Anti-WNT2 antibodies and antibody-drug conjugates

Description

UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO ANTI-WNT2 ANTIBODIES AND ANTIBODY-DRUG CONJUGATES CROSSREFERENCE TORELATEDAPPLICATIONS

[0001] Pursuant to 35 U.S.C. § 119(e), this application claims priority to the filing date of United States Provisional Patent Application Serial No. 63 / 668,694 filed July 8, 2024, the disclosure of which is herein incorporated by reference in its entirety. INTRODUCTION

[0002] Despite recent advances in the understanding of Wnt2 signaling, the ability of an antibody or an antibody-drug conjugate (ADC) to bind Wnt2 and to treat Wnt2-associated diseases is unclear. Thus, the prior art fails to provide clear evidence that antibodies or ADCs that target Wnt2 could be useful for example, for the treatment of cancer. The present invention addresses these and other needs. SUMMARY

[0003] The present disclosure provides antibodies and / or antibody conjugates (e.g., antibody- drug conjugates (ADCs)) specific for Wnt2. The disclosure also encompasses methods of production of such conjugates, as well as methods of using the same. Embodiments of each are described in more detail in the sections below. Also provided are compositions that include the antibody and / or ADC of the present disclosure, including in some instances, pharmaceutical compositions. In certain aspects, provided are methods of using the antibodies and / or ADC that include administering to an individual having a cell proliferative disorder a therapeutically effective amount of the antibody and / or ADC of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0004] FIG 1A shows the tumor volume results in mice when a CaCo2 xenografted tumor is not treated, treated with 10 mg / kg of G7-MMAE, or treated with 10 mg / kg of Lib11-MMAE.

[0005] FIG 1B shows the mice body weight results when a CaCo2 xenografted tumor is not treated, treated with 10 mg / kg of G7-MMAE, or treated with 10 mg / kg of Lib11-MMAE.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0006] FIG 2A shows the tumor volume results in mice when a CaCo2+CAF115 xenografted tumor is not treated, treated with 10 mg / kg of G7-MMAE, or treated with 10 mg / kg of Lib11- MMAE.

[0007] FIG 2B shows the mice body weight results when a CaCo2+CAF115 xenografted tumor is not treated, treated with 10 mg / kg of G7-MMAE, or treated with 10 mg / kg of Lib11-MMAE.

[0008] FIG 3A shows the tumor volume results in mice when an A549 xenografted tumor is not treated or treated with 10 mg / kg of Lib11-MMAE.

[0009] FIG 3B shows the mice body weight results when an A549 xenografted tumor is not treated or treated with 10 mg / kg of Lib11-MMAE.

[0010] FIG 4A shows the tumor volume results in mice when an A549+CAF117 xenografted tumor is not treated or treated with 10 mg / kg of Lib11-MMAE.

[0011] FIG 4B shows the mice body weight results when an A549+CF117 xenografted tumor is not treated or treated with 10 mg / kg of Lib11-MMAE.

[0012] FIG 5A shows the tumor volume results in mice when a 211H xenografted tumor is not treated or treated with 10 mg / kg of Lib11-MMAE.

[0013] FIG 5B shows the mice body weight results when a 211H xenografted tumor is not treated or treated with 10 mg / kg of Lib11-MMAE.

[0014] FIG 6A shows the tumor volume results in mice when a 211H+CAF117 xenografted tumor is not treated or treated with 10 mg / kg of Lib11-MMAE.

[0015] FIG 6B shows the mice body weight results when a 211H+CAF117 xenografted tumor is not treated or treated with 10 mg / kg of Lib11-MMAE.

[0016] FIG 7 shows Wnt2 relative expression in small cell lung cancer (SCLC) tumors.

[0017] FIG 8A shows cell viability versus ADC concentration in Wnt2-negative cell line C57mg after 3 days of treatment where the ADCs are DNP-MMAE, Lib11-MMAE, Lib3-MMAE, Lib5- MMAE, and Lib6-MMAE.

