFFSGYAMSWFRQAPDKREWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 66) >DBG6 MDIVMTQSPSSLSTSVDDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPGRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEINRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTFFSGYAMSWFRQAPEKREWVATISSGGSYYYLDSVKGRFTVSRDNSKNTLYLQMSSLRSEDTAYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 67) >DAD3 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVERGGSLKLSCAAGFTSGYAMSWRQAPEKRLEWVATISSGGSYYYLDVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLLTTDEYEYWGQGTLVTVSS (SEQ ID NO: 68) >DAD4 MDIVMTQSPSSLNASVGGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGLTFSGYAMSWRQAPEKRLEWVGTISSGGSYYYLDVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYEYWGQGTLVTVSS (SEQ ID NO: 69) >DAG4 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGFTSGYAMSWRQAPEKRLEWVATISSGGSYYYLDVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYLEYWGQGTLVTVSS (SEQ ID NO: 70) >DAC2 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTFTFSGYAMSWRQAPEKRLEWVATISSGGSYTHYLDSVKGRFTISRDNSKNTLYLQMSSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 71) >DBF5 MDIVMTQSPSSQSASIGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIERGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTFTFSGYAMSWRQAPEKRLEWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQTSSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 72) >DAD10 MDIVMTQSPGLSASVGDRVTITCHASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGSDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLFESGGGLVKPGGSLKLSCAASTFTFSGYAMSWRQAPEKRPEWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 73) >AC10 MDIVMTQSPSSLSASVGDRVTITCSASQDVTAGAWYQQKPGQSPKLLIYWASRHTGVPDRSGSGSGTDFTLTISGLQSEDDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGDSGSGGSEVQLVESGGGLVKRGGSLLKSCAASGFTLSGYAMSWFRQAPGKREWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 74) >DBB10 MDIVMTQSPSSLSASVGDRVTTCRASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDRSGSGSGTDFTLTISGLQSEDDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLLKSCAASGFTFSGYAMSWFRQAPEKRLWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 75) >DBD2 MDIVMTQSPSSLSASVGDRVTITCHASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDRSGSGSGTDFNLTLISGLQSEDDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLLKSCAASGFTFSGYAMSWFRQAPDKRLEWVATISSGGGYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGALVTSS (SEQ ID NO: 76) >DBG2 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASRTYTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSKVQLVESGGGLVKRGGLKLSCAAGFTSGYAMSWRQAPEKRLEWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQLSSLRSSEDTVYYCLASLITTDEYFWGQGTLVTVSS (SEQ ID NO: 77) >DAD5 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASRTYTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGGGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGLKLSCAAGLTFSGYAMSWRQAPEKRLEWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTVYYCLASLITTDEYFWGQGTLVTVSS (SEQ ID NO: 78) >DAG2 MDIVMTQSPSSLSASVGDRVTITCRTSQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGAGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGLKLSCAAGLTFSGYAMSWRQAPEKRLEWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTVYYCLASLITTDEYFWGQGTLVTVSS (SEQ ID NO: 79) >DAG7 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYRQKPGQSPKLLIYWASTRHTGVPDRFSSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKGGGGSLKLSCAASTFFSGSYAMSWFRQAPEKRLWVATISSSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAYYCLASLITTDEYFWQGGTLVTVSS (SEQ ID NO: 80) >DAB6 MDIVMTQSPSSLSASVGDRVTIACRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEVKRGBGGGGGSGGGGGSGSGGGSGGGGSEVQLVESGGGLVKPGGGSLKLSCAASTFSGSYAMSWFRQAPDKRLEWVATISSSGGSYTYYLDSVKGRYTISRDNSKNTLYLQMSSLRSEDTAYYCLASRITTDEYFWQGGTLVTVSS (SEQ ID NO: 81) >DAC3 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAAVAWYKKKPGQSPKLLIYWASTRHTGVPDRFSSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGBGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGGSLKLSCAASTFFSGSYAMSWFRQAPEKRLWVATISSSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAYYCLASLITTDEYFWQGGTLVTVSS (SEQ ID NO: 82) >DAC4 MDIVMTQSPSSLSASVGDRVTITCHASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDRFSSGSGSGTDFTLTISGLQSEDEADYSCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGRVKPGGSLKLSCAASTFFSGYAMSWRQAPEKRLEWVATISSSGYTYYLDSVKGRFTISRDNSKNTLYLQMSLRSEDTAYYCLASLITTDEYFWGQGTLVTVSS (SEQ ID NO: 83) >DAC9 MDIVMTQSPSSLSASVGDRVTITCHASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDRFSSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTFFSGYAMSWRQAPDKRLEWVATISSSGYTYYLDSVKGRFTISRDNSKNTLYLQMSLRSEDTAYYCLASLITTDEYFWGQGTLVTVSS (SEQ ID NO: 84) >DAD9 