EP4774009A1 - Anti-camptothecin antibodies and antibody fragments - Google Patents

Abstract

Provided are compositions and methods for reducing off-target toxicity of antibody-drug conjugates (ADCs). The compositions comprise an ADC, and an agent targeted to the drug (payload) that is delivered by or derived from the ADC. The ADC and the agent targeted to the payload may be delivered together or separately in the treatment of various conditions (such as tumors) by ADCs. Examples of agents targeted to payload include antibodies, fragments, or modifications thereof.

Description

ANTI-CAMPTOTHECIN ANTIBODIES AND ANTIBODY FRAGMENTS

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. provisional patent application no. 63/581,647, filed September 9, 2023, the entire disclosure of which is incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under grant numbers CA256928 and CA261343 awarded by the National Institutes of Health. The government has certain rights in the invention.

SEQUENCE LISTING

The instant application contains a Sequence Listing which is submitted in xml format and is hereby incorporated by reference in its entirety. Said xml file is named “011520_01860_ST26.xml”, was created on September 9, 2024, and is 123,185 bytes in size.

BACKGROUND OF THE DISCLOSURE

Anti-cancer antibody-drug conjugates (ADCs) are used for targeted delivery of drugs, which may be toxins or other cell growth inhibitors (termed here as drug or payload molecules) to cancer cells. Twelve ADCs are currently marketed in the US, and approximately 100 ADCs are in 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, many ADCs have failed in clinical trials as a result of substantial off-target toxicity, which has limited tolerable doses below levels needed 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 associated toxicity to non-target sites, the early promise of ADCs is not fully realized and therefore, and there is an ongoing need in the area of cancer therapy to develop new approaches to minimize non-target toxicity of therapeutic payload drug molecules without compromising their anti-tumor efficacy. BRIEF DESCRIPTION OF THE FIGURES

FIG 1: ABC0545 binding affinity for SN38, Dxd and Belotecan. ABC0545 at a concentration of 3 nM (black circles) and 0.3 nM (squares) was incubated with free SN38/Dxd/Belotecan across a range of concentrations. AKinexa 3200 was used to assess free ABC0545 concentration as a function of the concentration of SN38/Dxd/Belotecan. Observed data was fit to obtain an estimate for the equilibrium dissociation rate constant (KD) for SN38 (189 pM), Dxd (820 pM) and Belotecan (432 pM).

FIG 2: ABC0545 does not bind sacituzumab govitecan. Sacituzumab govitecan (SG) was captured on a TROP2 immobilized SPR chip at a density of 150 response units (black top left). Subsequently, ABC0545 was serially injected at concentrations between 617 nM-50 pM (black top left). The chip was regenerated using 10 mM glycine pH 2.0. Subsequently, ABC0545 was injected over the TROP2 chip at concentrations between 617 nM-50 pM to determine the background signal (gray top left). The top right graph shows the SG specific binding signal (signal observed with SG minus signal observed without SG) at individual ABC0545 concentrations (0 nM, 617 nM, 1.85 pM, 5.5 pM, 16.6 pM, 50 pM). No binding signal is observed, indicating that ABC0545 does not bind to SN38 that is conjugated to SG.

FIG 3: ABC0545 blocks neutropenia in-vitro. Trastuzumab deruxtecan (T-Dxd) or Sacituzumab govitecan (SG) were incubated with differentiating human hematopoietic stem cells alone or in combination with ABC0545 for six days. Subsequently, total viable cells and total neutrophils were determined using flow cytometry. A sharp decrease in cell-viability (both total cell counts and neutrophil counts) was observed for T-Dxd and SG at low nanomolar concentrations. A decrease in cell viability was not observed with SG in combination with ABC0545 up to a concentration of 300 nM. ABC0545 increased the concentration of T-Dxd required to cause a 50% decrease in cell-viability by approximately 100-fold. These results demonstrate the ABC0545 can inhibit a primary mechanism of neutrophil toxicity for camptothecin based ADCs (i.e., extracellular linker catabolism and subsequent diffusion of free SN38/Dxd into differentiating hematopoietic cells).

FIG 4: ABC0545 half-life extension through albumin binding peptides. Provided are observed plasma concentration time profiles for ABC0545 alone, or ABC0545 linked to a low affinity albumin binding peptide (Hll >20 pM KD for human and mouse albumin) or linked to a peptide (PepH) with high affinity for mouse serum albumin (KD=~50 nM) and moderate affinity for human serum albumin (KD=~500 nM). The plot on the left shows the observed concentration time profile following a 5 mg/kg dose of ABC0545 (and variants) to Swiss-Webster mice with concentrations determined using a tracer dose of I¹²⁵ labeled Fab. The plot on the right shows the observed pharmacokinetic profile for ABC0545 and albumin binding variants following a dose of 25 mg/kg to humanized mice expressing human serum albumin and human FcRn. Plasma concentrations were determined using a quantitative ELISA. These results demonstrate that the half-life of ABC0545 can be extended through the genetic fusion of albumin binding peptides which can be tuned as a function of the peptides binding affinity for serum albumin.

FIG 5: Provided is a graph comparing the ELISA signal for single amino acid point mutants of ABC0545. Mutations were designed to remove potential sequence liabilities that are present in the primary amino acid sequence of the variably heavy (VH) or variable light chain (VL). Mutations VL_D56S and VH_N57S negligibly impact the ELISA binding signal to SN38-peg-biotin coated on neutravidin wells in-comparison to ABC0545. Mutations VL_N31 S and VH_D31 S demonstrate a large decrease in binding signal, indicating that these point mutations decrease SN38 binding affinity.

FIG 6: Provided is a sequence alignment for disulfide stabilized scFv derivatives of ABC0545 (ABC0545 dscFv; SEQ ID NO:74). The scFvs were identified following generation of a randomly mutated phage display library based on the ABC0545 sequence. Phage panning was completed to identify clones with improved stability and binding affinity. Variants of ABC0545 incorporating one or more of the identified residue substitutions (i.e., depicted within the figure) are anticipated to demonstrate desirable binding properties (e.g., improved affinity and/or reduced dissociation rates for binding to camptothecin payloads (SN38, Dxd, belotecan, etc.). Preferable residue substitutions for the ABC0545 heavy chain include V72A, T105A, I109T and I109N. A preferable residue substitution for the ABC0545 light chain is F71Y.

FIG 7: Provided are observed binding signals for human heavy chain single domain antibodies that were identified from a naive phage display library. Clones show increased binding signal for plates coated with biotin conjugated SN38 (top left) with free Dxd causing a concentration dependent reduction in signal for several clones (i.e., VF5, VF10 in top right panel).

FIG 8: Provided is observed fractional binding signals for the human heavy chain single domain antibodies BMBG2 and BMBC2. Addition of the anti-camptothecin antibody 8C2 results in a decrease in binding signal demonstrating camptothecin specific binding activity for both BMBG2 AND BMBC2. Addition of free SN38 or free Dxd results in a decreased binding signal indicating both antibodies bind to free drug. FIG 9: Results from ABC0550 diluted in PBS with 1 mg/ml bovine serum albumin to a final concentration of 3 nM or 0.15 nM. SN38 or Belotecan was serially diluted with constant concentrations of ABC0545 (3 nM and 0.15 nM) and incubated on an inverting platform at room temperature for 24 hours. ABC0550 with and without free drug was injected over a KinExA 3200 (Sapidyne, Boise, Idaho) using an autosampler. Free ABC0550 was captured on polystyrene beads coated with neutravidin and SN38-peg-biotin. ABC0550 was detected using a 0.5 pg/ml mixture of anti-human Fab (109-605-003) and anti-human H+L (109-607-003) AlexFluor647 conjugated secondary antibody (Jackson Immunoresearch Laboratories Inc., West Grove, PA). Observed binding signals at 3 nM and 0.15 nM were opened in n-curve analysis software (Sapidyne) to fit an equilibrium dissociation rate constant to observed binding data for each payload. ABC0550 is predicted to have greater affinity, relative to ABC0545, for SN38 (ABC0550: 12.7 pM, ABC0545: 189 pM) and Belotecan (ABC0550: 206.7 pM vs ABC0545: 432 pM).

SUMMARY OF THE DISCLOSURE

This disclosure provides compositions and methods for reducing off-target toxicity of ADCs wherein in some examples the drug component is camptothecin or a camptothecin derivative, non-limiting examples of which are discussed below. For example, the present compositions and methods can be used for treatment of tumors with ADCs, while reducing off-target toxicity of the ADCs. The drug in the ADC may be referred to herein as “payload.” The compositions comprise an ADC and an agent targeted to the payload that is delivered by or derived from the ADC. The agent targeted to the payload is termed herein as “payloadbinding agent” or PBA. The ADC and the payload-binding agent may be provided in the same composition or in different compositions. The payload binding agent may be a peptide or an antibody or a fragment or an antibody mimetic or a modification thereof directed to the ADC payload, and which binds to the payload. If the payload binding agent is an antibody or a fragment or modification thereof, it may be referred to as “anti-payload antibody”

In an aspect, this 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 the payload binding agent may be administered in the same composition or different compositions, via the same routes or via different routes, or using the same regimen or different regimen. In an aspect, this disclosure provides peptides or antibodies or antibody fragments or modifications, which are specific for an ADC payload molecule. The anti-payload antibody may be whole immunoglobulin molecules such as polyclonal or monoclonal antibodies or chimeric antibodies including humanized antibodies. The antibody fragments or modification can be antigen-binding fragments 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) and the like. Antibody mimetics may include affibodies, nanofitins, or the like. The fragments of the antibodies may be produced synthetically or by enzymatic or chemical cleavage of intact immunoglobulins or may be genetically engineered by recombinant DNA techniques. These techniques are well known in the art. The antibody or fragments or modifications thereof may be modified so as to impart longer half-life, stability and the like. In an example, the disclosure provides antibodies or fragments or derivatives thereof directed to several ADC payload, including full length antibodies, scFv, Fab and other fragments directed specifically to camptothecins and derivatives thereof.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure provides compositions and methods for treatment of diseases (e.g., cancer) using ADC, while reducing off-target toxicity associated with the ADC. The method comprises administering to an individual in need of treatment an ADC and one or more payload binding agents directed to the drug portion of the ADC, or treating an individual who has received an ADC with the one or more payload binding agents. The payload binding agent is effective in reducing the non-target toxicity of the ADC or the nontarget toxicity derived from the free drug dissociated therefrom. The compositions comprise antibodies (including fragments or modifications thereof), which are directed to the drug of the ADC. Compositions are also provided that comprise the ADC and an agent (such as an antibody) which is directed to the drug that makes up the ADC The agents bind to free drug and may or may not bind to the drug when it is part of the ADC. The present disclosure relates in part to PCT application PCT/US2020/063453, and its publication, published as PCT publication WO 2021/113740, published June 10, 2021, the entire disclosure of which is incorporated herein by reference.

An ADC comprises an antibody group, a linking group, and a drug group. The antibody group targets an antigen, such as a tumor cell antigen, 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 the targeted cell. The antibody group may be referred to as an antibody or by the name of the antibody. Similarly, the drug group may be referred to as a drug or by the name of the drug.

The term “treatment” as used herein refers to reduction or delay in one or more symptoms or features associated with the presence of the particular condition being treated. Treatment does not necessarily mean complete cure and does not preclude relapse, but may be used in connection with any such relapse.

The term “therapeutically effective amount” as used herein is the amount sufficient to achieve, in a single or multiple doses, the intended purpose of treatment. The exact amount desired or required will vary depending on the mode of administration, patient specifics and the like. Appropriate effective amounts can be determined by one of ordinary skill in the art (such as a clinician) with the benefit of the present disclosure.

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

As used in this disclosure, the singular forms include the plural forms and vice versa unless the context clearly indicates otherwise. The indefinite articles “a” and “an” as used in the specification and claims should be understood to mean “at least one” unless clearly indicated otherwise.

A general reference to an antibody in this disclosure is also intended to include all full-length antibodies, antibody fragments containing antigen binding domains, as well as modified antibodies or fragments containing substitutions or modifications of the amino acid residues, and including where antibody fragments, modified or not, may be linked together via covalent linkages with or without linkers. When a reference is made to an antibody being “targeted to payload” or “directed to payload” or similar phrases, it means the antibody has specific affinity for the payload, when the payload is in the form of free payload, including when it is cleaved from the ADC. The anti-payload antibody may or may not bind to the payload when the payload is conjugated to the antibody part of the ADC.