[0018] FIG 8B shows cell viability versus ADC concentration in Wnt2-negative cell line C57mg after 6 days of treatment where the ADCs are DNP-MMAE, Lib11-MMAE, Lib3-MMAE, Lib5- MMAE, and Lib6-MMAE.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0019] FIG 8C shows cell viability versus ADC concentration in Wnt2-positive cell line C57Wnt2 after 3 days of treatment where the ADCs are DNP-MMAE, Lib11-MMAE, Lib3- MMAE, Lib5-MMAE, and Lib6-MMAE.

[0020] FIG 8D shows cell viability versus ADC concentration in Wnt2-positive cell line C57Wnt2 after 6 days of treatment where the ADCs are DNP-MMAE, Lib11-MMAE, Lib3- MMAE, Lib5-MMAE, and Lib6-MMAE.

[0021] FIG 8E shows cell viability versus ADC concentration in a 211H cell line after 3 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, Lib9- MMAE, and Lib11-MMAE.

[0022] FIG 8F shows cell viability versus ADC concentration in a 211H cell line after 5 days of treatment where the ADCs are IgG-MMAE, DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6- MMAE, Lib7-MMAE, Lib9-MMAE, and Lib11-MMAE.

[0023] FIG 8G shows cell viability versus ADC concentration in a H2052 cell line after 3 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, Lib9-MMAE, and Lib11-MMAE.

[0024] FIG 8H shows cell viability versus ADC concentration in a H116 cell line after 3 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, Lib9- MMAE, and Lib11-MMAE.

[0025] FIG 8I shows cell viability versus ADC concentration in an A549 cell line after 3 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0026] FIG 8J shows cell viability versus ADC concentration in an A549 cell line after 6 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0027] FIG 8K shows cell viability versus ADC concentration in a Panc1 cell line after 5 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0028] FIG 8L shows cell viability versus ADC concentration in a Panc1 cell line after 7 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0029] FIG 8M shows cell viability versus ADC concentration in a Capan1 cell line after 5 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0030] FIG 8N shows cell viability versus ADC concentration in a Capan1 cell line after 7 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0031] FIG 8O shows cell viability versus ADC concentration in an ASPC1 cell line after 5 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0032] FIG 8P shows cell viability versus ADC concentration in an ASPC1 cell line after 7 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0033] FIG 8Q shows cell viability versus ADC concentration in a CFPAC1 cell line after 5 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0034] FIG 8R shows cell viability versus ADC concentration in a CFPAC1 cell line after 7 days of treatment where the ADCs are DNP-MMAE, Lib3-MMAE, Lib5-MMAE, Lib6-MMAE, and Lib11-MMAE.

[0035] FIG 9A shows the tumor volume results in mice when a 211H xenografted tumor is not treated or treated with 10 mg / kg of Lib3-MMAE.

[0036] FIG 9B shows the mice body weight results when a 211H xenografted tumor is not treated or treated with 10 mg / kg of Lib3-MMAE.

[0037] FIG 9C shows the tumor volume results in mice when a 211H xenografted tumor is not treated or treated with 10 mg / kg of Lib5-MMAE.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0038] FIG 9D shows the mice body weight results when a 211H xenografted tumor is not treated or treated with 10 mg / kg of Lib5-MMAE.

[0039] FIG 9E shows the tumor volume results in mice when a 211H xenografted tumor is not treated or treated with 10 mg / kg of Lib6-MMAE.

[0040] FIG 9F shows the mice body weight results when a 211H xenografted tumor is not treated or treated with 10 mg / kg of Lib6-MMAE. DEFINITIONS

[0041] The chemical names provided for the intermediate compounds and / or the compounds of this disclosure described herein may refer to any one of the tautomeric representations of such compounds (in some instances, such alternate names are provided with the experimental). It is to be understood that any reference to a named compound (an intermediate compound or a compound of the disclosure) or a structurally depicted compound (an intermediate compound or a compound of the disclosure) is intended to encompass all tautomeric forms including zwitterionic forms of such compounds and any mixture thereof.

[0042] It is to be understood that the terms "In some embodiments", "In some embodiments of the present disclosure", and "In some embodiments of a compound of the present disclosure" may be used interchangeably where appropriate.

[0043] The term "about", "approximately", or "approximate", when used in connection with a numerical value, means that a collection or range of values is included. In some embodiments, "about X" includes a range of values that are ±25%, ±20%, ±15%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.l% of X, where X is a numerical value. In some embodiments, the term "about' refers to a range of values which are 5% more or less than the specified value. In some embodiments, the term "about" refers to a range of values which are 2'% more or less than the specified value. In some embodiments, the term "about" refers to a range of values which are 1% more or less than the specified value.

[0044] Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. A range used herein, unless otherwise specified, includes the two limits of theUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO range. In some embodiments, the expressions "x being an integer between 1 and 6" and "x being an integer of 1 to 6" both mean "x being 1, 2, 3, 4, 5, or 6", i.e., the terms "between X and Y" and "range from X to Y, are inclusive of X and Y and the integers there between.

[0045] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0046] The term "antibody" as used herein, is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity. Various methods are known in the art for numbering the amino acids sequences of antibodies and identification of the complementary determining regions. For example, the Kabat numbering system (See Kabat, E.A., et al., Sequences of Protein of immunological interest, Fifth Edition, US Department of Health and Human Services, US Government Printing Office (1991)) or the IMGT numbering system (See IMGT, the international ImMunoGeneTics information system. Available online: http: / / www.imgt.org / ). The IMGT numbering system is routinely used and accepted as a reliable and accurate system in the art to determine amino acid positions in coding sequences, alignment of alleles, and to easily compare sequences in immunoglobulin (IG) and T-cell receptor (TR) from all vertebrate species. The accuracy and the consistency of the IMGT data are based on IMGT-ONTOLOGY, the first, and so far unique, ontology for immunogenetics and immunoinformatics (See Lefranc. M.P. et al., Biomolecules, 2014 Dec; 4(4), 1102-1139). IMGT tools and databases run against IMGT reference directories built from a large repository of sequences. In the IMGT system the IG V-DOMAIN and IG C-DOMAIN are delimited taking into account the exon delimitation, whenever appropriate. Therefore, the availability of more sequences to the IMGT database, the IMGT exon numbering system can be and "is used" by those skilled in the art reliably to determine amino acid positions in coding sequences and for alignment of alleles. Additionally, correspondences between the IMGT unique numbering with other numberings (i.e., Kabat) are available in the IMGT Scientific chart (See Lefranc. M.P. et al., Biomolecules, 2014 Dec; 4(4), 1102-1139).

[0047] The term "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and that binds the antigen to which the intact antibodyUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments.

[0048] The term "antibody that binds to the same epitope" as a reference antibody as used herein, refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50%) or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more. An exemplary competition assay is provided herein.

[0049] The term "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called α, β, ε, γ, and μ, respectively.

[0050] The term "monoclonal antibody" as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0051] The term "native antibodies" refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chams that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from - to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light cham of an antibody may be assigned to one of two types, called kappa (K) and lambda (λ), based on the amino acid sequence of its constant domain.

[0052] An "isolated antibody" is one which has been separated from a component of its natural environment. In some embodiments, an antibody is purified to greater than 95%) or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0053] The term "epitope" refers to the particular site on an antigen molecule to which an antibody binds.

[0054] “Fv” is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRS of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0055] The “Fab” fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments differ from Fab’ fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH1domain including one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab’)2 antibodyUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0056] The “light chains” of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

[0057] “Single-chain Fv” or “sFv” antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain. In some aspects, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the sFv to form the desired structure for antigen binding.