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPGRFSGSGSGTDFTLTIROLQSEDEADYFCQQYSNYPYTFGGGTKLDIRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTFFSGYAMSWRQAPDKRLEWVATISSSGYTYYLDSVKGRFTISRDNSKNTLYLQMSLRSEDTAYYCLASLFTTDEYFWGQGTLVTVSS (SEQ ID NO: 85) >DAE2 MDIVMTQSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIHWASTRHTGVPDRFSGSGSGSTDFTLTISGLQSEDDEADYFCQQYSNYPYTFGGGTKMEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTFTFSGYAMSWRQAPGKREWVATISSSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 86) >DAG5 MDIVMTQSSLSASVGGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRYTGVPDRFSGSGSGSTDFTLTISGLQSEDDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTLTFGSYAMSWRQAPEKREWVATISSSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 87) >DAG10 MDIVMTQSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRYTGVPDRFSGSGSGSTDFTLTISGLQSEDDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASTFTFSGYAMSWRQAPEKREWVATISSSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 88) >DBC8 MDIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFSGSGSGSADFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGSFTFSGYAMSWFRQAPEKRLEWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQMNLSRSEDTVYYCLASLITTDEYFWGQGTLVTVSS (SEQ ID NO: 89) >DBD5 MDIVMTQSPGSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRLSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGSSTFSGYAMSWFRQAPEKRPEWVATISSGGSYYYLDSVKGRFTISRDNSKNTLYLQMSSSLRSSEDTVYYCLASLITTDEYFWGQGTLVTVSS (SEQ ID NO: 90) >DBD9 MDIVMTQSPSSLRASVGGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIHWASTRHTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGSTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGSFTFSGYAMSWFRQAPEKRLEWVATISSGGSYYYLDSVKGRFTISRDNISINTLYLQMSSSLRSSEDTVYYCLASQFTTDDYFEYWGQGNLVTVSS (SEQ ID NO: 91) >DBD11 MDNVMTQSSPSSSLSSAVGDRVTITCHASQDVTAVAWYQQKPGRSPKLLIYWASRHTGVPDRFSSGSGSGTDFTLTISGLQSVDGADYFCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGFTSGSYAMSWFRQAPEKRLEWVATISSSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 92) >DBG3 MDIVMTQSSPSSSLSSAVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASRHTGVPDRFSSGSGSGTDFTLTISGLQSEDDEADYFCQQYSNYPYTFGGGTKLEINRGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGFTLSGSYAMSWFRQAREKRLEWVATISSSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGPTVTVSS (SEQ ID NO: 93) >DBG4 MDIVMTQSSPSSSLSSAVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLTYWASRHTGVPDRFSSGSGSGTDFTLTISGLQSEDDEADYSCQQYSNYPYTFGGGTKLEIKRGGGGSGGGGGSGGGGGTGGGGSEVQLVESGGGLIKPGGSLKLSCAAGFTFSGSYAMSWFRQAPEKRLEWVATISSSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 94) >DBG8 MDIVMTQSLSSLSSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTLISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGSFTFSGYAMSWRQAPEKRLEWVATISSGGNYYYLDSVKGRFTISRDNSKNILYLQMSSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 95) >DBG11 MDIVMTQSPSSLSSASVGDRVTITCRASQDVTAVAWYQQNPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTLISSLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRGGGGGSGGGGGSGGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAAGSFTFSGYTMSWRQAPEKRLEWVATISSGGSYYYLDSVKGRFTISRDNSKKTLYLQMSSSLRSEDTAVYYCLASLITTDYFEYWGQGTLVTVSS (SEQ ID NO: 96) ABC3317 Sequence Light chain DIVMTQSPSSLSSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRHTVPDRFSGSGSGTDFTLTLISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRTVAAPSVIFFPPSEQLKSGTASVVCLNNFYPREAKVQWKVDNAQLSGNSQESVTEDSKDSTYSLSSLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNREGEC (SEQ ID NO: 97) Heavy chain EVQLVESGGGLVKPGGSLKLSCASGFTFSGYAMSWRQAPEKRLWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAYYCLASLITTDYFEYWGQGTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDDKKVEPKSCGGGSRLIEDICLPRWGCLWEDD (SEQ ID NO: 98) >ABC3320 Light chain DIVMTQSPSSLSASVGDRVTITCRASQDVTAVAWYQQKPGQSPKLLIYWASTRYTGVPDRFSGSGSGTDFTLTISGLQSEDEADYFCQQYSNYPYTFGGGTKLEIKRTVAAPSVIFFPPSEDQLKSGTASVVCLNNFYPREAKVQWKVDNAQLSGNSQESVTEQDSKDSSTYSLSSLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 3) Heavy chain EVQLVESGGGLVKPGGSLKLSCASGLTFSGYAMSWRQAPEKRLWVATISSGGSYTYYLDSVKGRFTISRDNSKNTLYLQMSSLRSEDTAYYCLASLITTDYFEYWGQGTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDDKKVEPKSC (SEQ ID NO: 4) >hFM1 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAYYVHWYQQVPGTAPRLLIFDNDNRPSGVPDRFSAASKSGTSASLAIIGLQAEDAEYYCQSVDSLGDGVVFGGGGKLTVL (SEQ ID NO: 99) QVQLVESGPGLVKPSETLSLTCAVSGGSISSNNWWSWRQTPGKGLEWIGEIYHSGSNYNPSLKSRVTISVDKSKNQFSLLSSVTAAADTAVYYCANLRGQWGQGTVTVSS (SEQ ID NO: 100) >hFM2 QSVVTPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPRLLISGNTRPSGVPDRSGSKSGTSASLAITGLQAED EADYYCQSYDSSLSGHVVFGGG TKLVL (SEQ ID NO: 101) QVQLQQWGAGLLKPSSETLSLTCAVYGGFSGSYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFS LKLSSVTAA DTAVYYCARGKRNFDYWGQGTLVTVSS (SEQ ID NO: 102) >hFM3 QSVLTQPPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYDNINRPSGVPDRSGSKSGASASLAITGLQAED EADYYCQSYDSSLSGLRVFG TGKVTVL (SEQ ID NO: 103) QVQLQESGPGLEEPSGTLSLTCAVSGSVISSRNWWSWRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFS LKLSSVTAA DTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) >hFM4 QSVLTQPPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYDNINRPSGVPDRSGSKSGASASLAITGLQAED EADYYCQSYDSSLSGLRVFG TGKVTVL (SEQ ID NO: 103) QVQLQESGPGLEEPSGTLSLTCAVSGSVISSRNWWSWRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFS LKLSSVTAA DTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) >hFM5 QSVLTQPPSSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQT GDEA EYYCAVWDSSSLNGYVFGGG TKLVL (SEQ ID NO: 128) QVQLQQWGAGLLKPSSETLSLTCAVYGGFSGSYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFS LKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111) > hFM6 QAVLTQPSCSVSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYSNTNRPSGVPDRSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSLSGSLVFGGTKVTVL (SEQ ID NO: 129) QLQLQESGPGLEEPSGTLSLTCAVSGSVISSRNWWSWVRTQPGKGLEWIGEISHSGIPNYNPSLASRVTISIDRSQNQFSKLTSVTAAADTAVYYCARGGGRFDFWGQGTLVTVSS (SEQ ID NO: 130) > hFM7 QAVLTQPSCSVSSGAPGQRVTISCTGTNSNIGAGYDVHWYQQFPGAAAPKVLIYGNTRPSGVPGRFSASKSGTSASLAITGLQAEDeadYYCQTYDSSLSLGTWVFGGGGKLTVL (SEQ ID NO: 137) QVQLQQWGPGLVKPSGTLSLTCAVSGSVISSSNWWSWVRTQPGKGLEWIGEISHSGSPNYNPSLKSRVTISVDTSKNQFSKLTSVTAAADSAYYCARGGGPIPHIWGQGTTVTVSS (SEQ ID NO: 140) > hFM8 QAVLTQPSCSVSSGAPGQRVTISCTGSSTNIGADFDVHWYQQRPGTAPKLLIHGDNNRPSGVPDRSGSKSGTSAYLAISGLQAEDeadYYCQTYDRSSSGSRVFGGGGKVTVL (SEQ ID NO: 139) QLQLQESGPGLVKPSGTLSLTCAVSGSVISSRNWWSWVRTQPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDTSKNQFSKLSSSVTAAADTAVYYCARNAGDIWGQGTMVTVSS (SEQ ID NO: 107) > hFM9 QSVLTQPPCSVSAAPGQKVTISCSGTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGTSATLGITGLQTGAEAEYYCAVWDSSSLNGYVFGGGKLTVL (SEQ ID NO: 128) QVQLQQWGAGLLKPSETLSLTCAVYGGSSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLLKLSSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111) >hFM11 QSVVTQPPPSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSSGSKSGTSASLAITGLQAED EADYYCQSYDSSLSGSSEVFGGGGTKLT VL (SEQ ID NO: 131) QVQLQQSGPGLVKP SGTLSLTCDVSGGSSISSRNWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLESRA MSVDKSRYQFSLLKLS SVTAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 132) >hFM12 QAVLTQPS SSVSGAPGQRVAISCTGSSSNIAAGYDVQWYQQLPGTAPKLLIYGNSNRPSGVPDRFSSGSKSGT SASLAITGLQAED EADYYCQSYDSSLSVLYVFGTGTKVTVL (SEQ ID NO: 156) QLQLQESGPGLVKP SGTLSLTCAVSGGSSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLLKLS SVTAADTAVYYCAKRPRNSGYLGAFDIWGQGTMVTVSS (SEQ ID NO: 157) >hFM13 DVVM TQSP LSLAVTLGQPA SISCRSSQ SLLHSSGYKF LNWY LQKPGQSP QLLIYLGSNRASGVPDRFSSGSGSGTDFTLKISRVEAEDVGVYYCMQALQSPTFGGGGTKEIK (SEQ ID NO: 158) EVQLVESGGGLVQPGGS LRLSCTASGFTFSSFSMNWVRQAPGKGPEWVSAISGSGGGTTYYADS VKGRFTISRDNAKNSLYLQ MSSLRAEDTAVYYCARVRVPQA FDIWGQGTMVTVSS (SEQ ID NO: 159) >hFM14 QSVLTQPPVSVSAAPGQKVTSCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGT SATLGITGLQTGAEYYCAVWDSLN GYVFGGGTKLTVL (SEQ ID NO: 128) QVQLQQWGAGLLKPSSETLSLTCAVYGGFSGSYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLLKLS SLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111) >hFM15 QAVLTQPSSSVSGAPGQRVTISCTGSSTNIGADFDVHWYQQ LPGTAPKLLIHGDNNRPSGVPD RFSGSKSGT SAYLAISGLQAED EADYYCQTYDSSRSSGSRVFGGGTKVTVL (SEQ ID NO: 139) QLQLESGPGLVKPSGTLSLTCAVSGVSISS RNWWSWVRQTPGKGLEWIGEISH SGSTNYNPSLKSRVTISVDTSKNQFSLLKLSSVTAA DTAVYYCARNAGDIWGQGTMVTVSS (SEQ ID NO: 107) >hFM16 QSVV TQPPVSVSGAPGQRVTISCTGSSSNIGAGYD VHWYQQ LPGTAPKLLIYGDTNRPSGVPD RFSGSKSGT SASLAITGLQAED EADYYCQSYDSSLSSGVVFGGGTKLTVL (SEQ ID NO: 177) QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISH SGITNYNPSLQSRVTISVDTSKNQFSLLNLSVTAA DTAVYYCARVGEGAFKDLGQGTLVTVSS (SEQ ID NO: ......) >hFM18 QAVLTQPSSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQ LPGTAPKLLIFNDNIRPSGVPD RFSGSKSGT SASLAITGLQAED EADYYCQSYDSSLSSGVVFGGGTKLTVL (SEQ ID NO: 121) QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISH SGITNYNPSLQSRVTIALDKSKNHFS LNVNSVTAA DTAVYYCASYWLGNF DYWGQGTLVTVSS (SEQ ID NO: 122) > hFM19 QAVLTQPSCSVSGAPGQRVTISCTGSSSNIGAGYDVQWYYQQRPGTAPKLLIYADSNRPSGVPDRFSSKSSGTSASLAITGLQAEDYADYYCQSYDSSLSSKVFGGTKLVL (SEQ ID NO: 117) QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDSKNHFSLNLSSVTAAADTAVYYCANADYYTHHYWGQGTLVTVSS (SEQ ID NO: 118) > hFM20 QAVLTQPSCSVSGAPGQRVTISCTGSSSNIGAGYDVHWYYQQRPGRAPKLLIYGNNQRPSGVPDRFSSGSGSGTSASLAITGPQAEDYADYYCQSYDSSLNGIWLVFGGGGTKLVL (SEQ ID NO: 119) QVQLQESGPGLVKPSGTLSLTCAVSGSISSTTNWWSWVRQPPGKGLEWIGEINPSGSTNYNPSLKSRVTMSLDTKSNQFSLLRSVTAAADTALYYCATRDWGQGTLVTVSS (SEQ ID NO: 120) > hFM21 QAVLTQPSCSVSGAPGQRVTISCTGSRSNIGANYDVHWYYQQRPGTAPKLLIFDNIRPSGVPDRFSSKSSGTSASLAITGLQAEDYADYYCQSYDSSLSSGVVFGGGGTKLVL (SEQ ID NO: 121) QVQLQESGPGLVKPSGTLSLTCAVSGSISSTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAAADTAVYYCASYWLGNFDWGQGTLVTVSS (SEQ ID NO: 122) > hFM23 QAVLTQPSCSVSGAPGQRVTISCTGSRSNIGANYDVHWYYQQRPGTAPKLLIFDNIRPSGVPDRFSSKSSGTSASLAITGLQAEDYADYYCQSYDSSLSSGVVFGGGGTKLVL (SEQ ID NO: 121) QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAAADTAVYYCASYWLGNFDYWGQGTVTVSS (SEQ ID NO: 122) >hFM24 QSVVTQPPVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRSGSKSGTSASLAITGLQAED EADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131) QVQLQQSGPGLVKPSGTLSLTCDVSGGGSSSRNWWTWRQPPGKGLEWIGEIYHSGSNYNPSLESRA MSVDKSRYQFSLLSSVTAAADTAVYYCARRRDGYFDYWGQGTVTVSS (SEQ ID NO: 132) >hFM28 QSVLTQPPVSAAAPGQKVTI SCSSSDIGNNFVSWYQQLPGTAPKRLIYDNSKRPSGIPERFSGSKSGT SATLGITGLQT GDEADYYCGAWDT SL SAYVFGTGTKVTVL (SEQ ID NO: 108) QVQLQQWGPGLVKPSETLSLTCAVYGGSFSGYYSWI RQPPGKGLEWIGEINHSGSNYNPSLKSRVTISVDTSK NQFSLLSSVTAAADTAVYYCARYSNYRHYYYGM DWGQGTVTVSS (SEQ ID NO: 109) >hFM29 QSVLTQPPVSAAAPGQKVTI SCSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRFSGSKSGT SATLGITGLQT GDEAEYYCAVWDS SL NG YVFGGGGTKLTVL (SEQ ID NO: 110) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYSWI RQPPGKGLEWIGEINHSGSNYNPSLKSRVTISVDTSK NQFSLLSSLTAAADTAVYYCARVNGGESDYWGQGTVTVSS (SEQ ID NO: 111) >hFM30 QAVLTQPSCSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQRPGTAPKLLIFNDIRPSGVPDRSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSSGVVFGGGTKLTVL (SEQ ID NO: 121) QVQLQESGPGLVKPSGTLSLTCAVSGSVSISTTNWWSWVRQPPGKGLWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAAADTAVYYCASYWLGNFDYWGQGTVTVSS (SEQ ID NO: 122) >hFM31 QSVLTQPPCSVSAAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYDINRPSGVPDRSGSKSGSASASLAITGLQAEDEADYYCQSYDSSLSLGLRVFGGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLEPSGTLSLTCAVSGSVSISSRNWWSWVRQTPGKGLWIGEINHSGSTNYNPSLKSRVTISVDTSKNNFSLLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) >hFM32 QAVLTQPSCSVSGAPGQRVIIISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYGNTRPSGVPDRSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSLGNYVFGPGTVTVL (SEQ ID NO: 155) QVQLQESGPGLVKPSETLSLTCAVSGSVSISSHNWWSWVRQTPGKGLWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLLSSVTAADTAVYYCARGSTGAFDVWGQGTVTVSS (SEQ ID NO: 127) >hFM33 QSVLTQPPCSVSAAPGQKVTISCSGSSSNIGNYHVSWYQQRPGTAPKLLIYDNNKRPIGPDRSGSKSGTSATLDLTGLLTGDEADYYCGTWDSSSLAVLFGREGTTLVL (SEQ ID NO: 169) QLQLQESGPGLVKPSGTLSLTCAVSGGSSISSSGGYYWSSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLLKLSSTVTAADTAVYYCARLRGSGRWGQGTLVTVSS (SEQ ID NO: 170) > hFM34 QSVLTQPPPSVSAAAPGQKVTISCSGSSSNIGNYHVSWYQQLPGTAPKLLIYDNNKRPISGIPDRFSGSKSGTSTATLDTGLQTGADEADYYCGTWDSSSLSLFGRTKLTVL (SEQ ID NO: 169) QLQLQESGPGLVKPSGTLSLTCAVSGGSSISSSGGYYWSSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLLKLSSTVTAADTAVYYCARLRGSGRWGQGTLVTVSS (SEQ ID NO: 170) > hFM36 QAVLTQPSSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDIRPSGVPDRFGSKSGTSSASLAITGLQAEDDEADYYCQSYDSSLSGSVVFGGGGRTKLTVL (SEQ ID NO: 121) QVQLQESGPGLVKPSGTLSLTCAVSGSVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122) > hFM39 QAVLTQPSSSVSGAPGQRVTISCTGSSSNIGAGYDVMWYQQLPGTAPKLLIYGNSNRPSGVPDRFGSKSGTSSASLAITGLQAEDDEADYYCQSYDSSLSGLYVFGTGRTKTVL (SEQ ID NO: 145) QVQLQESGPGLVKPSETLSLTCAVSGSVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLKSRVTISVDKAKNQFSLLNLSVTAADTAVYYCARGYGMVDWGQGTMVTVSS (SEQ ID NO: 146) > hFM40 QAVLTQPSCSVSSGAPGQRVTISCTGSSSNIGAGYDVQWYYQQRPGTAPKLLIYADSNRPSGVPDRFSSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117) QVQLVESGPGLVKPSGTLSLTCAVSGGSSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDSKNHFSLNLSSTAAADTAVYYCANADYYTHHYWGQGTVTVSS (SEQ ID NO: 118) >hFM41 QAVLTQPSCSVSSGAPGQRVIIISCTGSSSNIGAGYDVHWYYQQRPGTAPKLLIYGNTRPSGVPDRFSSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155) QVQLQESGPGLVKPSSETLSLTCAVSGSVISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSAGFDVWGQGTVTVSS (SEQ ID NO: 127) >hFM42 QAVLTQPSCSVSSGAPGQRVIIISCTGSSSNIGAGYDVHWYYQQRPGTAPKLLIYGNTRPSGVPDRFSSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155) QVQLQESGPGLVKPSSETLSLTCAVSGSVISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSAGFDVWGQGTVTVSS (SEQ ID NO: 127) >hFM43 QAVLTQPSCSVSSGAPGQRVTISCTGSSSNIGAGYDVQWYYQQRPGTAPKLLIYADSNRPSGVPDRFSSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117) QVQLVESGPGLVKPSGTLSLTCAVSGGSSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVISM DKSKNHFSLNLSSVTAA DTAVYYCANADYYTHHYWGQGTVTVSS (SEQ ID NO: 118) > hFM44 QAVLTQPSSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQ LPGTAPKLLIFND NIRPSGVPDRFSGSKSGT SASLAITGLQAED EADYYCQSYDSSLSGSVVF GGGTKLTVL (SEQ ID NO: 