The terms “off-target’ ’ and “non-targef ’ in reference to toxicity refer to toxicity that accompanies the administration of many chemotherapeutic agents. While the intended purpose of administration of a chemotherapeutic agent is to reduce or inhibit the growth of tumors or any accompanying metastases, the growth, function, and/or physiology of normal cells are often adversely affected in the course of treatment of cancer. A reduction of off- target or non-target toxicity is intended to reduce any adverse effects on the non-tumor or non-metastatic cells.

The term “payload binding agent” (PBA) as used in this disclosure refers to an agent that specifically binds to a payload (drug) portion of an ADC. The PBA may be an antibody, a fragment or modification thereof, a peptide, an aptamer, a Spiegelmer, a fibronectin, a DARPin, a cyclodextrin, or an aflfitin. When the PBA is an antibody, the PBA may be referred to herein as an anti-drug antibody or anti-payload antibody. The anti-payload antibody may be whole immunoglobulin molecules such as polyclonal or monoclonal antibodies or chimeric antibodies including humanized antibodies or may be antigen-binding fragments 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, and the like. The fragments of the antibodies may be produced synthetically or by enzymatic or chemical cleavage of intact immunoglobulins or may be genetically engineered by recombinant DNA techniques. These techniques are well known in the art.

The term “chimeric antibody” refers to an antibody that has 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 binds a payload. In a chimeric antibody, some portions of the heavy and/or light chains 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 decreased immunogenicity and increased stability. Techniques for cloning murine immunoglobulin variable domains known in the art - such as, for example, see 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, polynucleotides encoding the variable domains of the light chain or the heavy chain of an antibody derived from an animal (e.g., mouse, rat, or chicken) other than human can be linked to polynucleotides encoding the constant domains of the light chain or the heavy chain derived from a human antibody to produce a polynucleotide (such as DNA) encoding a chimeric antibody.

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

A “humanized antibody” is typically a human antibody that has one or more amino acid residues imported into it (i.e., introduced into it) from a source that is non-human. For example, a humanized antibody is a recombinant protein in which the CDRs of an antibody from a species such as rodent, rabbit, dog, goat, or horse are imported into human heavy and light variable domains. The constant domains (also referred to as framework regions) of the antibody molecule are generally the same as those of a human antibody. The non-human immunoglobulin providing the CDRs can be termed as “donor” and the human immunoglobulin providing the framework can be termed as “acceptor”. For example, all the CDRs can be from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be always present, but if they are, they can be substantially identical to human immunoglobulin constant regions, i.e., at least about 85-90%, such as about 95% or more identical. A humanized antibody binds to the same payload as the donor antibody that provides the CDRs. The acceptor framework of a humanized immunoglobulin or antibody may have a limited number of substitutions by amino acids taken from the donor framework. Humanized or other monoclonal antibodies can have additional conservative amino acid substitutions that have substantially no effect on antigen binding or other immunoglobulin functions. Humanized immunoglobulins can be constructed by means of genetic engineering (see for example, U.S. Pat. No. 5,585,089, and U.S. Publication No. 2010/0196266). For example, murine monoclonal antibodies may be isolated or generated and then humanized.

Antibody fragments can be produced by enzymatic digestion. For example, papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, and a “Fc” fragment. The Fab fragment contains an entire light (L) chain and the variable region domain of the heavy hain (VH), and 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 yields a single large F(ab')2 fragment that roughly corresponds to two disulfide linked Fab fragments having divalent antigenbinding activity and is capable of cross-linking antigen. “Fv” is the minimum antibody fragment that contains a complete antigen-recognition and -binding site and single-chain Fv also abbreviated as “sFv” or “scFv” are antibody fragments that comprise the variable heavy (VH) and variable light (VL) antibody domains connected into a single polypeptide chain. The term “diabodies” refers to small antibody fragments prepared by constructing sFv fragments with short linkers between the VH and VE domains such that inter-chain but not intra-chain pairing of the variable (V) domains is achieved, resulting in a bivalent fragment, i.e., fragment having two antigen-binding sites. A single domain antibody (sdAb) is an antibody fragment which has a single monomeric variable antibody domain. sdAbs can be made from heavy-chain antibodies found in camelids. An antibody fragment can be a single variable region or a peptide consisting of or comprising a single CDR. A single-chain antibody has a heavy chain variable domain and a light chain variable domain linearly linked to each other via a linker. A polynucleotide (such as DNA) encoding the single-chain antibody can be produced by binding a polynucleotide encoding the heavy chain variable domain, a polynucleotide encoding the linker (typically 10-20 nucleotides), and a polynucleotide encoding the light chain variable domain, with the heavy chain variable domain and the light chain variable domain being both derived from a human antibody.

The antibody may be of any class (for example, IgG, IgE, IgM, IgD, IgA and IgY), or any subclass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2). In an example, single domain antibodies or nanobodies produced by camelids in response to introducing APP cleavage products (or peptide fragments thereof) into the camelids can be used. The nanobodies are typically heavy chain antibodies and thus contain heavy chain homodimers and do not contain antibody light chains. These antibodies typically comprise a single variable domain and two constant domains (CH2 and CH3).

The present disclosure also provides sequences that have homology with the protein or peptides sequences (including antibody sequences) described herein. In various examples, the homologous sequences have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a protein or peptide sequence of the present disclosure.

The payload molecule may be a drug molecule that causes cell toxicity. For example, any molecule that is used for treatment of cancer may be used. Examples include compounds, DNA, RNA, peptides and the like. In an example, the drug molecule may be covalently bound to an N-terminal amino acid of the antibody via a reactive group or via a linker. Examples of reactive groups that cross link with the N-terminal alpha amine group of the antibody (such as light or heavy chain) include isothiocyanate, isocyate, acyl azide, NHS ester, sulfonyl ester, aldehyde, glyoxal, epoxide, carbonate, aryl halide, imidoester, carbodiimide, anhydride, fluorophenyl ester and the like. The reactive groups aldehyde or NHS ester are commonly used. Reduced cysteines (free sulfhydryls) may also be used. Conjugation methods of payload molecules to antibody are known. For example, conjugation of payload molecules to antibody is described in U.S. Patent No. 10,071,170, the description of which is incorporated herein by reference.

Examples of payload molecules that relate to this disclosure include Camptothecin and derivatives thereof. In examples, the present PBAs bind specifically to a DX-8951 derivative referred to in the art as “DXd”, and/or to SN-38, and/or to Exatecan, and/or to Belotecan. SN-38 is the active metabolite of irinotecan.

In various examples, the ADC, which includes conjugates of antibodies with cytotoxic agents, may comprise any antibody or a fragment or modification thereof that is useful against a tumor antigen or that is useful for delivering the cytotoxic drug to the tumor cells. For example, there are several monoclonal antibodies that have been demonstrated as successful therapeutic agents for the treatment of human cancers. These include rituximab, trastuzumab, cetuximab, panitumumab, bevacizumab and many others. Examples of monoclonal antibodies indicated against solid tumors include pertuzumab, ramucirumab, nivolumab, pembrolizumab, necitumumab, dinutuximab, olaratumab, atezolizumab, avelumab, cemiplimab, carotuximab, margetuximab, bemarituzumab, naxitamab, relatlimab, brentuximab, lorvotuzumab, glembatumumab, BCD-100, spartalizumab, IB 1308, CS1001, tremelimumab, TSR-042). Any of these antibodies may be used to make an antibody drug conjugate.

Examples of antibodies and ADCs that are pertinent to this disclosure include, but are not limited to, gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine (TDM1), inotuzumab ozogamicin, polatuzumab vedotin, trastuzumab deruxtecan, trastuzumab duocarmazine, sacituzumab govitecan, loncastuximab tesirine, oportuzumab monatox, zolbetuximab claudiximab, depatuxizumab mafodotin, mirvetuximab sorvatansine, rovalpituzumab tesirine, enfortumab vedotin, ladiratuzumab vedotin, zilovertamab vedotin, tisotumab vedotin, disitamab vedotin, BAT8001, L19IL2, and L19TNF.

In examples when the PBA is an antibody, the anti-drug antibody can be directed to the toxin (also referred to herein as the drug or payload) part of the ADC. In examples, the anti-drug antibody can be a fragment of the whole antibody. The fragment of the anti-drug antibody may be Fab, a Fab', a F(ab')2, a Fv, a scFv, a single domain antibody, or a diabody, or any other epitope binding fragment. The fragment of the antibody can be in the range of 0.5 kDa-110 kDa (Note: F(ab’)2 is -100 kDa), including all Da values and ranges therebetween. In an example, the antibody fragment is about 15 kDa. In an example, the antibody is a single domain antibody (nanobody) containing only VHH (generally, 13 kDa to 15 kDa). The anti-drug antibody has a binding affinity for the drug that may be expressed in terms of dissociation constant ( D). In an example, the KD of the anti-drug antibody is from 1 pM to 50 nM, including all 0.1 pM values and ranges therebetween. In an example, the KD is less than 1 nM In an example, the KD is from 10 pM to 800 pM. In an example, the KD can be from 1-100 pM. In an example, the anti-drug antibody is a Camelid, chimeric, or humanized single domain antibody — also termed as a nanobody. These antibodies possess many characteristics that are ideal for the present approach. Single domain antibodies are a small antibody format (~15 kDa), are highly stable, can be expressed in E. coli and can be humanized to limit immunogenicity. Additionally, camelid immunization and phage display technologies allow rapid and inexpensive development of novel inhibitors.

The antibody (including fragments or modifications) may bind to the free payload or payload cleaved from the ADC. When the payload is cleaved from the ADC, such as via enzymatic action, hydrolysis, oxidation, or some other mechanism, the cleaved payload may comprise a portion of the linking group, all of the linking group, or none of the linking group. The cleaved payload may further comprise substituents that may be added during or after cleavage, or functional groups 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, and the like), alcohol groups, amines, thiols, sulfonic acids, sulfoxides, sulfides, sulfones, carboxylic acids, esters, amides, and the like, and combinations thereof.

Multiple antibodies (including fragments or modifications) are described in the examples herein, and sequences are disclosed. Full-length antibodies, scFv, Fab and others, directed specifically to Camptothecins, including derivatives are included within the disclosure. Generation of the antibodies, screening of the antibodies to identify the candidates with the desired binding specificity and affinity, and their binding and inhibitory characteristics are described.

The sequences of any of the antibodies or fragments described herein may include a polyhistidine tag, or a linker, and the sequences may be used without the polyhistidine tag (e.g., to reduce immunogenicity), and when a linker is used the binding construct is not limited to the specific linker. Any specific sequences disclosed here with polyhistidine tags also include the corresponding sequences without the polyhistidine tags, and any sequences disclosed herein without the polyhistidine tags also include sequences with the polyhistidine tags. Variants of the sequences of antibodies or fragments disclosed herein include sequences which have at least 85% identity with the disclosed sequences providing the binding affinity is not adversely affected. For example, the binding affinity of variants may be 10% less, the same, or better than the disclosed sequences. In examples, the variants may have at least 90%, at least 95%, at least 98%, at least 99% homology (identity) with the disclosed sequences without adversely affecting the binding affinity. The disclosure also includes nucleotide sequences that encode for the amino acid sequences, or their variants as described herein.

The disclosure includes all polynucleotides that encode the described antibodies and antigen binding fragments thereof. Such polynucleotides include expression vectors that comprise the coding polynucleotides. The disclosure includes cell cultures that comprise the expression vectors, and methods of making the described antibodies and antigen binding fragments thereof by producing the antibodies or antigen binding fragments using the cell cultures, and separating the antibodies or antigen binding fragments from the cell cultures. Bacterial and mammalian cell cultures are included. The disclosure also includes all polynucleotides that can hybridize to a polynucleotide encoding a described antibodies or antigen binding fragments. The hybridization can be such that hybridization occurs in a solution at a temperature of about 20 degrees C. The solution may comprise a salt, such as a sodium salt, which may be at a concentration of about 0.15 M.

The PBA may be a peptide comprised of ten or more amino acids, and with an equilibrium dissociation constant (KD) for binding to the payload that is 50.0 nM or lower.