[0058] The term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.

[0059] As used herein, the term “affinity” refers to the equilibrium constant for the reversible binding of two agents and is expressed as a dissociation constant (Kd). Affinity can be at least 1- fold greater, at least 2-fold greater, at least 3-fold greater, at least 4-fold greater, at least 5-fold greater, at least 6-fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, at least 10-fold greater, at least 20-fold greater, at least 30-fold greater, at least 40-fold greater, at least 50-fold greater, at least 60-fold greater, at least 70-fold greater, at least 80-fold greater, at least 90-fold greater, at least 100-fold greater, or at least 1000-fold greater, or more, than the affinity of an antibody for unrelated amino acid sequences. Affinity of an antibody to a target protein can be, for example, from about 100 nanomolar (nM) to about 0.1 nM, from about 100 nM to about 1 picomolar (pM), or from about 100 nM to about 1 femtomolar (fM) or more. As used herein, the term “avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution. The terms “immunoreactive” and “preferentially binds” are used interchangeably herein with respect to antibodies and / or antigen-binding fragments.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0060] The term “binding” refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and / or hydrogen-bond interactions, including interactions such as salt bridges and water bridges.

[0061] As used herein, the term “CDR” or “complementarity determining region” is intended to mean the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. CDRs have been described by Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat et al., U.S. Dept. of Health and Human Services, “Sequences of proteins of immunological interest” (1991); by Chothia et al., J. Mol. Biol. 196:901-917 (1987); and MacCallum et al., J. Mol. Biol. 262:732-745 (1996), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or grafted antibodies or variants thereof is intended to be within the scope of the term as defined and used herein. The amino acid residues which encompass the CDRs as defined by each of the above cited references are set forth below in Table 1 as a comparison. Table 1: CDR Definitions Kabat1Chothia2MacCallum3V CDR1 31 35 26 32 30352 Residue numbering follows the nomenclature of Chothia et al., supra 3 Residue numbering follows the nomenclature of MacCallum et al., supra

[0062] The term "humanized antibody" of an antibody refers to an antibody that is derived from a non-human antibody (e.g., murine) that retains or substantially retains the antigen-binding properties of the parent antibody but is less immunogenic in humans. Humanized as used herein is intended to include deimmunized antibodies.

[0063] The term "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0064] The term "competes with" or "cross-competes with" when used herein in the context of two or more antibodies, indicates that the two or more antibodies compete for binding to Wnt2, e.g., compete for Wnt2 binding. An antibody "blocks" or "cross-blocks" one or more other antibodies from binding to Wnt2 if the antibody competes with the one or more other antibodies 25% or more, with 25%-74% representing "partial block" and 75%-400% representing "full block". Unless otherwise defined or negated by context, the terms "competes with", "cross competes with", "blocks" or "cross-blocks" when used herein is also intended to cover such pairs of antibodies.

[0065] As used herein, an antibody that "specifically binds to human Wnt2" is intended to refer to an antibody that binds to human Wnt2 with a KDof l x 10-7M or less, more typically 5 x 10-8M or less, more typically 3 x 10-8M or less, more typically l x 10-9M or less, even more typically 5 x 10-9M or less.

[0066] The term "does not substantially bind" to a protein or cells, as used herein, means does not bind or does not bind with a high affinity to the protein or cells, 1.e. binds to the protein or cells with a KD of l x 10-8M or more, more preferably 1 x 10-5M or more, more preferably 1 x 10-4M or more, more preferably 1 x 10-3M or more, even more preferably 1 x 10-2M or more.

[0067] As used herein, the terms "anti-Wnt2 antibody", "Wnt2 antibody" and "an antibody that binds to Wnt2" refer to an antibody that is capable of binding Wnt2 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting Wnt2.