121) QVQLQESGPGLVKPSGTLSLTCAVSGV SISTTNWWSWVRQPPGKGLEWIGEISH SGTTNYNPSLQSRVTIALDKSKNHFSLNVNSVTAA DTAVYYCASYWLGNF DYWGQGTVTVSS (SEQ ID NO: 122) > hFM45 QAVLTQPSSSVSGAPGQRVTISCTGSSSNIGAYYVHWYQQ VPGTAPRLLIFND NRPPSGVPDRFSASK SGT SASLAIIGLQAED EAEYYCQSV DYS LG DG VVF GGGTKLTVL (SEQ ID NO: 99) QVQLVESGPGLVKPSETLSLTCAVSGGSSISSN NWWSWVRQTPGKGLEWIGEIYHSGS TNYNPSLKSRVTISVDKSKNQFSLLSSVTAA DTAVYYCANLRGQW GQGTVTVSS (SEQ ID NO: 100) > hFM46 QS VLTQPPSSVSGAPGQRVTISCTGSSSNIGAGYD VHWYQQ LPGTAPKVLIYGN SNRPSGVPDRFSGSKSGT SASLAITGLQAED EADYYCQSYDSSLSGSVVF GGGTKLTVL (SEQ ID NO: 148) QVQLQQWGPGLVKPSGTLSLTCAVSGGSSISSSNWWSWVRQFP GKGLEWIGEMSHTGS TNYNPSFKSRVTISVDKSKNQFSLLSPVTAA DTAVYYCAR GSTGAFDVWGQGTVTVSS (SEQ ID NO: 147) > hFM47 QAVLTQPSCSVSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYGNRNRPSGVDRFSGSKSGTSASLAITGLQAEDYCYQSYDSSLGSKVFGTGKVTVL (SEQ ID NO: 134) QLQLESGPGLVKPSSETLSLTCTVSGGSSISSGNYWSWRQSPKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTADTAVYYCVGTLRTWFDDWGQGTLVTVSS (SEQ ID NO: 105) >hFM48 QSVLTQPPCSVSAAPGQKVTISCSGSSSNIGNYVSWYQQRPGTAPKLLIDNNKRPSGIPDRFSGSKSGTSATLGVTGLQTGDEADYCYGTWDSSSLAYVFGTGKVTVQ QVQLESGPGLVKSSSETLSLICAVSGGSSISSNWWSWVRQPPGKGLWIGEIHHSGTTINYNPSLKSRVTISVDKSKNFSLQLNSVTEDTAVYFCARSASGAFDWGQGTMVTVSS (SEQ ID NO: 142) >hFM49 QAVLTQPSCSVSSGAPGQRVTISCTGSSSNIGAGYDVQWYQQRPGTAPKLLIYADNRPSGVDRFSGSKSGTSASLAITGLQAEDYCYQSYDSSLGSKVFGTGKVTVP (SEQ ID NO: 143) QVQLESGPGLVELSGTLSLTCAVSGVISSRNWWSWVRQTPGKGLWIGEISHSGIPNYNPSFVSRVTISIDRSQNFSLKLTSTAAVTYYCARLYSGYGHGMDVWGQGTTVTVSS (SEQ ID NO: 144) >hFM51 QAVLTQPSCSVSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYGNSNRPSGVDRFSGSKSGTSASLAITGLQAEDYCYQSYDSSLGLYVFGTGKVTVL (SEQ ID NO: 145) QLQLESGPGLVKPSGTLSLNCAVSGVISSTNWWSWVRQFPGKGLWIGEINHSGTTNYNPSLKSRVTISVDTSKNQFSLQLNSVTEDTAVYFCQHLTVWGQGTLVTVSS (SEQ ID NO: 179) > hFM52 QAVLTQPSSSLSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLISGNRNRPSGVPDRFSSKSGTSSASLAITGLQAEDeadYYCQSYDSSLSGSFVFGGTKVTVL (SEQ ID NO: 164) QLQLQESGPGLEPSSGTLSLTCAVSGVSISTRNWWSWVRTQPGKGLEWIGEISHSPNYNPSFVSRVTISVDASKNLSKLTSVTVADTAVYYCSRKGVDAFDIGQGTMVTVSS (SEQ ID NO: 165) > hFM53 QAVLTQPSSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQRPGTAPKLLIFNDNIRPSGVPDRFSSKSGTSSASLAITGLQAEDeadYYCQSYDSSLSGSVVFGGGGTKLVL (SEQ ID NO: 121) QVQLQESGPGLVKPSSGTLSLTCAVSGVSISTTNWWSWVRTPPGKGLEWIGEISHSPTNYNPSLQSRVTIALDKSKNHFSLNVNSVTAAADTAVYYCASYWLGNFDAYWGQGTLVTVSS (SEQ ID NO: 122) > hFM57 QSVLTQPPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYDINRPPSGVPDRFSSKSGSASASLAITGLQAEDeadYYCQSYDSSLSGLRVFGGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLEPSSGTLSLTCAVSGVSISSRNWWSWVRTQPGKGLEWIGEINHSPTNYNPSLKSRVTISVDTSKNQFSLLKSSVTAAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) > hFM58 QAVLTQPSSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQRPGTAPKLLIYADNNRPPSGVPDRFSSKSGTSSASLAITGLQAEDeadYYCQSYDSSLSGSKVFGGTKVTVP (SEQ ID NO: 143) QVQLQESGPGLVEPSSGTLSLTCAVSGVSISSRNWWSWVQRQPGKGLEWIGEISHSGIPNYNPSFVSRVTISIDRSQNQFSLLKLTSMTAADTAVYYCARLYSGYGHGMDVWGQGTTVTVSS >hFM59 QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQRPGTAPKLLIFNDIRPSGVPDRFSGSKSGTSASLAITGLQAEDYAYCQSYDSSLSSGVVFGGGGTKLTVL (SEQ ID NO: 121) QVQLQESGPGLVKPSSGTLSLTCAVSGVSISTTNWWSWVQRPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVSVTAAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122) >hFM60 QSVVTQPPVSGAPGQRVTISCTGSSSNIGARYDVHWYQQRPGGAPKLLIHSNSNRPSGVPDRFSGSKSGTSATLDIITGLQTGDEADYYCGTWDSSSLNSYVFGTGTVTVL QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLLSSVTAAADTAVYYCASLRRGYWGQGTLVTVSS >hFM62 QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQRPGTAPKLLIFNDIRPSGVPDRFSGSKSGTSASLAITGLQAEDYAYCQSYDSSLSSGVVFGGGGTKLTVL (SEQ ID NO: 121) QVQLQESGPGLVKPSSGTLSLTCAVSGVSISTTNWWSWVQRPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVSVTAAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122) >hFM64 QSVVTQPPVSAAAPGQKVTISCSGSSSNIGNYYVAWYQQVPGAAAPKLLIYD TNKRPSGIPDRFSGSKSGTSATLDIITGLRTGDEADYYCGTWDSSDLTDVVFGGGGTKLTVL (SEQ ID NO: 167) QVQLQESGPGLVKPSSETLSLTCAVSGGSSISSSGSSWWSSWVQRQAPGKGLEWIGEISHSGTTTTYNPSLKSRVTISLDKSSTHLSLSLKSVTAAADTAVYYCARELGGGAYDIWGQGTIVTVSS (SEQ ID NO: 168) >hFM65 QSVVTQPPSSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNNSRPSGVPDRSGSKSGTSASLAITGLQAED EADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131) QVQLQQSGPGLVKPSGTLSLTCDVSGGSSISSRNWWTWVQRPPGKGLEWIGEIYHSGS TNYNPSLESRA MSVDKSRYQFSLLSSVTAAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 132) >hFM66 QSVLTQPPSSVSAAAPGQKVTI SCSGSTSNGNY YVAWYQKLPEGAPKVLIHDNNRRPSGIPVRFSGSKSGT SATLGITGLQT GDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128) QVQLQQWGAGLLKPSSETLSLTCAVYGGSFSGYYW SWIRQPPGKGLEWIGEINHSGS TNYNPSLKSRVTISVDTSKNQFSLLSSLTAAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111) >hFM68 