It was surprising that a binding agent, such as an antibody, directed to the payload (drug) portion of the ADC such as a camptothecin derivative does not adversely affect its efficacy with respect to cytotoxicity for cancer cells, but is able to reduce toxicity associated with the unconjugated payload. While not intending to be bound by any particular theory, it is possible the entry and intra-cellular processing of an ADC may be unaffected by binding to payload binding agents, and that the cellular entry of unconjugated payload is affected (reduced) by binding to a payload binding agent. However, the ability of payload binding agents to reduce toxicity of unconjugated payload relative to the anti-cancer cytotoxicity of ADCs, thereby enabling enhanced anti-cancer selectivity, is unexpected. In an example, the potency of ADC may increase when used in conjunction with a PBA (such as an antibody), In such a case, not only does the non-target toxicity reduce, but the ADC efficacy is unexpectedly enhanced. In some examples, the PBA may not bind to the drug when it is a part of the ADC. Rather, it may bind to only free drug. In this case, it is expected there would be little or no impact on ADC efficacy, but a significant reduction in non-target toxicity.

The present disclosure provides a composition for reducing off-target toxicity comprising means for reducing toxicity of an unconjugated or cleaved payload (e.g., drug) from an ADC while not adversely affecting the efficacy of the ADC in the intended treatment (such as treatment for cancer cells). The means for reducing off-target toxicity includes antidrug antibodies and fragments and modifications thereof, a peptide, an aptamer, a Spiegelmer, a fibronectin, a DARPin, a cyclodextrin, and/or an affitin.

In examples, a binding partner referred to herein as ABC0545 comprises a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), and CDR3 sequence WGAIITLGG (SEQ ID NO:20); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR2 sequence QHFWSTPFT (SEQ ID NO:38). In examples, the ABC0545 VH and VL sequences comprise:

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 42) and

VL DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:43)

In examples a binding partner referred to herein as ABC0545_dscFv comprises a heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38). In an example, ABC0545_dscFv comprises the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLEIKR (SEQ ID NO:74)

In examples any binding partner described herein may contain one or more changed amino acid residues as shown in FIG. 6. The changed amino acids are shown relative to the sequence of an scFv of ABC0545 (ABC0545 dscFv). The disclosure includes but is not necessarily limited to each amino acid change alone, and all combinations thereof, shown in FIG. 6. The disclosure also includes all PBAs that are described in Table 1.

Table 1: Comparison of Humanized Fab Variants

1 1

Fab Expression Yield (mg/L) ELISA Signal (Relative to Chimeric)

Chimeric 16 1

*ABC0545 46 2.24

ABC0544 62 1.44

ABC0543 68 1.57

ABC0542 38 0.20

ABC0541 23 0 11

ABC0540 39 0.55

ABC0539 72 0.05

ABC0538 41 0.07

ABC0537 50 0.04

ABC0536 19 0.09

ABC0535 24 0.04

ABC0534 5 0.03

ABC0533 12 0.42

ABC0532 20 1.1

ABC0531 20 0.31

ABC0530 25 0.57

As such, the disclosure expressly includes all binding partners that comprise or consist of the described amino acid sequence. In non-limiting examples, a binding partner of this disclosure includes only one or only a combination of amino acid substitutions shown in FIG. 6. As such, the disclosure expressly includes all binding partners that include one or more of those amino acid substitution, and all sequences that comprise or consist of any one or any combination of the described substitutions. Further, the amino acid sequences of each of the described binding partners that comprise single amino acid substitutions as shown in FIG. 6 are each expressly included within this disclosure. However, it is shown herein that changes of VL_N31 S and VH_D31 S within the ABC0545 dscFv sequence showed a markedly decreased binding signal relative to the parent sequence. Thus, in examples, any binding partner described herein may exclude either or both of these amino acid changes.

Representative and non-limiting examples of PBA sequences of this disclosure include the following sequences, which may be provided in any antibody format described herein, and wherein the CDR sequences are provided below. VH is the variable heavy chain sequence. VL is the variable light chain sequence.

>ABC0545

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 42)

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:43)

>ABC0549

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLASGVP SRFSGSGSGTDYTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:44) VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLANDS TKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ

ID NO:45)

ABC0550 (albumin binding peptide underlined)

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLASGVP SRFSGSGSGTDYTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:46)

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLANDS TKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHLGGGS RLIEDICLPRWGCLWEDD (SEQ ID NO: 47)

>ABC0549

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLASGVP SRFSGSGSGTDYTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:48)

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLANDS TKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 49)

As noted above, in examples, the PBA may be engineered for binding to substances within blood (e.g., albumin, red blood cell membrane proteins, etc.). PBA that have been engineered for binding to substances in blood may be expected to demonstrate reduced clearance (i.e., enabling greater convenience in dosing) and increased blood:tumor exposure, enabling greater pharmacokinetic selectivity (i.e., enabling greater inhibition of released payload molecules in blood relative to inhibition of released payload molecules within tumors). In examples, a component of a described binding agent comprises an amino acid sequence that binds to albumin, further representative and non-limiting examples of which include the following sequences, which may be connected to the binding partner with or without a linker:

QRLIEDICLPRWGCLWEDDF (SEQ ID NO: 125); RLIEDICLPRWGCLWEDD (SEQ ID NO: 126); QRLMEDICLPRWGCLWEDDF (SEQ ID NO: 127);

QRLMEDICLPRWGCLWEDD (SEQ ID NO: 128); QRLMEDICLPRWGCLWE (SEQ ID NO: 129); DICLPRWGCL (SEQ ID NO: 130); DICLPRWGCLWEDD (SEQ ID NO : 131)

In an example, a binding partner described herein is adapted to bind to a red blood cell. The adaptation may be in the form of another binding partner that becomes a component of an anti-payload agent. In examples, a binding partner of this disclosure thus comprises an amino acid sequence that imparts to the binding partner the ability to bind to a red blood cell. In examples, the red blood cell binding component comprises a single domain antibody.

In an aspect, the disclosure provides pharmaceutical compositions comprising or consisting essentially of the ADCs and the anti -payload agents as described herein. The formulations typically contain physiologically acceptable carriers, excipients, or stabilizers and may be in the form of aqueous solutions, lyophilized or other dried or solid formulations. 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 such as phosphate, citrate, histidine and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl 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 immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™, polyethylene glycol (PEG) and the like. In an example, the pharmaceutical composition may comprise buffer components and stabilizers, including, but not limited to, sucrose, polysorbate 20, NaCl, KC1, sodium acetate, sodium phosphate, arginine, lysine, trehalose, glycerol, and maltose. In examples, the ADCs and the anti-payload antibodies or fragments or modifications thereof are the only protein molecules present in the compositions. In examples, the ADCs and the anti-payload antibodies or fragments or modifications thereof, are the only antibodies present in the composition.

Compositions comprising the ADC and the payload binding agent may be administered together, or separately and independently using any suitable route including parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The administration(s) may be carried out in a continuous manner or may be intermittent. Appropriate dosage will depend upon the particular tumor being treated, the specifics and condition of the individual patient, the mode of administration etc. Determination of appropriate dosage is within the purview of one skilled in the art, such as a treating physician. In an example, the ADC may be delivered locally, while the PBA is delivered so as to be available systemically. For example, and ADC may be delivered at or near the site of a tumor or intraperitoneally, while the PBA may be delivered i.v. In an example, the ADC may be delivered systemically, and the anti-payload antibody is delivered so as to be available systemically. For example, an ADC may be delivered i.v., while the antipayload antibody may be delivered subcutaneously.

The ADC and the PBA may be administered as a single composition or may be administered as separate compositions. When administered as separate compositions, they may be administered sequentially or concurrently. The two compositions may be administered at the same or different times, by the same or different routes, for same or different lengths of time, on the same or different regimens. In an example, the amount of the ADC and the PBA separately or together are in amounts sufficient enough to reduce the non-target toxicity of the ADC by at least 5% relative to that expected with the ADC alone at the same concentration as used in the combination. In examples, the reduction in toxicity may be 10%, 20%, 30%, 40%, 50% or more. Reduction in non-target toxicity can be evaluated by methods known in the art. For example, reduction could be classified as a reduction in the percent of patients at a specific dose that experience a grade 3 or higher adverse reaction with and without the PBA (Clin. Invest. (2013) 3(12), 1157-1165). Additionally, within an individual patient, reduction in non-target toxicity could be classified as a reduction in the severity of an adverse reaction (e.g., neutropenia) with, versus without the PBA.

The ADC and the PBA can be administered to an individual in need of treatment at dose(es) that is/are effective to treat a solid tumor. In general, suitable dosages of the PBA and the ADC can range from about 0.1 mg/kg to 100 mg/kg, including all 0.1 mg/kg values and ranges therebetween. Examples of 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. A variety of dosage regimens are contemplated including dosage regimens in which the ADC and the PBA may be administered repeatedly, e.g., on a daily, weekly or monthly schedule, over a short period or an extended period of time, e.g., months to years (e.g., maintenance therapy). The range for administration of the PBA may be from 0.01-100 mg/kg, including all 0.01 mg/kg values and ranges therebetween. A suitable ratio of the ADC to the PBA may be determined by one skilled in the art. For example, a molar ratio can be from 1 :1 to 1 : 100 ADC:PBA.

The amount of ADC and the anti-payload antibody can be administered to an individual in need of treatment at a dose that is effective to treat a solid tumor. In general, suitable dosages of the antibodies or fragments thereof — for both the ADC and the antipayload antibody — can range from about 0.1 mg/kg to 100 mg/kg, including all 0.1 mg/kg values and ranges therebetween. Examples of 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. A variety of dosage regimens are contemplated including dosage regimens in which the ADC and the antipayload antibody may be administered repeatedly, e.g., on a daily, weekly or monthly schedule, over a short period or an extended period of time, e.g., months to years (e.g., maintenance therapy). The range for administration of the anti-payload antibody may be from 0.01-100 mg/kg, including all 0.01 mg/kg values and ranges therebetween. A suitable ratio of the ADC to the anti-drug antibody may be determined by one skilled in the art. In an example, the molar ratio can be from 1 : 1 to 1 : 100 ADC:anti-Drug antibody. As discussed above, in examples, half-life extension strategies can be used to increase plasma half-life of the anti-payload antibodies including fusion of moieties to the sdAb or Fab that bind blood components such as albumin, red blood cells (e g., Band 3 of RBCs) or endogenous IgG as well as PASylation and PEGylation. Thus, in examples, the anti-payload antibody may be fused to moieties that bind to albumin, red blood cells or endogenous IgG, or fragments 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 of RBCs). In an example, the antibodies or fragments do not contain a polyhistidine tag. It is therefore considered that sdAb-sdAb fusion proteins that combine anti-payload binding activity and anti-albumin or anti-red cell binding activity may exhibit desirable pharmacokinetic attributes (restricted distribution within tissues and tumors relative to distribution within blood, elimination via renal filtration due to low molecular weight, long half-life) and can provide optimal enhancement of ADC therapeutic selectivity (increasing the ratio of efficacy to off-site toxicity). It is also considered that sdAb-peptide or Fab-peptide fusion proteins that combine anti-payload binding affinity (via the sdAb or Fab) and albumin binding affinity (via the peptide) may exhibit desirable pharmacokinetic attributes (restricted distribution within tissues and tumors relative to distribution within blood, elimination via renal filtration due to low molecular weight, long half-life) and can provide optimal enhancement of ADC therapeutic selectivity (increasing the ratio of efficacy to off-site toxicity).