[0068] The term "Wnt2," as used herein, refers to any native, mature Wnt2 which results from processing of a Wnt2 precursor protein in a cell. The term includes Wnt2 from any vertebrate source, including mammals such as primates (e.g. humans and cynomolgus monkeys) and rodents (e.g., mice and rats), unless otherwise indicated. The term also includes naturally occurring variants of Wnt2, e.g., splice variants or allelic variants.

[0069] The term "Wnt2-positive cancer" refers to a cancer comprising cells that express Wnt2 in the cell and / or on their surface. In some embodiments, expression of Wnt2 in the cell and / or on the cell surface is determined, for example, using antibodies to Wnt2 in a method such as immunohistochemistry, FACS, etc.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0070] Alternatively, Wnt2 mRNA expression is considered to correlate to Wnt2 expression on the cell surface and can be determined by a method selected from in situ hybridization and RTPCR (including quantitative RT-PCR).

[0071] The term "Wnt2-positive cell" refers to a cell that expresses Wnt2 in the cell and / or on its surface.

[0072] A “therapeutically effective amount” or “efficacious amount” refers to the amount of a subject anti-Wnt2 Ab that, when administered to a mammal or other subject for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the anti-Wnt2 Ab, the disease and its severity and the age, weight, etc., of the subject to be treated.

[0073] The terms "Wnt protein" or "Wnt ligand" refer to a family of mammalian proteins related to the Drosophila segment polarity gene, wingless. In humans, the Wnt family of genes typically encode 38 to 43 kDa cysteine rich glycoproteins having hydrophobic signal sequence, and a conserved asparagine-linked oligosaccharide consensus sequence (Shimizu et al., Cell Growth Differ 8(12):1349-58 (1997)). The Wnt family contains at least 19 mammalian members. Exemplary Wnt proteins include Wnt1, Wnt2, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt10A, Wnt10B, Wntl1, Wnt12, Wnt13, Wnt14, Wnt15, and Wnt16. A preferred Wnt protein of the invention is Wnt2, preferably a human Wnt2 protein.

[0074] The terms "frizzled protein" or "frizzled receptor" refer to a family of mammalian proteins related to the Drosophila frizzled genes, which play a role in the development of tissue polarity. The Frizzled family comprises at least 10 mammalian genes. Exemplary human Frizzled receptors include Frizzled1, Frizzled2, Frizzled3, Frizzled4, Frizzled5, Frizzled6, Frizzled7, Frizzled8, Frizzled9 and Frizzled10. The mammalian homologues of the Drosophila frizzled protein share a number of common structural motifs. The N-terminus located at the extracellular membrane surface is followed by a signal sequence, a domain of 120 amino acids with an invariant pattern of 10 cysteine residues, and a highly divergent region of 40-100 largely variable hydrophilic amino acids. Putative hydrophobic segments form seven membrane- spanning helices linked by hydrophilic loops, ending with the C terminus located at the intracellular face of the membrane. The cysteine-rich domains (CRDs) and the transmembrane segments are strongly conserved, suggesting a working model in which an extracellular CRD isUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO tethered by a variable linker region to a bundle of seven membrane-spanning helices. Frizzled protein receptors are, therefore, involved in a dynamic model of transmembrane signal transduction analogous to G-protein-coupled receptors with amino-terminal ligand binding domains. For example, Frizzled1, Frizzled2, and Frizzled7 are involved in lung and colorectal cancers, (Sagara et al., Biochem Biophys Res Commun 252(1):117-22 (1998)); Frizzled3 in human cancer cells including lung, cervical and colorectal cancers, (Kirikoshi et al., Int J Oncol 19(4):767-71 (2001)); Frizzled7 in gastric cancer (Kirikoshi et al., Int J Oncol 19(4):767-71 (2001)); Frizzled10 in gastric and colorectal cancer, Kirikoshi et al., Int J Oncol 19(4):767-71 (2001); Terasaki et al., Int J Mol. Med 9(2):107-12 (2002).