QAVLTQPSSSVSGAPGQRVII SCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTRRPSGVPDRSGSKSGT SASLAITGLQAED EADYYCQSYDSSLSGN YVF GPGTKVTVL (SEQ ID NO: 155) QVQLQESGPGLVKPSSETLSLTCAVSGV SISSHNWWSSWVQRTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAAADTAVYYCAR GSTGAFDVWGQGTMVT VSS (SEQ ID NO: 127) >hFM69 QAVLTQPSCSVSSGAPGQRVTISCTGTNSNIGAGYDVHWYQQFPGAAPKVLIYGNTRPSGVPGRFSASKSGTSASLAITGLQAEDeadYYCQTYDSSLSLGTWVFGGGKTTVL QVQLQQWGPGLVKPSGTLSLTCAVSGVSISSSNWWSWVRTQPGKGLEWIGEISHSSGSPNYNPSLKSRVTISVDTSKNQFSLLTSVTAADSAVYYCARGGGPIPHIWGQGTTVTVS (SEQ ID NO: 140) >hFM70 QAVLTQPSCSVSSGAPGQRVTISCTGTNSNIGAGYDVHWYQQFPGAAPKVLIYGNTRPSGVPGRFSASKSGTSASLAITGLQAEDeadYYCQTYDSSLSLGTWVFGGGKTTVL QVQLQQWGPGLVKPSGTLSLTCAVSGVSISSSNWWSWVRTQPGKGLEWIGEISHSSGSPNYNPSLKSRVTISVDTSKNQFSLLTSVTAADSAVYYCARGGGPIPHIWGQGTTVTVS (SEQ ID NO: 140) >hFM71 QSVLTQPPCSVSAAPGQKVTIISCSSSSNIGNYYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGVTGLQTGAEDeadYYCGTWDSSSLSAYYVFG TGTVTQ QVQLQESGPGLVKSSETLSLICAVSGGSSISSNWWSSWVRTQPPGKGLEWIGEIHHSGTTINYNPSLKSRVTISVDKSKNQFSLLNSVTPEDTAVYFCARSASGAFDIWGQGTMVTVS (SEQ ID NO: 142) >hFM72 QSVLTQPPCSVSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDINRPSGVDRFSGSKSGASASLAITGLQAEDeadYYCQSYDSSLSLGLRVFG TGTVTL (SEQ ID NO: "103") QVQLQESGPGLEPSGTLSLTCAVSGVSISSRNWWSWVRTQPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLLSSSVTAADTAVYYCARGGSDMDVWGKGTMVTVS (SEQ ID NO: "104") >hFM73 QAVLTQPSCSVSSGAPGQRVIISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYGNTNRPSGVPDRSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSGNYYVFGPGTKVTVL (SEQ ID NO: 155) QVQLQESGPGLVKPSSETLSLTCAVSGSVISSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAAADTAVYYCARGSFGDVWGQGTVTVSS (SEQ ID NO: 127) >hFM74 QSVLTQPPCSVSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYDNINRPSGVPDRSGSKSGASASLAITGLQAEDeadYYCQSYDSSLSGLRVFGGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLVEPSSGTLSLTCAVSGSVISSRNWWSWVQRQTPGKGLEWIGEINHSGSINYNPSLKSRVTISVDTSKNQFSLLKLSSVTAAADTAVYYCARGGSDMDVWGKGTMTVSS (SEQ ID NO: 104) >hFM75 QAVLTQPSCSVSSGAPGQRVTISCTGSSSNIGAGYDVNWHQQFPGTAPKVLIFGDNARPSGVPDRFYASKSGTSASLTIIGVQSDDEADYYCSTWDDSLNAVVFGGGTTLTVL (SEQ ID NO: 149) QLQESGPGLVKPSGTLSLTCAVSGGGSISSGNWWSWVQRPPGRGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQFSLLKLSSVTAAADTAVYYCARRADGYFQPWGQGTVTVSS >hFM76 QSVLTQPPCSVSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYDNINRPSGVPDRSGSKSGASASLAITGLQAEDeadYYCQSYDSSLSGLRVFGGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLVEPSSGTLSLTCAVSGSVISSRNWWSWVQRQTPGKGLEWIGEINHSGSINYNPSLKSRVTISVDTSKNQFSLLKLSSVTAAADTAVYYCARGGSDMDVWGKGTMTVSS (SEQ ID NO: 104) >hFM77 QAVLTQPSCSVSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYSNTNRPSGVPDRSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSLSGFGTKVTVL (SEQ ID NO: 129) QLQLQESGPGLEPSGTLSLTCAVSGVSISSRNWWSWRVQTPGKGLEWIGEISHSGIPNYNPSLASRVTISIDRSQNQFSLLKTSVTAAADTAVYYCARGGGRFDFWGQGTLVTVSS (SEQ ID NO: 130) >hFM78 QAVLTQPSCSVSSGAPGQRVAISCTGSSSNIGAGYDVQWYQQRPGTAPKLLIYGNNSNRPSGVPDRSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSLSGRVFGGGGKLTVL (SEQ ID NO: 162) QLQLQESGPGLVKPSSQLSLTCTVSGASISSSNWWSWRVQTPGKGLEWIGEISHSGSPNYNPSLKSRVTISVDTSKNQFSLLKVSSVTAAADTAVYYCAREPRYWGQGTLVTVSS (SEQ ID NO: 163) >hFM80 QAVLTQPSCSLSSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLISGNRNRPSGVPDRSGSKSGTSASLAITGLQAEDeadYYCQSYDSSLSLSGSFVFGGTKVTVL (SEQ ID NO: 164) QLQLQESGPGLEPSGTLSLTCAVSGVSISTRNWWSWRVQTPGKGLEWIGEISHSGIPNYNPSFVSRVTISVDASKNLSLLKTSVTVAADTAVYYCSRKGVDAFDIWGQGTMVTVSS (SEQ ID NO: 165) QLQLQESGPGLEPSGTLSLTCAVSGVSISTRNWWSWRVQTPGKGLEWIGEISHSGIPNYNPSFVSRVTISVDASKNLSLLKTSVTVAADTAVYYCSRKGVDAFDIWGQGTMVTVS (SEQ ID NO: 166) >hFM81 QSVVTQPPCSVSAAPGQKVTI SCSGSSSNIGNYYVAWYQQVPGAAPKLLIYDTNKRP SGIPDRFSGSKSGTSATLDTITGLRTGDEADYYCGTWDSSDLDTVDVFGGGTKVTVL (SEQ ID NO: 167) QVQLQESGPGLVKPSSETLSLTCAVSGGSSISSSGSWWSWVRQAPGKGLEWIGEISHSGTTTYNPSLKSRVTISLDKS TSHLSLSLKSVTAA DTAVYYCARELGGGAYDIWGQGTIVTVSS (SEQ ID NO: 168) > hFM82 QSVLTQPPSSVSAAPGQKV TISCSGSSSNIGNYHVSWYQQ LPGTAPKLLIYDNNKRP SGIPDRFSGSKSGTSATL DITGLQT GDEADYYCGTWDSSSLSA VLFG RG TKLVL (SEQ ID NO: 169) QLQLQESGPGLVKPSGTLSLTCAVSGGSSISSSGY YWSWIRQPPGKGLEWIGEINHSGS TN YNP SLKS RVTISVDTSKNQFS LKLSSVTAA DTAVYYCARLRGSGRW GQGTLVTVSS (SEQ ID NO: 170) > hFM84 QAVLTQPS SSVSGAPGQR LTI SCTGSTS NIGAGYD VQW YQKLPGAAPKLLVYGNTNRP SGVPDRFSGSKSGTSASLAITGLQAEDEGHYYCQSYDSSLSGWVVF GGGTKLVL (SEQ ID NO: 171) QLVQS GPGLVKPSGILSLTCAVSGGSSITSSNWWSWVRQPPGKGLEWIGEISHGS TN YNP SLKS RVTMSVDKS KNQLSLKLSSLTAA DTAVYYCARGGSSLP IWGQGT TVTVSS (SEQ ID NO: 172) > hFM85 QAVLTQPS SSVSGAPGQTVTISCTGSSSNIGADYDVHWYQQ LPGTAPKLLIYGNNNRP SGVPDRFSGSKSGASASLAITGLQADDEADYYCHSYDSTR SGLYIFGGT RVI V (SEQ ID NO: 173) QLQLQESGPGLVKPSGTLSLTCAVSGV SISTTNWWSWVRQPPGKGLEWIGEISHGSITNYNP SLQS RVTISVDKS KNQFS LKLSSVT AE