Representative examples of single domain antibodies that have been demonstrated to bind to red blood cells via Band 3 are as follows:

>RMC1 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYKYRTYD YWGQGTQVTVSS (SEQ ID NO: 104)

>RA8

QVQLVQSGGGLVQAGGSLRLSCAASERTFSTYAMGWFRQIPGKERLFVAAVNWNGK TIRYADSVKGRFTISRDNAKNTIALQMNSLKPEDTAVYYCALRSTPMYFTNLASQESY NYWGPGTQVTVSS (SEQ ID NO: 105)

>RB12 QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYEYRTYD YWGQGTQVTVSS (SEQ ID NO 106)

>RD1

QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYEYRTYD YWGQGTQVTVSS (SEQ ID NO: 107)

>RD11

EVQLVESGGGLVQPGGSLRLSCAASGRIFSISNMGWYRQAPGKQRELVATITSGGSTN YGDSVKGRFTISMANAKNAVYLQMNSLKPEDTAVYYCNAGISRRTGTYSGGRYSDY WAQGTQVTVSS (SEQ ID NO: 108)

>RE8

QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTMGWYRQAPGKQRELVALITSTSST MYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARQTKWYAAGYEYRT YD YWGQGTQVTVSS (SEQ ID NO: 109)

>RG10

QVQLQESGGGLVQAGGSLRLSCAASERTFSTYAMGWFRQTPGKERLFVAAVNWNGK TIRYADSVKGRFTISRDNAKNTMSLQMNSLKPEDTAVYYCALRSTPMYFTNLASQES YNYWGPGTQVTVSS (SEQ ID NO: 110)

>RH5

QVQLVQSGGGLVQPGGSLRLSCAASGRIFSISNMGWYRQAPGKQRELVATITSGGSTN YGDSVKGRFTISMVNAKNAVYLQMNSLKPEDTAVYYCNAGISRRTGTYSGGRYSDY WGQGTQVTVSS (SEQ ID NO : 111)

>RMA1

QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYTDSVKGRFTISRDKAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYVYRTY D YWGQGTQVTVSS (SEQ ID NO: 112) >RMD1

QVQLVQSGGGLVQPGGSLRLGCAASGRVSEINTMGWYRQAPGKQRGLVALITSTSST MYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARLTRWYAAGYKYRTY D YWGQGTQVTVSS (SEQ ID NO: 113)

>RMF1

QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYIDSVNGRFTISRDNAKNTVYLQMTSLEPEDTAVYYCHARQTKWYAAGYKYRTYD YWGQGTQVTVSS (SEQ ID NO: 114)

>RMG1

QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTMGWYRLAPGKQRELVALITSTSST MYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARQTKWYAAGYKYRT YD YWGQGTQVTVSS (SEQ ID NO:115)

>RMC2

QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTMGWYRQAPGKQRELVALITSTSST MYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARQTIWYAAGYKYRTY DYWGLGTQVTVSS (SEQ ID NO: 116)

>RME2

QVQLVQSGGGLVQSGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTTN YIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYEYRTYDY WGQGTQVTVSS (SEQ ID NO : 117)

>RMF2

QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNNDTT NYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYKYRTYD YWGQGTQVTVSS (SEQ ID NO: 118)

>RMG2

QVQLVQSGGGQVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYKYRTYD YWGQGTQVTVSS (SEQ ID NO: 119) >RMH2 QVQLVQSGGGLAQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTKWYAAGYKYRTYD YWGQGTQVTVSS (SEQ ID NO: 120)

>RMB3

QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTMGWFRQAPGKQRELVALITSTSST MYSDSVKGRFTVSRDVAKNMVYLQMNSLKPEDTAVYYCNARQTKWYAAGYKYRT YD YWGQGTQVTVSS (SEQ ID NO: 121)

>RMD3

QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYIDSVKGRFTISRDNAKNTVYLQMASLEPEDTAVYYCNARQTRWYAAGYKYRTYD YWGQGTQVTVSS (SEQ ID NO: 122)

>RME3

QVQLVQSGGGLVQPGGSLRLSCAASGRVSEINTVGWYRQAPGKQRELVALFTSTSST MYSDSVKGRFTVSRDVAI<NMVYLQMNSLRPEDTAVYYCNARQTI<WYAAGYI<YRT YD YWGQGTQVTVSS (SEQ ID NO: 123)

>RMG3

QVQLVQSGGGLVQAGGSLRLSCAASGSSSSIIAMGWYRQAPGKQRELVATISNGDTT NYIDSVKGRFTISRDNAKNTVYLRMASLEPEDTAVYYCNARQTKWYAAGYKYRTYD YWGQGTQVTVSS (SEQ ID NO: 124)

The present composition/compositions may be administered alone or in combination with other types of treatments (e.g., surgical resection, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or other anti-tumor agents).

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

In an aspect, this disclosure provides a method for generating and identifying antipayload antibodies that are suitable to be used in combination with an ADC therapy to reduce non-target cytotoxicity. The method comprises generating or obtaining a library of antibodies, identifying specific antibodies based upon positive binding to the payload molecule by ELISA and/or by surface plasmon resonance techniques, identifying antibodies that have the desired affinity (such as KD equal to or less than 50 nM, determining binding kinetic parameters, and determining in vivo efficacy.

In an example, the present disclosure provides compositions and methods for treatment of cancer using ADC, where the drug portion of the ADC is a camptothecin or camptothecin analog or camptothecin derivative. The method comprises administering to an individual in need of treatment an ADC, where the drug portion is an aforementioned camptothecin or camptothecin analog or camptothecin derivative, and a PBA directed to a described a camptothecin or camptothecin analog or camptothecin derivative portion of the ADC. The ADC and the PBA may be administered in the same composition or in separate compositions as described elsewhere in this disclosure.

The disclosure includes antibodies and antigen binding fragments thereof with all amino acid substitutions individually and in all combinations as shown in FIG. 6.

In an aspect, this disclosure provides kits comprising an ADC and components for reducing non-target toxicity of the ADC. The kits may comprise in the same or different composition, i) ADC, and ii) an anti-payload antibody, wherein the anti-payload antibody is specific for the drug portion of the ADC. The ADC and the anti-payload antibody may be provided in a powdered, lyophilized form, along with reconstitution media, where the antibody and the ADC can be reconstituted prior to use. The kit may also optionally comprise instructions for administration of the compositions comprising the ADC, and the composition comprising the anti-payload antibody, which may be administered via different routes.

The disclosure includes the amino acid sequences below which may include amino acid substitutions as further described herein. The CDR sequences for the heavy chain and light chain (for binding partners that include a light chain) are provided Table 1. In examples, a binding partner of this disclosure includes: a) a heavy chain CDR1 that is DTYIH (SEQ ID NO: 1); DYEMS (SEQ ID NO:2); or YYEMS (SEQ ID NO: 3); b) a heavy chain CDR2 that is MIDLANDNTKYDPKFQG (SEQ ID NON); MIDLANDNTKYSQKFQG (SEQ ID NO:5); MIDLANDNTKYADSVKG (SEQ ID NO:6); MIDQANDNTKYDPKFQG (SEQ ID NOY); MIDLAIDNTKYEPKFQG (SEQ ID NO:8); MIDLANDNTKYDPKLQG (SEQ ID NO: 9); MIDLANDNTKYDAKFQG (SEQ ID

NO: 10); MIDLANDITKYDPKSQG (SEQ ID NO: 11); MIDLANDNTKYDPKFLG (SEQ ID NO: 12); AIAASGERTYYADSVKG (SEQ ID NO: 13); AISGSGDSTYYADSVKG (SEQ ID NO: 14): AISGSGGSTYYADSVKG (SEQ ID NO: 15); SISGSGDITHYADSVKG (SEQ ID NO: 16); SISGSAGSTYYADSVKG (SEQ ID NO: 17); VISYDGSNKYYADSVKG (SEQ ID NO: 18) or GISSSGDTTHYADSVKG (SEQ ID NO: 19); and c) a heavy chain CDR3 that is WGAIITLGG (SEQ ID NO:20); WGATITLGG (SEQ ID NO:21); WGANITLGG (SEQ ID NO:22); WGAITTLGG (SEQ ID NO:23); SWYYYDSSGYYGFDY SEQ ID NO 24); VSSGWYMDY (SEQ ID NO:25); PTMSRDYFDY (SED ID NO:26); VASGWWVDY (SEQ ID NO:27); APGGGYQYDLYHYYAMDV (SEQ ID NO:28); LPRYGSGSYWSLG (SEQ ID NO:29); or HPLSGRHYFDY (SEQ ID NO:30).

In examples, a binding partner with of this disclosure includes: i) a light chain CDR1 that is RASGNIHNSLA (SEQ ID NO:31); ii) a light chain CDR2 that is NAKTLAD (SEQ ID NO:32); NAKTLAS (SEQ ID NO 33); KAKTLAD (SEQ ID NO:34); NAKTQAD (SEQ ID NO:35); NAKTLAE (SEQ ID NO:36); or NAKTLSD (SEQ ID NO:37); and iii) a light chain CDR3 that is QHFWSTPFT (SEQ ID NO:38) or QHFLSTPFT (SEQ ID NO:39).

Representative CDR sequences for antibody constructs of this disclosure are shown in Table 1. Antibody names as used in this disclosure are in the left column. SEQ ID NO’s are as assigned in the column to the right of each sequence. CDR-H1 is the heavy chain CDR1 sequence. CDR-H2 is the heavy chain CDR2 sequence. CDR-H3 is the heavy CDR3 sequence. CDR-L1 is the light chain CDR1 sequence. CDR-L2 is the light chain CDR2 sequence. CDR-L3 is the light chain CDR3 sequence. Table 1

Any VH chain of this disclosure may have a C-terminal amino acid sequence that ends with the sequence LVTVSS (SEQ ID NO:40) if this sequence is in the VH chain, even though longer VH sequences may be shown, provided the VH chain sequence includes three described CDRs. The disclosure accordingly includes each VH sequence referred to herein by a SEQ ID NO, with the proviso that the C-terminal amino acid sequence of the antibody ends with LVTVSS (SEQ ID NO:40). Any VL sequence of this disclosure may have a C-terminal amino acid sequence that ends with the sequence KLEIKS (SEQ ID NO:41) if this sequence is in the VL chain, even though longer VL sequences may be shown, provided the VL chain sequence includes three described CDRs. The disclosure accordingly includes each VL sequence referred to herein by a SEQ ID NO, with the proviso that the C-terminal amino acid sequence ends with the sequence KLEIK (SEQ ID NO:41). Representative heavy and light chain sequences comprising the described heavy and light chain (if present) CDR1, CDR2 and CDR3s, and LVTVSS (SEQ ID NO:40) and KLEIK (SEQ ID NO:41) sequences are as follows.

>ABC0545

ABC0545 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4), and CDR3 sequence WGAIITLGG (SEQ ID NO: 20); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR2 sequence QHFWSTPFT (SEQ ID NO:38).

ABC0545 VH and VL sequences: VH EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 42) VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:43) >ABC0544 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 8) and CDR3 sequence WGAIITLGG (SEQ ID NO:20); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:2) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

ABC0544 VH and VL sequences:

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 44)

VL

DIVLTQSPSSLSASVGQRVTISCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PDRF SGSGSGTDF SLKIS SLQPEDFADYYCQHFWSTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:45)

>ABC0543

ABC0543 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4), and CDR3 sequence WGAIITLGG (SEQ ID NO:20); and a light chain with CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 QHFWSTPFT (SEQ ID NO:38).

>ABC0543 VH and VL sequences:

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 46)

VL

DIQMTQSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:47)

>ABC0542

ABC0542 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4), CDR3 sequence WGAIITLGG (SEQ ID NO: 20), and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

ABC0542 heavy and light chain sequences:

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO:48)

VL

DVVLTQSPLSLAVLLGQPASISCRASGNIHNSLAWYQQRPGQSPRLLIYNAKTLADSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYFCQHFWSTPFTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:49)

>ABC0541

ABC0541 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20); and light chain comprising CDR1 sequence RASGNIHNSLA(SEQ ID N0:31), CDR2 sequence NAKTLAD (Seq ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLVESGGGLVKPGGSLRLSCAASGFNIKDTYIHWVRQAPGQGLEWIGMIDLANDN TKYDPKFQGRATISRDTSKNTLYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 50) VL

DIVLTQSPSSLSASVGQRVTISCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PDRF SGSGSGTDF SLKIS SLQPEDFADYYCQHFWSTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:51)

>ABC0540

ABC0540 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a heavy chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLVESGGGLVKPGGSLRLSCAASGFNIKDTYIHWVRQAPGQGLEWIGMIDLANDN TKYDPKFQGRATISRDTSKNTLYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 52) VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:53) >ABC0539 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a heavy chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:36).