[0075] The terms "Dishevelled" or "Dvl" refer to a member of a family of Dishevelled proteins, the full-length sequences of which typically possess three conserved domains, a DIX domain, present in the Wnt antagonizing protein Axin; a PDZ domain involved in protein-protein interactions, and a DEP domain found in proteins that regulate Rho GTPases. Dvl proteins include, for example, Dvl-1, Dvl-2, and Dvl-3. Nucleic acid and protein Dvl sequence are known from a variety of species, including mouse and human. Exemplary human Dvl-1, Dvl-2, and Dvl- 3 protein sequences are available under reference sequences NP _004412, NP 004413, and NM_004414, respectively.

[0076] ''Inhibitors" of Wnt signaling and in particular Wnt2 signaling refers to compounds or agents that, e.g., bind to Wnt or Frizzled proteins, or partially or totally block Wnt signaling as measured in known assays for Wnt signaling ( e.g., measurement of β-catenin levels, or oncogene expression controlled by Tcf and Lef transcription factors). Inhibitors, include modified versions of Wnt or Frizzled proteins, as well as naturally occurring and synthetic ligands, antagonists, agonists, antibodies, small chemical molecules, and the like. Assays for detecting inhibitors of the invention are described in more detail below.

[0077] The phrases "cell that overexpresses Wnt2 protein," "cell that overexpresses Wnt2 mRNA," "cancer cell that overexpresses Wnt2 protein" or "cancer cell that overexpresses Wnt2 mRNA" or grammatical equivalents thereof refer to a cell or cancer cell in which expression of a Wnt2 protein or Wnt2 mRNA is at least about 2 times, usually at least about 5 times the level of expression in a normal cell from the same tissue. Methods for determining the level ofUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO expression of a particular gene are well known in the art. Such methods include RT-PCR, use of antibodies against the gene products, and the like.

[0078] "Biological sample" as used herein is a sample of biological tissue or fluid that contains nucleic acids or polypeptides, e.g., of a Wnt protein, polynucleotide or transcript. Such samples include, but are not limited to, tissue isolated from primates, e.g., humans, or rodents, e.g., mice, and rats. Biological samples may also include sections of tissues such as biopsy and autopsy samples, frozen sections taken for histologic purposes, blood, plasma, serum, sputum, stool, tears, mucus, hair, skin, etc. Biological samples also include explants and primary and / or transformed cell cultures derived from patient tissues. A biological sample is typically obtained from a eukaryotic organism, most preferably a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish.

[0079] "Providing a biological sample" means to obtain a biological sample for use in methods described in this invention. Most often, this will be done by removing a sample of cells from an animal, preferably a human, but can also be accomplished by using previously isolated cells (e.g., isolated by another person, at another time, and / or for another purpose), or by performing the methods of the invention in vivo. Archival tissues, having treatment or outcome history, will be particularly useful.

[0080] The "level of Wnt2 mRNA" in a biological sample refers to the amount of mRNA transcribed from a Wnt2 gene that is present in a cell or a biological sample. The mRNA generally encodes a functional Wnt2 protein, although mutations may be present that alter or eliminate the function of the encoded protein. A "level of Wnt2 mRNA" need not be quantified, but can simply be detected, e.g., a subjective, visual detection by a human, with or without comparison to a level from a control sample or a level expected of a control sample.

[0081] The "level of Wnt2 protein or polypeptide" in a biological sample refers to the amount of polypeptide translated from Wnt2 mRNA that is present in a cell or biological sample. The polypeptide may or may not have Wnt2 protein function. A "level of Wnt2 protein" need not be quantified, but can simply be detected, e.g., a subjective, visual detection by a human, with or without comparison to a level from a control sample or a level expected of a control sample.

[0082] The term "cytotoxic agents" or "cytotoxic drug moiety" refer to compounds which cause cell death primarily by interfering directly with the cell's functioning or inhibit or interfere withUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO cell myosis, including, but not limited to, alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.