DTAVYYCTTGSSGY WGQGTLVTVSS (SEQ ID NO: 174) > hFM87 QSVLTQPPSSVSGAPGQRVTISCTGSSSNIGADYDVQWYYQQRPGTAPKLLIYANNRPSGVPDRSGSKSGTSASLAITGLQAED EADYYCQSYDSSLSLGLRVFGGGTKLVL (SEQ ID NO: 175) QVQLQQWGAGLLKPSSETLSLTCAVYGGFSGYWWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLLSSVTAA DTAVYYCARGRRSSWIDYWGQGTLVTVSS (SEQ ID NO: 176) >hFM88 QAVLTQPSSSVSAAPGQKVTISCSGSDSNIGNYYVWYYQQRPGAAPKLLIYDNHRRPSGVPDRSGSKSGTSATLDI TGLQTGD EADYYCGTWDGSLTGYVFPGTKLVL (SEQ ID NO: 125) QVQLQQWGAGLLKPSSETLSLTCAVYGGFSGYWWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRATISVDTSKNQFSLLSSVTAA DTAVYYCARGRVRGRWLPYYWGQGTLVTVSS (SEQ ID NO: 126) >hFM90 QAVLTQPSSSVSGAPGQRVTISCTGTNSNIGAGYDVHWWYYQQFPGAAPKVLIYGNTRPSGVPGRFSASKSGT SASLAITGLQAED EADYYCQTYDSSLSLGTWVFGGGGKLTVL QVQLQQWGPGLVKPSGTLSLTCAVSGVSISSSNWWSWVQRTPGKGLEWIGEISHSPNYNPSLKSRVTISVDTSKNQFSLLTSVTAA DSAVYYCARGGGPIPHIWGQGTTVTVSS (SEQ ID NO: 140) >hFM91 QSVLTQPPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWWYYQQRPGTAPKLLIYDNINRPSGVPDRSGSKSGASASLAITGLQAED EADYYCQSYDSSLSLGLRVFGTGTKLVL (SEQ ID NO: 103) QVQLQESGPGLEPSGTLSLTCAVSGVSISSRNWWSWVQRTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLLSSVTAA DTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) >hFM92 SEQ ID NO:160) QVQLVQSGAEVKKPGSSVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSVSVVTDAFDIWGQGTTVTVSS (SEQ ID NO: 161) >hFM93 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) >hFM94 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVL (SEQ ID NO: 153) QVQLQESGPGLVKPSGTLSLTCDVSGGSISSNNWWSWVRQSPGKGLEWIGEIIHTGRTNYNPSLTSRVTILIDKSKNQFSLKLTSVTPEDTALYYCARLRGPFDIWGQGTMVTVSS (SEQ ID NO: 154) >hFM96 QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155) QVQLQESGPGLVKPSETLSLTCAVSGVSISSSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127) >hFM97 QAVLTQPSSVSGAPGQRVTISCTGSSTNIGADFDVHWYQQLPGTAPKLLIHGDNNRPSGVPDRFSGSKSGTSAYLAISGLQAEDEADYYCQTYDSRSSGSRVFGGGTKVTVL (SEQ ID NO: 139) QLQLQESGPGLVKPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNAGDIWGQGTMVTVSS (SEQ ID NO: 107) >hFM98 DVVMTQSPLSLAVTLGQPASISCRSSQSLLHSSGYKFLNWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQSPTFGGGTKVEIK (SEQ ID NO: 158) EVQLVESGGGLVQPGGSLRLSCTASGFTFSSFSMNWVRQAPGKGPEWVSAISGSGGGTYYADSVKGRFTISRDNAKNSLYLQMSSLRAEDTAVYYCARVRVPQAFDIWGQGTMVTVSS (SEQ ID NO: 159) >hFM99 QAVLTQPSSVSGAPGQRVTISCTGSRSNIGANYDVHWYQQLPGTAPKLLIFNDNIRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 121) QVQLQESGPGLVKPSGTLSLTCAVSGVSISTTNWWSWVRQPPGKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCASYWLGNFDYWGQGTLVTVSS (SEQ ID NO: 122) >hFM100 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYEVHWYQQLPGRAPRLLIFDNNNRPSGVPDRFSASKSGTSASLAITGLRAEDEGDYYCQSYDSKRTPPYVFGTGTRVTVL (SEQ ID NO: 123) QVQLQQSGAEVKKPGASVKVSCKASGYSFSKYGMSWVRQAPGQGLEWMGWINAGNGDTKYSQKFQGRVTITRDTSASTAYMELSSLKYEDTAIYYCARRLSYYGMDVWGQGTTVTVSS (SEQ ID NO: 124) >hFM101 QAVLTQPSSVSAAAPGQKVTISCSGSDSNIGNYYVWWYQQLPGAAPKLLIYDNHRRPSGVPDRFSGSKSGTSATLDITGLQTGDEADYYCGTWDGSLTGYVFGPGTKVTVL (SEQ ID NO: 125) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCARGRVRGRWLPYYWGQGTLVTVSS (SEQ ID NO: 126) >hFM102 QAVLTQPSSVSGAPGQRVIISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGNYVFGPGTKVTVL (SEQ ID NO: 155) QVQLQESGPGLVKPSETLSLTCAVSGVSISSSHNWWSWVRQTPGKGLEWIGEISHSGITNYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 127) >hFM103 QSVLTQPPSSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111) >hFM104 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGFWVFGGGTKLTVL (SEQ ID NO: 112) QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSSNWWSWVRQPPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDNSKNQFSLQLSSVTAADTAVYYCVSNASGRRGFAWGQGTLVTVSS (SEQ ID NO: 113) >hFM105 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVNWHQQFPGTAPKVLIFGDNARPSGVPDRFYASKSGTSASLTIIGVQSDDEADYYCSTWDDSLNAVVFGGGTTLTVL (SEQ ID NO: 149) VQLQESGPGLVKPSGTLSLTCAVSGGSISSGNWWSWVRQPPGRGLEWIGEISHSGTINYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRADGYFQPWGQGTLVTVSS (SEQ ID NO: 150) >hFM106 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKVLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGSVVFGGGTKLTVL (SEQ ID NO: 148) QVQLQQWGPGLVKPSGTLSLTCAVSGGSISSSSNWWSWVRQFPGKGLEWIGEMSHTGSTNYNPSFKSRVTISVDKSKNQFSLKLSPVTAADTAVYYCARGSTGAFDVWGQGTMVTVSS (SEQ ID NO: 147) >hFM107 QSVLTQPPSSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111) >hFM108 VLTQPPSVSGAPGQRVTISCTGSDSNIGAGYDVHWYQQYPGIAPKLLIYAHHKRPSGVPDRFSGSTSGTSASLAITGLQAEDEADYYCQSYDSSLSGHYVFGTGTQVSVL (SEQ ID NO: 151) QVQLQESGPGLVKPSETLSLTCAVSGGSISSNNWWSWVRQTPGKGLEWIGEIYHSGNTNYNPSLKSRVTISVDKSKNQFSLKLNSVTAADTAVYYCARGRQGAFDPWGQGTLVTVSS (SEQ ID NO: 152) >hFM109 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLSVFGTGTKVTVL (SEQ ID NO: 129) QLQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSLASRVTISIDRSQNQFSLKLTSVTAADTAVYYCARGGGRDFWGQGTLVTVSS (SEQ ID NO: 130) >hFM110 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGFWVFGGGTKLTVL (SEQ ID NO: 112) QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSSNWWSWVRQPPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDNSKNQFSLQLSSVTAADTAVYYCVSNASGRRGFAWGQGTLVTVSS (SEQ ID NO: 113) >hFM112 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLVELSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 114) >hFM113 QSVLTQPPSSVSGAPGQRITISCTGSSSNIGAGYDVQWYQQVPGKAPKHLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYFCQSYDSSLSGYVVFGGGTKLTVL (SEQ ID NO: 115) QVQLQESGPGLVKPSETLSLTCAVSGGSISSSSNWWSWVRQPPGKGLEWIGEISHTGSPNYNPSLASRVTISMDKSKNQFSLNLRSVTAADTSVYYCARYGRGAFDIWGQGTMVTVSS (SEQ ID NO: 116) >hFM114 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117) QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDKSKNHFSLNLSSVTAADTAVYYCANADYYTHHYWGQGTLVTVSS (SEQ ID NO: 118) >hFM115 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) >hFM116 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVL (SEQ ID NO: 153) QVQLQESGPGLVKPSGTLSLTCDVSGGSISSNNWWSWVRQSPGKGLEWIGEIIHTGRTNYNPSLTSRVTILIDKSKNQFSLKLTSVTPEDTALYYCARLRGPFDIWGQGTMVTVSS (SEQ ID NO: 154) >hFM117 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVQWYQQLPGTAPKLLIYADSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGSKVFGTGTKLTVL (SEQ ID NO: 117) QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSDWWSWVRQPPGKGLEWIGEMRLSGTTNYNPSLKSRVAISMDKSKNHFSLNLSSVTAADTAVYYCANADYYTHHYWGQGTLVTVSS (SEQ ID NO: 118) >hFM118 VLTQPPSVSGAPGQRVTISCTGGSTNIGAGYDVHWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSQSGASASLAITGLQADDEADYYCQSYDSRLDGSKVFGTGTKVTVL (SEQ ID NO: 135) QVQLQESGPGLVKPSETLSLTCAVSGVSISSSHNWWSWVRQTPGKGLEWIGEMS HSGIPNYNPSLESRVTISLDKSKNQFSLILRSVTAADTAMYYCVGGSGSYSYWGQGTLVTVSS (SEQ ID NO: 136) >hFM120 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGFWVFGGGTKLTVL (SEQ ID NO: 112) QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSSNWWSWVRQPPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDNSKNQFSLQLSSVTAADTAVYYCVSNASGRRGFAWGQGTLVTVSS (SEQ ID NO: 113) >hFM121 QSVLTQPPSSVSAAPGQKVTISCSGSTSNVGNYYVAWYQKLPGEAPKVLIHDNNRRPSGIPVRRFSGSKSGTSATLGITGLQTGDEAEYYCAVWDSSLNGYVFGGGTKLTVL (SEQ ID NO: 128) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSLTAADTAVYYCARVNGGESDYWGQGTLVTVSS (SEQ ID NO: 111) >hFM122 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) >hFM123 QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGLSVFGTGTKVTVL (SEQ ID NO: 129) QLQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGIPNYNPSLASRVTISIDRSQNQFSLKLTSVTAADTAVYYCARGGGRDFWGQGTLVTVSS (SEQ ID NO: 130) >hFM124 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131) QVQLQQSGPGLVKPFGRPCPLTCDVSGGSISSRNWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLESRVAMSVDKSRYQFSLRLSSVTAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 133) >hFM125 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGANYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDSSLSGSSVFGGGTKLTVL (SEQ ID NO: 131) QVQLQQSGPGLVKPSGTLSLTCDVSGGSISSRNWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLESRVAMSVDKSRYQFSLRLSSVTAADTAVYYCARRRDGYFDYWGQGTLVTVSS (SEQ ID NO: 132) >hFM126 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNINRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDSSLSGLRVFGTGTKVTVL (SEQ ID NO: 103) QVQLQESGPGLVEPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSDMDVWGKGTMVTVSS (SEQ ID NO: 104) >hFM127 QAVLTQPSSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNRNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSKVFGTGTKVTVL (SEQ ID NO: 134) QLQLQESGPGLVKPSETLSLTCTVSGGSISSGNYWSWVRQSPEKGLEWIGEISHSGITNYNPSLQSRVTIALDKSKNHFSLNVNSVTAADTAVYYCVGTLRTWFDYWGQGTLVTVSS (SEQ ID NO: 105) >hFM128 QAVLTQPSSVSGAPGQRVTISCTGSSTNIGAGFDVHWYQQLPGTAPKLLIYGDKNRPSGVPDRFSGSKSGTSAYLAITGLQAEDEADYYCQTYDSRLSGSKVFGGGTKVTVL (SEQ ID NO: 106) QLQLQESGPGLVKPSGTLSLTCAVSGVSISSRNWWSWVRQTPGKGLEWIGEISHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNAGDIWGQGTMVTVSS (SEQ ID NO: 107) >hFM130 QSVLTQPPSSVSAAPGQKVTISCSGSSSDIGNNFVSWYQQLPGTAPKRLIYDNSKRPSGIPERFSGSKSGTSATLGITGLQTGDEADYYCGAWDTSLSAYVFGTGTKVTVL (SEQ ID NO: 108) QVQLQQWGPGLVKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYSNYRHYYYGMDVWGQGTLVTVSS (SEQ ID NO: 109).

22. 22. A method comprising administering the binding partner of claim 21 to an individual who has received an antibody-drug conjugate (ADC), thereby reducing non-target toxicity of the ADC.

23. A polynucleotide encoding the binding partner of claim 21.

24. A polynucleotide that hybridizes to the polynucleotide of claim 23.

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