VH

EVQLVESGGGLVKPGGSLRLSCAASGFNIKDTYIHWVRQAPGQGLEWIGMIDLANDN TKYDPKFQGRATISRDTSKNTLYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHLDIQMT QSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGVPSRFS GSGSG (SEQ ID NO: 54) VL TDFTLTISSLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:55)

>ABC0538 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLVESGGGLVKPGGSLRLSCAASGFNIKDTYIHWVRQAPGQGLEWIGMIDLANDN TKYDPKFQGRATISRDTSKNTLYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 56) VL

DVVLTQSPLSLAVLLGQPASISCRASGNIHNSLAWYQQRPGQSPRLLIYNAKTLADSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYFCQHFWSTPFTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 57) >ABC0537 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYSQKFQG (SEQ ID NO: 5), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA(SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLQESGAELVKPGASVKLSCKASGFNIKDTYIHWVRQAPGQGLEWIGMIDLAND NTKYSQKFQGRVTITRDTSKSTAYMELSSLRSEDTAVYYCATWGAIITLGGWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQ S SGLYSL S S WTVP S S SLGTQT YICNVNHKP SNTKVDKK VEPKSCDKTHLDIQ MTQSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGVPSR FSGSGSG (SEQ ID NO 58) VL

TDFTLTISSLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:60)

>ABC0536 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYSQKFQG (SEQ ID NO: 5), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLQESGAELVKPGASVKLSCKASGFNIKDTYIHWVRQAPGQGLEWIGMIDLAND NTKYSQKFQGRVTITRDTSKSTAYMELSSLRSEDTAVYYCATWGAIITLGGWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQ S SGLYSL S S WTVP S S SLGTQT YICNVNHKP SNTKVDKK VEPKSCDKTHL (SEQ ID NO:61)

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:62)

>ABC0535 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYSQKFQG (SEQ ID NO: 5), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLQESGAELVKPGASVKLSCKASGFNIKDTYIHWVRQAPGQGLEWIGMIDLAND NTKYSQKFQGRVTITRDTSKSTAYMELSSLRSEDTAVYYCATWGAIITLGGWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQ S SGLYSL S S WTVP S S SLGTQT YICNVNHKP SNTKVDKK VEPKSCDKTHL (SEQ ID NO:63)

VL

DIVLTQSPSSLSASVGQRVTISCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PDRF SGSGSGTDF SLKIS SLQPEDFADYYCQHFWSTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:64)

>ABC0534 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYSQKFQG (SEQ ID NO: 5), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLQESGAELVKPGASVKLSCKASGFNIKDTYIHWVRQAPGQGLEWIGMIDLAND NTKYSQKFQGRVTITRDTSKSTAYMELSSLRSEDTAVYYCATWGAIITLGGWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQ S SGLYSL S S WTVP S S SLGTQT YICNVNHKP SNTKVDKK VEPKSCDKTHL (SEQ ID NO:65) VL

DVVLTQSPLSLAVLLGQPASISCRASGNIHNSLAWYQQRPGQSPRLLIYNAKTLADSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYFCQHFWSTPFTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 57)

>ABC0533 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYADSVKG (SEQ ID NO: 6), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:36).

VH

EVQLVESGGGLVQPGGSLILSCAASGFNIKDTYIHWVRQAPGKGLEWVSMIDLANDN TKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 66)

VL

DVVLTQSPLSLAVLLGQPASISCRASGNIHNSLAWYQQRPGQSPRLLIYNAKTLADSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYFCQHFWSTPFTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:67)

>ABC0532 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYADSVKG (SEQ ID NO:6), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:3I), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLVESGGGLVQPGGSLILSCAASGFNIKDTYIHWVRQAPGKGLEWVSMIDLANDN TKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO 68)

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:69)

>ABC0531 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDNTKYADSVKG (SEQ ID NO:6), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

VH

EVQLVESGGGLVQPGGSLILSCAASGFNIKDTYIHWVRQAPGKGLEWVSMIDLANDN TKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 70)

VL

DIVLTQSPSSLSASVGQRVTISCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PDRF SGSGSGTDF SLKIS SLQPEDFADYYCQHFWSTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:71)

>ABC0530 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYADSVKG (SEQ ID NO:6), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38). VH

EVQLVESGGGLVQPGGSLILSCAASGFNIKDTYIHWVRQAPGKGLEWVSMIDLANDN TKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 72) VL

DIQMTQSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:73)

The following sequences are disulphide stabilized single chain variable fragments (dscFv) derivatives of ABC0545 that were identified following phage display panning and screening to identify mutations to increase binding affinity and stability. Heavy chain and light chain refer to segments of the single chain scFv.

>ABC0545_dscFv comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>ABC0545_dscFv

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLEIKR (SEQ ID NO:74)

>Th7 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDQANDNTKYDPKFQG (SEQ ID NOY), CDR3 sequence WGANITLGG (SED ID NO:22), and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38). >Th7

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDQAND NTKYDPKFQGRVTS S VDT STNKAYLQL S SLTSEDTAVYYC ATWGANITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSPSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDYTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 75)

>TB5 comprising a heavy chain CDR1 DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 36).

>TB5

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGHVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTTTCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 76)

>TB9 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLAIDNTKYEPKFQG (SEQ ID NO:8), CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence KAKTLAD (SEQ ID NO:34) and CDR sequence QHFWSTPFT (SEQ ID NO:38).

>TB9

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAIDN TKYEPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLAW YQQIKGKAPKLLIYKAKTLADGVPSRFSGSGSGTDYTLTISGLQPEDFATYYCQHFWS TPFTFGCGTKLEIKR (SEQ ID NO:77) >TE6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGATITLGG (SEQ ID NO 21) and a light chain sequence CDR1 RASGNIHNSLA (SEQ ID NO: 31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38)

>TE6

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLNSLTSEDTAVYYCATWGATITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSSSGSGTVFTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 78)

>TD6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDQANDNTKYDPKFQG (SEQ ID NO: 7), and CDR3 sequence WGANITLGG (SEQ ID NO:22) and a light sequence comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>TD6

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDQAND NTKYDPKFQGRVTS S VDT STNKAYLQL S SLTSEDTAVYYC ATWGANITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDYTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 79)

>TG2 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain sequence CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>TG2

GVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLAND NTKYDPKFQGHVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSLSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSSSGTDFTLTISGLQPEDFATYYCQHF WSTPFTFGGGTKLEIKR (SEQ ID NO: 80)

>TH11 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), CDR3 sequence WGAIITLGG (SEQ ID NO:20), and a light chain sequence CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>TH11

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFQGRDTISVDTSTNKAYLQLSSLTSEDTAVYYCAAWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSLSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSSSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGGGTKLEIKR (SEQ ID NO:81)

>TA3 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), CDR3 sequence WGATITLGG (SEQ ID NO:21), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>TA3

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTQV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLVIKR (SEQ ID NO: 82)

>TA32 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>TA32

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLAW YQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWS TPFTFGCGTKLEIKR (SEQ ID NO: 83)

>TF6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), and CDR3 sequence WGAITTLGG (SEQ ID NO 23), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38).

>TF6

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISDDTSTNKAYLQLSSLTSEDTAVYYCATWGAITTLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPGSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEFKR (SEQ ID NO: 84)

>TD4 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), and CDR3 sequence WGAIITLGG (SEQ ID NO:20), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>TD4

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLEIKR (SEQ ID NO:85)

>TG6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), and CDR3 sequence WGATITLGG (SEQ ID NO:21) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>TG6

EVQLQESGGGLVKPGGSLNLICAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLAW YQQNKGKAPKLLIYNAKTLADGVPSRFRGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGRGTKLEIKR (SEQ ID NO: 86)

>KD11 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKLQG (SEQ ID NO: 9) and CDR3 sequence WGATITLGG (SEQ ID NO:2I), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFLSTPFT (SEQ ID NO 39)

>KD11

EVQLQESGGGLVKPGDSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKLQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSGIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTNFTLTISGLQPEDFATYYCQHFL STPFTFGCGTKLEIKR (SEQ ID NO: 87)

>KF6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTQAD (SEQ ID NO:35), and CDR3 sequence QHFWSTPFT (SEQ ID NO 38) >KF6

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCAAWGAIITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGASDIVLTQSPSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTQADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 88)

>KG7 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain sequence CDR1 RASGNIHNSLA (SEQ ID NO:31), and CDR2 sequence NAKTLAD (SEQ ID NO:32) and a CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

>KG7

GVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSGGGGSCGGGSGGSGSGGGGSDIVLTQSPSSLSASVGETVTLTCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGSKLEINR (SEQ ID NO: 89)

>KB7 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDAKFQG (SEQ ID NO: 10), and CDR3 sequence WGANITLGG (SEQ ID NO:22), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38)

>KB7

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDAKFQGRVTISVDTSTNKAYLQLSSLASEDTAVYYCATWGANITLGGWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNS LAWYQQIKGKAPKLLIYNAKTLADGVPNRFSGSGSGTDFTLTISGLQPEDFATYYCQH FWSTPFTFGCGTKLEIKR (SEQ ID NO:90)

>TA11 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDITKYDPKSQG (SEQ ID NO:11), and CDR3 sequence WGAIITLGG (SEQ ID NO:20), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID N0:31), CDR2 sequence NAKTLAE (SEQ ID NO:36) and a CDR3 sequence QHFWSTPFT (SEQ ID NO 38)

>TA11

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDI TKYDPKSQGRVTISADTSTNKAYLQLSSMTSEDTAVYYCAAWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLAEGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLEIKR (SEQ ID N0:91)

>TG11 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFLG (SEQ ID NO: 12) and CDR3 sequence WGAIITLGG (SEQ ID NO:20), and a heavy chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLSD (SEQ ID NO:37) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38)

>TG11

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFLGRFTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGEAVTITCRASGNIHNSLAW YQQIKGKAPKLLIYNAKTLSDGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWS TPFTFGCGTKLEIKR (SEQ ID NO:92)

VHH Sequences (identified from a naive human heavy chain only phage library) >VD4 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence AIAASGERTYYADSVKG (SEQ ID NO: 13) and CDR3 sequence SWYYYDSSGYYGFDY (SEQ ID NO: 24)

>VD4

QVQLVQSGGGLVQPGGSLRLSCAASAFDFDDYEMSWVRQAPGQRLEWVSAIAASGE RTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARSWYYYDSSGYYGFD YWGQGTLVTVSS (SEQ ID NO:93) >VF5 comprising CDR1 sequence YYEMS (SEQ ID NO:3), CDR2 sequence

AISGSGDSTYYADSVKG (SEQ ID NO: 14) and CDR3 VSSGWYMDY (SEQ ID NO:25)

>VF5

QVQLVQSGGGLVQPGGSLRLSCAASDFYFAYYEMSWVRQAPGQGLEWVSAISGSGD STYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARVSSGWYMDYWGQG TLVTVSS (SEQ ID NO:94)

>VF8 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence

AISGSGGSTYYADSVKG (SEQ ID NO: 15) and CDR3 sequence PTMSRDYFDY (SEQ ID NO:26)

>VF8

QVQLVQSGGGLVQPGGSLRLSCAASDFDFADYEMSWVRQAPGQGLEWVSAISGSGG STYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARPTMSRDYFDYWGQG TLVTVSS (SEQ ID NO:95)

>VF10 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence SISGSGDITHYADSVKG (SEQ ID NO: 16) and CDR3 sequence VASGWWVDY (SEQ ID NO: 27)

>VF10

QVQLVQSGGGLVQPGGSLRLSCAASAFDFDDYEMSWVRQAPGQRLEWVSSISGSGD ITHYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAMYYCGRVASGWWVDYWGQG TLVTVSS (SEQ ID NO:96)

>VG4 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence SISGSAGSTYYADSVKG (SEQ ID NO: 17) and CDR3 sequence APGGGYQYDLYHYYAMDV (SEQ ID NO:28)

>VG4

QVQLVQSGGGLVQPGGSLRLSCAASDFDFADYEMSWVRQAPGQRLEWVSSISGSAG STYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARAPGGGYQYDLYHYY AMDVWGQGTTVTVSS (SEQ ID NO:97) >BMBG2 comprising CDR1 sequence YYEMS (SEQ ID NO:3), CDR2 sequence VISYDGSNKYYADSVKG (SEQ ID NO: 18) and CDR3 sequence LPRYGSGSYWSLG (SEQ ID NO: 29)

>BMBG2

QVQLVQSGGGLVQPGGSLRLSCAASSFYFDYYEMSWVRQAPGKGLEWVAVISYDGS NKYYADSVKGRFTISRDNTKNTLYLQMNTLRAEDTATYYCAGLPRYGSGSYWSLGW GQGTLVTVSSS (SEQ ID NO:98)

>BMBC2 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence GISSSGDTTHYADSVKG (SEQ ID NO: 19) and CDR3 sequence HPLSGRHYFDY (SEQ ID NO:30)

>BMBC2

QVQLVQSGGGLVQPGGSLRLSCAASYFSFSDYEMSWVRQAPGQRLEWVSGISSSGDT THYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTATYYCGRHPLSGRHYFDYWGQG TLVTVSSS (SEQ ID NO:99)

>ABC0550 (ABP underlined) comprising heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLAND STKYDPKFQ (SEQ ID NO:8) and CDR3 sequence WGATITLGG (SEQ ID NO:21) and light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAS (SEQ ID NO:33) and CDR3 sequence QHFWSTPFT (SEQ ID NO:36)

>ABC0550

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLASGVP SRFSGSGSGTDYTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 100)

VH EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLANDS TKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHLGGGS RLIEDICLPRWGCLWEDD (SEO ID NO: 101)

>ABC0549 comprising heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDSTKYDPKFQG (SEQ ID NO: 8) and CDR3 sequence WGATITLGG (SEQ ID NO:21) and light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38)

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLASGVP SRFSGSGSGTDYTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 102)

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLANDS TKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 103)

The invention is further demonstrated by way of the figures and data presented herein, whether provided in the detailed description or the figures.