[0083] The term "sugar" refers to a monosaccharide, for example glucose (Glc), galactose (Gal), mannose (Man) and fucose (Fuc). The term "sugar derivative" refers to a derivative of a monosaccharide sugar, i.e. a monosaccharide sugar comprising substituents and / or functional groups. Examples of a sugar derivative include, but are not limited to, amino sugars and sugar acids. Examples of a sugar derivative also include compounds denoted as S'(F')x1, wherein S' is a sugar or a sugar derivative, F' is a functional group and xi indicates the number of functional groups.

[0084] The term "nucleotide" is used in its normal scientific meaning and refers to a molecule that is composed of a nucleobase, a five-carbon sugar ( either ribose or 2-deoxyribose ), and one, two or three phosphate groups. Without the phosphate group, the nucleobase and sugar compose a nucleoside. A nucleotide can thus also be referred to as a nucleoside monophosphate, a nucleoside diphosphate or a nucleoside triphosphate. The nucleobase may be adenine, guanine, cytosine, uracil or thymine.

[0085] The term "protein" is used in its normal scientific meaning and includes polypeptides comprising about 10 or more amino acids. A protein may comprise natural or unnatural amino acids.

[0123] A nucleic acid or peptide (e.g. antibody) has a certain percent "sequence identity" to another nucleic acid or peptide (e.g. antibody), meaning that, when aligned, that percentage of bases or amino acids are the same, and in the same relative position, when comparing the two sequences. Sequence identity can be determined in a number of different manners. To determine sequence identity, sequences can be aligned using various methods and computer programs (e.g., BLAST, T-COFFEE, MUSCLE, MAFFT, etc.), available over the world wide web at sites including ncbi.nlm.nili.gov / BLAST, ebi.ac.uk / Tools / msa / tcoffee / ebi.ac.uk / Tools / msa / muscle / mafft.cbrc.jp / alignment / software / . See, e.g., Altschul et al. (1990), J. Mol. Biol. 215:403-10.

[0138] The disclosure provides for antibodies with an amino acid sequence described herein, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid resides from an amino acid sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, atUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with an amino acid sequence described herein.

[0086] The term "alkyl", as used herein, represents a saturated, straight or branched hydrocarbon group having the specified number of carbon atoms. The term "C1-C6alkyl" or "C1-6alkyl" refers to a methyl moiety or a straight or branched alkyl moiety comprising from 2 to 6 carbon atoms.

[0087] Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, s-butyl, t-butyl, pentyl and hexyl.

[0088] The term "halo(alkyl)", as used herein, represents a saturated, straight or branched hydrocarbon group having the specified number (n) of carbon atoms and one or more (up to 2n+1) halogen atoms. Examples of "halo(C1-4 alkyl)" groups include, but are not limited to, - CF, (trifluoromethyl), -CCl3 (trichloromethyl), 1,1- difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.

[0089] The term "alkenyl", as used herein, refers to straight or branched hydrocarbon group having the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon double bonds. Examples include ethenyl and propenyl.

[0090] The term "alkynyl", as used herein, refers to straight or branched hydrocarbon group having the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon triple bonds. Examples include ethynyl and propynyl.

[0091] The term "alkoxy-" or "(alkyl)oxy-", as used herein, refers to an "alkyl-oxy-" group, comprising an alkyl moiety, having the specified number of carbon atoms, attached through an oxygen linking atom. Exemplary "C1-4 alkoxy-" or "(C1-4 alkyl)oxy-" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy.

[0092] The term "halo(alkoxy)-", as used herein, represents a saturated, straight or branched hydrocarbon group having the specified number (n) of carbon atoms and one or more (up to 2n+l) halogen atoms, attached through an oxygen linking atom. Exemplary "halo(C1-4 alkoxy)-" groups include, but are not limited to, -OCHF2(difluoromethoxy), -OCF3(trifluoromethoxy), - OCH2CF3 (trifluoroethoxy), and -OCH(CF2)2 (hexafluoroisopropoxy).UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0093] The term "amino" as used herein refers to a substituent comprising at least one nitrogen atom. Specifically, -NH2, -NH(C1-4 alkyl), alkylamino, or (C1-4 alkyl)amino- or (C1-4 alkyl)(C1-4 alkyl)amino- or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents are included in the term "amino".