Example 1

This example demonstrates ABC0545 binding affinity for SN38, Dxd and Belotecan. The data are shown in FIG 1. For FIG. 1, ABC0545 at a concentration of 3 nM (circles) and 0.3 nM (squares) was incubated with free SN38/Dxd/Belotecan across a range of concentrations. AKinexa 3200 was used to assess free ABC0545 concentration as a function of the concentration of SN38/Dxd/Belotecan. Observed data was fit to obtain an estimate for the equilibrium dissociation rate constant (KD) for SN38 (189 pM), Dxd (820 pM) and Belotecan (432 pM). Example 2

This example demonstrates ABC0545 does not bind sacituzumab govitecan. The data are shown in FIG. 2. For FIG. 2, Sacituzumab govitecan (SG) was captured on a TROP2 immobilized SPR chip at a density of 150 response units (black top left). Subsequently, ABC0545 was serially injected at concentrations between 617 nM-50 pM (black top left). The chip was regenerated using 10 mM glycine pH 2.0. Subsequently, ABC0545 was injected over the TROP2 chip at concentrations between 617 nM-50 pM to determine the background signal (gray top left). The top right graph shows the SG specific binding signal (signal observed with SG minus signal observed without SG) at individual ABC0545 concentrations (0 nM, 617 nM, 1.85 pM, 5.5 pM, 16.6 pM, 50 pM). No binding signal is observed, indicating that ABC0545 does not bind to SN38 that is conjugated to SG.

Example 3

This example demonstrates ABC0545 blocks neutropenia in-vitro. The data are shown in FIG 3. For FIG. 3, Trastuzumab deruxtecan (T-Dxd) or Sacituzumab govitecan (SG) were incubated with differentiating human hematopoietic stem cells alone or in combination with ABC0545 for six days. Subsequently, total viable cells and total neutrophils were determined using flow cytometry. A sharp decrease in cell-viability (both total cell counts and neutrophil counts) was observed for T-Dxd and SG at low nanomolar concentrations. A decrease in cell viability was not observed with SG in combination with ABC0545 up to a concentration of 300 nM. ABC0545 increased the concentration of T-Dxd required to cause a 50% decrease in cell-viability by approximately 100-fold. These results demonstrate the ABC0545 can inhibit a primary mechanism of neutrophil toxicity for camptothecin based ADCs (i.e., extracellular linker catabolism and subsequent diffusion of free SN38/Dxd into differentiating hematopoietic cells).

Example 4

This example demonstrates ABC0545 half-life extension through albumin binding peptides. The data are shown in FIG 4. Provided in FIG. 4 are observed plasma concentration time profiles for ABC0545 alone, or ABC0545 linked to a low affinity albumin binding peptide (Hll >20 pM KD for human and mouse albumin) or linked to a peptide (PepH) with high affinity for mouse serum albumin (KD=~50 nM) and moderate affinity for human serum albumin (KD=~500 nM). The plot on the left shows the observed concentration time profile following a 5 mg/kg dose of ABC0545 (and variants) to Swiss-Webster mice with concentrations determined using a tracer dose of I¹²⁵ labeled Fab. The plot on the right shows the observed pharmacokinetic profile for ABC0545 and albumin binding variants following a dose of 25 mg/kg to humanized mice expressing human serum albumin and human FcRn. Plasma concentrations were determined using a quantitative ELISA. These results demonstrate that the half-life of ABC0545 can be extended through the genetic fusion of albumin binding peptides which can be tuned as a function of the peptides binding affinity for serum albumin.

Example 5

This example provides a graph comparing the ELISA signal for single amino acid point mutants of ABC0545, as shown in FIG. 5. Mutations were designed to remove potential sequence liabilities that are present in the primary amino acid sequence of the variably heavy (VH) or variable light chain (VL). Mutations VL_D56S and VH_N57S negligibly impact the ELISA binding signal to SN38-peg-biotin coated on neutravidin wells in-comparison to ABC0545. Mutations VL_N31S and VH_D31S demonstrate a large decrease in binding signal, indicating that these point mutations decrease SN38 binding affinity.

Example 6

This example provides a sequence alignment which is shown in FIG 6. The sequence alignment is for disulfide stabilized scFv derivatives of ABC0545 (ABC0545 dscFv). The scFvs were identified following generation of a randomly mutated phage display library based on the ABC0545 sequence. Phage panning was completed to identify clones with improved stability and binding affinity. Variants of ABC0545 incorporating one or more of the identified residue substitutions (i.e., depicted within the figure) are anticipated to demonstrate desirable binding properties (e.g., improved affinity and/or reduced dissociation rates for binding to camptothecin payloads (SN38, Dxd, belotecan, etc.). Preferable residue substitutions for the ABC0545 heavy chain include V72A, T105A, I109T and I109N. A preferable residue substitution for the ABC0545 light chain is F71Y

Example 7

This example provides observed binding signals for human heavy chain single domain antibodies that were identified from a naive phage display library. The data are shown in FIG. 7. Clones show increased binding signal for plates coated with biotin conjugated SN38 (top left) with free Dxd causing a concentration dependent reduction in signal for several clones (i.e., VF5, VF10 in top right panel).

Example 8

This example provides observed fractional binding signals for the human heavy chain single domain antibodies BMBG2 and BMBC2. The data are shown in FIG. 8. Addition of the anti-camptothecin antibody 8C2 results in a decrease in binding signal demonstrating camptothecin specific binding activity for both BMBG2 AND BMBC2. Addition of free SN38 or free Dxd results in a decreased binding signal indicating both antibodies bind to free drug.

Example 9

This example shows that ABC0550 is predicted to have greater affinity, relative to ABC0545, for SN38 (ABC0550: 12.7 pM, ABC0545: 189 pM) and Belotecan (ABC0550: 206.7 pM vs ABC0545: 432 pM). The data are presented in FIG. 9. For FIG. 9, ABC0550 was diluted in PBS with 1 mg/ml bovine serum albumin to a final concentration of 3 nM or 0.15 nM. SN38 or Belotecan was serially diluted with constant concentrations of ABC0545 (3 nM and 0.15 nM) and incubated on an inverting platform at room temperature for 24 hours. ABC0550 with and without free drug was injected over a KinExA 3200 (Sapidyne, Boise, Idaho) using an autosampler. Free ABC0550 was captured on polystyrene beads coated with neutravidin and SN38-peg-biotin. ABC0550 was detected using a 0.5 pg/ml mixture of anti-human Fab (109-605-003) and anti-human H+L (109-607-003) AlexFluor647 conjugated secondary antibody (Jackson Immunoresearch Laboratories Inc., West Grove, PA). Observed binding signals at 3 nM and 0.15 nM were opened in n-curve analysis software (Sapidyne) to fit an equilibrium dissociation rate constant to observed binding data for each payload. ABC0550 is predicted to have greater affinity, relative to ABC0545, for SN38 (ABC0550: 12.7 pM, ABC0545: 189 pM) and Belotecan (ABC0550: 206.7 pM vs ABC0545: 432 pM).

For the ELISA data that includes SN38 the following procedure was used.

SN38 was chemically conjugated to an amine-peg4 linker at the 10-hydroxl group by Cayman Chemical (Ann Arbor, MI). SN38-peg4-amine was chemically conjugated to NHS- pegl2-biotin (Thermo Scientific) to generate the capture substrate for ELISA (SN38-peg- biotin). Neutravidin was diluted to 10 pg/mL in 20 mM dibasic sodium phosphate and 100 pL added to individual wells of a Nunc ELISA plate and incubated overnight at 4 °C The following day the neutravidin solution was removed and 250 pL of 2% dry nonfat milk diluted in 20 mM dibasic sodium phosphate with a 1 : 1000 dilution of SN38-peg-biotin was added and incubated for 2-hours on a shaker platform. Individual wells were washed three times with 250 pL of phosphate buffered saline with 0.05% Tween-20 (PBST). Humanized or chimeric Fab was added at a concentration of 10 nM (unless otherwise listed) and incubated for 2-hours at room temperature on a shaking platform (300 rpm). Subsequently, wells were washed three times with PBST and a 250 ul of a 1 : 1000 dilution of anti-human alkaline phosphatase conjugated secondary antibody (A8542, Sigma-Aldrich) diluted in 0.5% non-fat milk in PBS added for 90 minutes. Wells were washed 2x with PBST and 2x with distilled water. 250 pL of 4 mg/ml p-nitrophenyl phosphate in diethanolamine was added to each well and the change in absorbance overtime at 405 nm was assessed for 10 minutes.

While the invention has been described through illustrative examples, routine modifications will be apparent to those skilled in the art, which modifications are intended to be within the scope of the present disclosure.

Claims

What is claimed is:

1. A binding partner that specifically binds to a drug that is used as a drug component of an antibody-drug conjugate (ADC) and wherein the drug component is Camptothecin or derivative thereof.

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

3. The binding partner of claim 2, wherein the binding partner comprises an antibody or antigen binding fragment thereof, and wherein the antigen binding fragment is optionally a Fab, Fab', or an F(ab')2.

4. The binding partner of claim 3, wherein the derivative of Camptothecin is selected from DXd, SN-38, Exatecan, and Belotecan.

5. The binding partner of any one of claims 1-4, wherein the binding partner comprises ABC0545 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), and CDR3 sequence WGAIITLGG (SEQ ID NO: 20); and a light chain comprising

CDR1 sequence RASGNMNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR2 sequence QHFWSTPFT (SEQ ID NO:38).

6. The binding partner of claim 5, wherein the ABC0545 comprises VH and VL sequences: VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 42)

VL DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:43).

7. The binding partner of any one of claims 1-4, wherein the binding partner comprises ABC0545_dscFv comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

8. The binding partner of claim 7 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLEIKR (SEQ ID NO:74).

9. The binding partner of any one of claims 1-4 comprising ABC0544 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 8) and CDR3 sequence WGAIITLGG (SEQ ID NO:20); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:2) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

10. The binding partner of claim 9 comprising VH and VL sequences:

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 44)

VL DIVLTQSPSSLSASVGQRVTISCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PDRFSGSGSGTDFSLKISSLQPEDFADYYCQHFWSTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:45).

11. The binding partner of any one of claims 1-4 comprising

ABC0543 comprising a heavy chain comprising CDR1 sequence DTYH4 (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4), and CDR3 sequence WGAIITLGG (SEQ ID NO:20); and a light chain with CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 QHFWSTPFT (SEQ ID NO 38).

12. The binding partner of claim 11 comprising VH and VL sequences:

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S S GLYSL S SWT VP S S SLGTQT YICNVNHKP SNTK VDKKVEPK SCDKTHL (SEQ ID NO:46) VL

DIQMTQSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:47).

13. The binding partner of any one of claims 1-4 comprising ABC0542 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), CDR3 sequence WGAIITLGG (SEQ ID NO 20), and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38).

14. The binding partner of claim 13 comprising heavy and light chain sequences: VH EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO:48)

VL

DVVLTQSPLSLAVLLGQPASISCRASGNIHNSLAWYQQRPGQSPRLLIYNAKTLADSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYFCQHFWSTPFTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:49).

15. The binding partner of any one of claims 1-4 comprising ABC0541 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20); and light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (Seq ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38).

16. The binding partner of claim 15 comprising heavy and light chain sequences

VH

EVQLVESGGGLVKPGGSLRLSCAASGFNIKDTYIHWVRQAPGQGLEWIGMIDLANDN TKYDPKFQGRATISRDTSKNTLYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 50) VL

DIVLTQSPSSLSASVGQRVTISCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PDRF SGSGSGTDF SLKIS SLQPEDFADYYCQHFWSTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:51).

17. The binding partner of any one of claims 1-4 comprising ABC0540 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID N0:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a heavy chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38).

18. The binding partner of claim 17 comprising heavy and light chain sequences VH EVQLVESGGGLVKPGGSLRLSCAASGFNIKDTYIHWVRQAPGQGLEWIGMIDLANDN TKYDPKFQGRATISRDTSKNTLYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 52)

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:53).

19. The binding partner of any one of claims 1-4 comprising ABC0539 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a heavy chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 36).

20. The binding partner of claim 19 comprising heavy and light chain sequences VH EVQLVESGGGLVKPGGSLRLSCAASGFNIKDTYIHWVRQAPGQGLEWIGMIDLANDN TKYDPKFQGRATISRDTSKNTLYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHLDIQMT QSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGVPSRFS GSGSG (SEQ ID NO: 54)

VL TDFTLTISSLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO 55).

21. The binding partner of any one of claims 1-4 comprising ABC0538 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38).

22. The binding partner of claim 21 comprising heavy and light chain sequences: VH EVQLVESGGGLVKPGGSLRLSCAASGFNIKDTYIHWVRQAPGQGLEWIGMIDLANDN TKYDPKFQGRATISRDTSKNTLYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 56)

VL

DVVLTQSPLSLAVLLGQPASISCRASGNIHNSLAWYQQRPGQSPRLLIYNAKTLADSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYFCQHFWSTPFTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 57).

23. The binding partner of any one of claims 1-4 comprising ABC0537 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYSQKFQG (SEQ ID NO: 5), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

24. The binding partner of claim 23 comprising heavy and light chain sequences: VH EVQLQESGAELVKPGASVKLSCKASGFNIKDTYIHWVRQAPGQGLEWIGMIDLAND NTKYSQKFQGRVTITRDTSKSTAYMELSSLRSEDTAVYYCATWGAIITLGGWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQ S SGLYSL S S WTVP S S SLGTQT YICNVNHKP SNTKVDKK VEPKSCDKTHLDIQ MTQSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGVPSR FSGSGSG (SEQ ID NO 58) VL

TDFTLTISSLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:60).

25. The binding partner of any one of claims 1-4 comprising ABC0536 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYSQKFQG (SEQ ID NO: 5), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

26. The binding partner of claim 25 comprising heavy and light chain sequences: VH EVQLQESGAELVKPGASVKLSCKASGFNIKDTYIHWVRQAPGQGLEWIGMIDLAND NTKYSQKFQGRVTITRDTSKSTAYMELSSLRSEDTAVYYCATWGAIITLGGWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQ S SGLYSL S S WTVP S S SLGTQT YICNVNHKP SNTKVDKK VEPKSCDKTHL (SEQ ID NO:61)

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:62).

27. The binding partner of any one of claims 1-4 comprising ABC0535 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYSQKFQG (SEQ ID NO: 5), and CDR3 sequence WGAIITLGG (SEQ ID N0:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38).

28. The binding partner of claim 27 comprising heavy and light chain sequences: VH EVQLQESGAELVKPGASVKLSCKASGFNIKDTYIHWVRQAPGQGLEWIGMIDLAND NTKYSQKFQGRVTITRDTSKSTAYMELSSLRSEDTAVYYCATWGAIITLGGWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQ S SGLYSL S S WTVP S S SLGTQT YICNVNHKP SNTKVDKK VEPKSCDKTHL (SEQ FD NO:63)

VL

DIVLTQSPSSLSASVGQRVTISCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PDRF SGSGSGTDF SLKIS SLQPEDFADYYCQHFWSTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:64).

29. The binding partner of any one of claims 1-4 comprising ABC0534 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYSQKFQG (SEQ ID NO: 5), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

30. The binding partner of claim 29 comprising heavy and light chain sequences: VH EVQLQESGAELVKPGASVKLSCKASGFNIKDTYIHWVRQAPGQGLEWIGMIDLAND NTKYSQKFQGRVTITRDTSKSTAYMELSSLRSEDTAVYYCATWGAIITLGGWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQ S SGLYSL S S WTVP S S SLGTQT YICNVNHKP SNTKVDKK VEPKSCDKTHL (SEQ ID NO:65)

VL

DVVLTQSPLSLAVLLGQPASISCRASGNIHNSLAWYQQRPGQSPRLLIYNAKTLADSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYFCQHFWSTPFTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 57).

31. The binding partner of any one of claims 1-4 comprising ABC0533 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence CDR2 MIDLANDNTKYADSVKG (SEQ ID NO:6), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 36).

32. The binding partner of claim 31 comprising heavy and light chain sequences: VH

EVQLVESGGGLVQPGGSLILSCAASGFNIKDTYIHWVRQAPGKGLEWVSMIDLANDN TKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 66)

VL

DVVLTQSPLSLAVLLGQPASISCRASGNIHNSLAWYQQRPGQSPRLLIYNAKTLADSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYFCQHFWSTPFTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:67).

33. The binding partner of any one of claims 1-4 comprising ABC0532 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYADSVKG (SEQ ID NO:6), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38).

34. The binding partner of claim 33 comprising heavy and light chain sequences: VH

EVQLVESGGGLVQPGGSLILSCAASGFNIKDTYIHWVRQAPGKGLEWVSMIDLANDN TKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO 68)

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLADGVP SRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:69).

35. The binding partner of any one of claims 1-4 comprising ABC0531 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYADSVKG (SEQ ID NO:6), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO 38).

36. The binding partner of claim 35 comprising heavy and light chain sequences:

VH

EVQLVESGGGLVQPGGSLILSCAASGFNIKDTYIHWVRQAPGKGLEWVSMIDLANDN TKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 70)

VL

DIVLTQSPSSLSASVGQRVTISCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PDRF SGSGSGTDF SLKIS SLQPEDFADYYCQHFWSTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:71).

37. The binding partner of any one of claims 1-4 comprising ABC0530 comprising a heavy chain comprising CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYADSVKG (SEQ ID NO:6), and CDR3 sequence WGAIITLGG (SEQ ID NO:2); and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38)

38. The binding partner of claim 37 comprising heavy and light chain sequences: VH EVQLVESGGGLVQPGGSLILSCAASGFNIKDTYIHWVRQAPGKGLEWVSMIDLANDN TKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWGAIITLGGWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGLYSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPK SCDKTHL (SEQ ID NO: 72)

VL

DIQMTQSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGQSPQLLIYNAKTLADGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:73).

39. The binding partner of any one of claims 1-4 comprising Th7 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDQANDNTKYDPKFQG (SEQ ID NO:7), CDR3 sequence WGANITLGG (SED ID NO:22), and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

40. The binding partner of claim 39 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDQAND NTKYDPKFQGRVTS S VDT STNKAYLQL S SLTSEDTAVYYC ATWGANITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSPSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDYTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 75).

41. The binding partner of any one of claims 1-4 comprising TB5 comprising a heavy chain CDR1 DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:36).

42. The binding partner of claim 41 comprising the sequence

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGHVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTTTCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 76).

43. The binding partner of any one of claims 1-4 comprising TB9 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLAIDNTKYEPKFQG (SEQ ID NO:8), CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence KAKTLAD (SEQ ID NO:34) and CDR sequence QHFWSTPFT (SEQ ID NO:38).

44. The binding partner of claim 43 comprising the sequence

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAI DNTKYEPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYKAKTLADGVPSRFSGSGSGTDYTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 77).

45. The binding partner of any one of claims 1-4 comprising TE6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4) and CDR3 sequence WGATITLGG (SEQ ID NO:21) and a light chain sequence CDR1 RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO: 38).

46. The binding partner of claim 45 comprising the sequence

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLNSLTSEDTAVYYCATWGATITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSSSGSGTVFTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 78).

47. The binding partner of any one of claims 1-4 comprising TD6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDQANDNTKYDPKFQG (SEQ ID NO: 7), and CDR3 sequence WGANITLGG (SEQ ID NO: 22) and a light sequence comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

48. The binding partner of claim 47 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDQAND NTKYDPKFQGRVTS S VDT STNKAYLQL S SLTSEDTAVYYC ATWGANITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDYTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 79)

49. The binding partner of any one of claims 1-4 comprising TG2 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 4), CDR3 sequence WGAIITLGG (SEQ ID NO: 20) and a light chain sequence CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO: 38).

50. The binding partner of claim 49 comprising the sequence GVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLAND NTKYDPKFQGHVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSLSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSSSGTDFTLTISGLQPEDFATYYCQHF WSTPFTFGGGTKLEIKR (SEQ ID NO: 80).

51. The binding partner of any one of claims 1-4 comprising TH11 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), CDR3 sequence WGAIITLGG (SEQ ID NO:20), and a light chain sequence CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

52. The binding partner of claim 51 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFQGRDTISVDTSTNKAYLQLSSLTSEDTAVYYCAAWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSLSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSSSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGGGTKLEIKR (SEQ ID N0:81).

53. The binding partner of any one of claims 1-4 comprising TA3 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), CDR3 sequence WGATITLGG (SEQ ID NO:21), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO: 38).

54. The binding partner of claim 53 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTQV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLVIKR (SEQ ID NO:82).

55. The binding partner of any one of claims 1-4 comprising TA32 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

56. The binding partner of claim 55 comprising the sequence

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLAW YQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWS TPFTFGCGTKLEIKR (SEQ ID NO: 83).

57. The binding partner of any one of claims 1-4 comprising TF6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), and CDR3 sequence WGAITTLGG (SEQ ID NO:23), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID N0:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO: 38).

58. The binding partner of claim 57 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISDDTSTNKAYLQLSSLTSEDTAVYYCATWGAITTLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPGSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEFKR (SEQ ID NO: 84).

59. The binding partner of any one of claims 1-4 comprising TD4 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), and CDR3 sequence WGAIITLGG (SEQ ID NO:20), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO: 38).

60. The binding partner of claim 59 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLEIKR (SEQ ID NO:85).

61. The binding partner of any one of claims 1-4 comprising TG6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4), and CDR3 sequence WGATITLGG (SEQ ID NO:21) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO:32) and CDR3 sequence QHFWSTPFT (SEQ ID NO: 38).

62. The binding partner of claim 61 comprising the sequence EVQLQESGGGLVKPGGSLNLICAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLAW YQQNKGKAPKLLIYNAKTLADGVPSRFRGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGRGTKLEIKR (SEQ ID NO: 86).

63. The binding partner of any one of claims 1-4 comprising KD11 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO: 9) and CDR3 sequence WGATITLGG (SEQ ID NO:21), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR3 sequence QHFLSTPFT (SEQ ID NO:39).

64. The binding partner of claim 63 comprising the sequence EVQLQESGGGLVKPGDSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKLQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSGIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTNFTLTISGLQPEDFATYYCQHFL STPFTFGCGTKLEIKR (SEQ ID NO: 87).

65. The binding partner of any one of claims 1-4 comprising KF6 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTQAD (SEQ ID NO:35), and CDR3 sequence QHFWSTPFT (SEQ ID NO: 38).

66. The binding partner of claim 65 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCAAWGAIITLGGWGQGTL VTVSSGGGGSGGGGSGGGGSGGGASDIVLTQSPSSLSASVGETVTITCRASGNIHNSL AWYQQIKGKAPKLLIYNAKTQADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHF WSTPFTFGCGTKLEIKR (SEQ ID NO 88).

67. The binding partner of any one of claims 1-4 comprising KG7 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFQG (SEQ ID NO:4) and CDR3 sequence WGAIITLGG (SEQ ID NO:20) and a light chain sequence CDR1 RASGNIHNSLA (SEQ ID NO:31), and CDR2 sequence NAKTLAD (SEQ ID

NO: 32) and a CDR3 sequence QHFWSTPFT (SEQ ID NO: 38).

68. The binding partner of claim 67 comprising the sequence GVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQCLEWIGMIDLAND NTKYDPKFQGRVTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLV TVSSGGGGSCGGGSGGSGSGGGGSDIVLTQSPSSLSASVGETVTLTCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLADGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGSKLEINR (SEQ ID NO: 89).

69. The binding partner of any one of claims 1-4 comprising KB7 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDAKFQG (SEQ ID NO: 10), and CDR3 sequence WGANITLGG (SEQ ID NO:22), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAD (SEQ ID NO 32) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

70. The binding partner of claim 69 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLAND NTKYDAKFQGRVTISVDTSTNKAYLQLSSLASEDTAVYYCATWGANITLGGWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNS LAWYQQIKGKAPKLLIYNAKTLADGVPNRFSGSGSGTDFTLTISGLQPEDFATYYCQH FWSTPFTFGCGTKLEIKR (SEQ ID NO:90).

71. The binding partner of any one of claims 1-4 comprising TA11 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDITKYDPKSQG (SEQ ID NO: 11), and CDR3 sequence WGAIITLGG (SEQ ID NO:20), and a light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAE (SEQ ID NO 36) and a CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

72. The binding partner of claim 71 comprising the sequence EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDI TKYDPKSQGRVTISADTSTNKAYLQLSSMTSEDTAVYYCAAWGAIITLGGWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGETVTITCRASGNIHNSLA WYQQIKGKAPKLLIYNAKTLAEGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFW STPFTFGCGTKLEIKR (SEQ ID NO:91).

73. The binding partner of any one of claims 1-4 comprising TG11 comprising a heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDNTKYDPKFLG (SEQ ID NO: 12) and CDR3 sequence WGAIITLGG (SEQ ID NO:20), and a heavy chain comprising CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLSD (SEQ ID NO:37) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

74. The binding partner of claim 73 comprising the sequence

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQSLEWIGMIDLANDN TKYDPKFLGRFTISVDTSTNKAYLQLSSLTSEDTAVYYCATWGAIITLGGWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPSSLSASVGEAVTITCRASGNIHNSLAW YQQIKGKAPKLLIYNAKTLSDGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQHFWS TPFTFGCGTKLEIKR (SEQ ID NO:92).

75. The binding partner of any one of claims 1-4 comprising VD4 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence AIAASGERTYYADSVKG (SEQ ID NO: 13) and CDR3 sequence SWYYYDSSGYYGFDY (SEQ ID NO:24).

76. The binding partner of claim 75 comprising the sequence

QVQLVQSGGGLVQPGGSLRLSCAASAFDFDDYEMSWVRQAPGQRLEWVSAIAASGE RTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARSWYYYDSSGYYGFD YWGQGTLVTVSS (SEQ ID NO:93).

77. The binding partner of any one of claims 1-4 comprising VF5 comprising CDR1 sequence YYEMS (SEQ ID NO:3), CDR2 sequence AISGSGDSTYYADSVKG (SEQ ID NO: 14) and CDR3 VSSGWYMDY (SEQ ID NO:25).

78. The binding partner of claim 77 comprising the sequence

QVQLVQSGGGLVQPGGSLRLSCAASDFYFAYYEMSWVRQAPGQGLEWVSAISGSGD STYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARVSSGWYMDYWGQG TLVTVSS (SEQ ID NO:94).

79. The binding partner of any one of claims 1-4 comprising VF8 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence AISGSGGSTYYADSVKG (SEQ ID NO: 15) and CDR3 sequence PTMSRDYFDY (SEQ ID NO:26).

80. The binding partner of claim 79 comprising the sequence

QVQLVQSGGGLVQPGGSLRLSCAASDFDFADYEMSWVRQAPGQGLEWVSAISGSGG STYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARPTMSRDYFDYWGQG TLVTVSS (SEQ ID NO:95).

81. The binding partner of any one of claims 1-4 comprising VF10 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence SISGSGDITHYADSVKG (SEQ ID NO: 16) and CDR3 sequence VASGWWVDY (SEQ ID NO: 27).

82. The binding partner of claim 81 comprising the sequence

QVQLVQSGGGLVQPGGSLRLSCAASAFDFDDYEMSWVRQAPGQRLEWVSSISGSGD ITHYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAMYYCGRVASGWWVDYWGQG TLVTVSS (SEQ ID NO:96).

83. The binding partner of any one of claims 1-4 comprising VG4 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence SISGSAGSTYYADSVKG (SEQ ID NO: 17) and CDR3 sequence APGGGYQYDLYHYYAMDV (SEQ ID NO:28).

84. The binding partner of claim 83 comprising the sequence

QVQLVQSGGGLVQPGGSLRLSCAASDFDFADYEMSWVRQAPGQRLEWVSSISGSAG STYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARAPGGGYQYDLYHYY AMDVWGQGTTVTVSS (SEQ ID NO:97).

85. The binding partner of any one of claims 1-4 comprising BMBG2 comprising CDR1 sequence YYEMS (SEQ ID NO:3), CDR2 sequence VISYDGSNKYYADSVKG (SEQ ID NO: 18) and CDR3 sequence LPRYGSGSYWSLG (SEQ ID NO:29).

86. The binding partner of claim 85 comprising the sequence

QVQLVQSGGGLVQPGGSLRLSCAASSFYFDYYEMSWVRQAPGKGLEWVAVISYDGS NKYYADSVKGRFTISRDNTKNTLYLQMNTLRAEDTATYYCAGLPRYGSGSYWSLGW GQGTLVTVSSS (SEQ ID NO:98).

87. The binding partner of any one of claims 1-4 comprising BMBC2 comprising CDR1 sequence DYEMS (SEQ ID NO:2), CDR2 sequence GISSSGDTTHYADSVKG (SEQ ID NO 19) and CDR3 sequence HPLSGRHYFDY (SEQ ID NO:30).

88. The binding partner of claim 87 comprising the sequence QVQLVQSGGGLVQPGGSLRLSCAASYFSFSDYEMSWVRQAPGQRLEWVSGISSSGDT THYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTATYYCGRHPLSGRHYFDYWGQG TLVTVSSS (SEQ ID NO:99).

89. The binding partner of any one of claims 1-4 comprising ABC0550-ABP comprising heavy chain CDR1 sequence DTYIH (SEQ ID NO: 1), CDR2 sequence

MIDLAND STKYDPKFQ (SEQ ID NO:8) and CDR3 sequence WGATITLGG (SEQ ID NO:21) and light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31), CDR2 sequence NAKTLAS (SEQ ID NO:33) and CDR3 sequence QHFWSTPFT (SEQ ID NO:36).

90. The binding partner of claim 89 comprising heavy and light chain sequences

VL

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLASGVP SRFSGSGSGTDYTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP P SDEQLKSGTAS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD STYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 100) VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLANDS TKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHLGGGS RLIEDICLPRWGCLWEDD (SEQ ID NO: 101).

91. The binding partner of any one of claims 1-4 comprising ABC0549 comprising heavy chain CDR1 sequence DTYIH (SEQ ID NO:1), CDR2 sequence MIDLANDSTKYDPKFQG (SEQ ID NO:8) and CDR3 sequence WGATITLGG (SEQ ID NO:21) and light chain CDR1 sequence RASGNIHNSLA (SEQ ID NO:31) and CDR3 sequence QHFWSTPFT (SEQ ID NO:38).

92. The binding partner of claim 91 comprising heavy and light chain sequences VI.

DIVLTQSPSSLSASVGETVTITCRASGNIHNSLAWYQQIKGKAPKLLIYNAKTLASGVP SRFSGSGSGTDYTLTISGLQPEDFATYYCQHFWSTPFTFGQGTKLEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO : 102)

VH

EVQLQESGGGLVKPGGSLKLSCAASGFNIKDTYIHWVRQRPGQGLEWIGMIDLANDS TKYDPKFQGRVTISADTSTNKAYLQLSSLTSEDTAVYYCATWGATITLGGWGQGTLVT VS S ASTKGPS VFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL (SEQ ID NO: 103).

93. A method comprising administering a binding partner of any one of claims 1-4 to an individual who has received an antibody-drug conjugate (ADC) to thereby reduce non-target toxicity of the ADC.

94. The method of claim 93, wherein the binding partner comprises a) a heavy chain CDR1 that is DTYIH (SEQ ID NO: 1); DYEMS (SEQ ID NO:2); or YYEMS (SEQ ID NO:3); b) a heavy chain CDR2 that is MIDLANDNTKYDPKFQG (SEQ ID NO:4); MIDLANDNTKYSQKFQG (SEQ ID NO:5); MIDLANDNTKYADSVKG (SEQ ID NO:6); MIDQANDNTKYDPKFQG (SEQ ID NO:7); MIDLAIDNTKYEPKFQG (SEQ ID NO:8); MIDLANDNTKYDPKLQG (SEQ ID NO: 9); MIDLANDNTKYDAKFQG (SEQ ID

NO: 10); MIDLANDITKYDPKSQG (SEQ ID NO:11); MIDLANDNTKYDPKFLG (SEQ ID NO: 12); AIAASGERTYYADSVKG (SEQ ID NO: 13); AISGSGDSTYYADSVKG (SEQ ID NO: 14): AISGSGGSTYYADSVKG (SEQ ID NO: 15); SISGSGDITHYADSVKG (SEQ ID NO: 16);SISGSAGSTYYADSVKG (SEQ ID NO: 17); VISYDGSNKYYADSVKG (SEQ ID NO: 18) or GISSSGDTTHYADSVKG (SEQ ID NO: 19); and c) a heavy chain CDR3 that is WGAIITLGG (SEQ ID NQ:20); WGATITLGG (SEQ ID NO 21); WGANITLGG (SEQ ID NO:22); WGAITTLGG (SEQ ID NO:23); SWYYYDSSGYYGFDY SEQ ID NO:24); VSSGWYMDY (SEQ ID NO 25); PTMSRDYFDY (SED ID NO:26); VASGWWVDY (SEQ ID NO:27); APGGGYQYDLYHYYAMDV (SEQ ID NO:28); LPRYGSGSYWSLG (SEQ ID NO:29); or HPLSGRHYFDY (SEQ ID NO:30).

95. The method of claim 94, wherein the binding partner comprises i) a light chain CDR1 that is RASGNIHNSLA (SEQ ID NO: 31); ii) a light chain CDR2 that is NAKTLAD (SEQ ID NO:32); NAKTLAS (SEQ ID NO 33); KAKTLAD (SEQ ID NO:34); NAKTQAD (SEQ ID NO:35); NAKTLAE (SEQ ID NO 36); or NAKTLSD (SEQ ID NO:37); and iii) a light chain CDR3 that is QHFWSTPFT (SEQ ID NO:38) or QHFLSTPFT (SEQ ID NO 39).

96. A binding partner comprising a) a heavy chain CDR1 that is DTYIH (SEQ ID NO:1); DYEMS (SEQ ID NO:2); or YYEMS (SEQ ID NO:3); or b) a heavy chain CDR2 that is MIDLANDNTKYDPKFQG (SEQ ID NO:4); MIDLANDNTKYSQKFQG (SEQ ID NO:5); MIDLANDNTKYADSVKG (SEQ ID NO:6); MIDQANDNTKYDPKFQG (SEQ ID NO:7); MIDLAIDNTKYEPKFQG (SEQ ID NO:8); MIDLANDNTKYDPKLQG (SEQ ID NO: 9); MIDLANDNTKYDAKFQG (SEQ ID

NO: 10); MIDLANDITKYDPKSQG (SEQ ID NO: 11); MIDLANDNTKYDPKFLG (SEQ ID NO: 12); AIAASGERTYYADSVKG (SEQ ID NO: 13); AISGSGDSTYYADSVKG (SEQ ID NO: 14): AISGSGGSTYYADSVKG (SEQ ID NO: 15); SISGSGDITHYADSVKG (SEQ ID NO: 16);SISGSAGSTYYADSVKG (SEQ ID NO: 17); VISYDGSNKYYADSVKG (SEQ ID NO: 18) or GISSSGDTTHYADSVKG (SEQ ID NO: 19); or c) a heavy chain CDR3 that is WGAIITLGG (SEQ ID NO:20); WGATITLGG (SEQ ID NO:21); WGANITLGG (SEQ ID NO:22); WGAITTLGG (SEQ ID NO:23); SWYYYDSSGYYGFDY SEQ ID NO:24); VSSGWYMDY (SEQ ID NO:25); PTMSRDYFDY (SED ID NO:26); VASGWWVDY (SEQ ID NO:27);

APGGGYQYDLYHYYAMDV (SEQ ID NO:28); LPRYGSGSYWSLG (SEQ ID NO:29); or HPLSGRHYFDY (SEQ ID NO:30).

97. The binding partner of claim 97, wherein the binding partner comprises i) a light chain CDR1 that is RASGNIHNSLA (SEQ ID NO:31); ii) a light chain CDR2 that is NAKTLAD (SEQ ID NO:32); NAKTLAS (SEQ ID NO:33); KAKTLAD (SEQ ID NO:34); NAKTQAD (SEQ ID NO:35); NAKTLAE (SEQ ID NO:36); or NAKTLSD (SEQ ID NO:37); or iii) a light chain CDR3 that is QHFWSTPFT (SEQ ID NO:38) or QHFLSTPFT (SEQ ID NO:39).

98. A polynucleotide that encodes a binding partner of any one of claims 1-91.

99. A polynucleotide that hybridizes to the polynucleotide of claim 98.