[0094] The term "carbocyclic group or moiety" as used herein, refers to a cyclic group or moiety in which the ring members are carbon atoms, which may be saturated, partially unsaturated (nonaromatic) or fully unsaturated (aromatic).

[0095] The term "cycloalkyl", as used herein, refers to a non-aromatic, saturated, hydrocarbon ring group comprising the specified number of carbon atoms in the ring. For example, the term "C3-6cycloalkyl" refers to a cyclic group having from three to six ring carbon atoms. Exemplary "C3-6cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0096] The term "aryl", as used herein, refers to a group with aromaticity, including ''conjugated" or multicyclic systems with one or more aromatic rings, which does not contain any heteroatom in the ring structure. The term aryl includes both monovalent spec1es and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In some embodiments, an aryl is phenyl.

[0097] The term "heterocyclic group or moiety", as used herein, refers to a cyclic group or moiety having, as ring members, atoms of at least two different elements, which cyclic group or moiety may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic).

[0098] The term "heteroatom", as used herein, refers to a nitrogen, sulfur, or oxygen atom, for example a nitrogen atom or an oxygen atom.

[0099] The term "heterocycloalkyl", as used herein, refers to a non-aromatic, monocyclic or bicyclic group comprising 3-10 ring atoms and comprising one or more (generally one or two) heteroatom ring members independently selected from oxygen, sulfur, and nitrogen. The point of attachment of a heterocycloalkyl group may be by any suitable carbon or nitrogen atom.

[0100] The term "heteroaryl", as used herein, refers to an aromatic monocyclic or bicyclic group comprising 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein at least a portion of the group is aromatic. For example, this term encompasses bicyclic heterocyclic-aryl groups comprising either a phenyl ring fused to aUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO heterocyclic moiety or a heteroaryl ring moiety fused to a carbocyclic moiety. The point of attachment of a heteroaryl group may be by any suitable carbon or nitrogen atom.

[0101] The terms "halogen" and "halo", as used herein, refers to a halogen radical, for example, a fluoro, chloro, bromo, or iodo substituent.

[0102] The term "oxo", as used herein, refers to a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C=O).

[0103] The term "hydroxy" or "hydroxyl", as used herein, is intended to mean the radical -OH.

[0104] The term "cyano", as used herein, refers to a nitrile group, -CN.

[0105] The term "optionally substituted", as used herein, indicates that a group (such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl group) or ring or moiety may be unsubstituted, or the group, ring or moiety may be substituted with one or more substituent(s). In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. Suitable substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arykarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0106] The term "independently", as used herein, means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

[0107] The term "pharmaceutically acceptable", as used herein, refers to those compounds, conjugates, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0108] As used herein, the term "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term "treat" can also include treatment of a cell in vitro or an animal model.

[0109] As used herein, the term "preventing," "prevent," or "protecting against" describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0110] The term "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0111] The term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent, including a conjugate of the disclosure, which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated.

[0112] A therapeutically "effective amount" is intended to mean that amount of a conjugate that, when administered to a patient in need of such treatment, is sufficient to effective treat or prevent, as defined herein. The amount of a given conjugate that will correspond to such an amount will vary depending upon factors such as the particular conjugate (e.g., the potency (pIC50), efficacy (EC50), and the biological half-life of the particular conjugate), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before / with / after meals) of the conjugate will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular conjugate and its properties (e.g., pharmacokinetic properties), disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0113] The term "composition" refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.

[0114] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.

[0115] The terms "conjugate(s) of the disclosure" or "conjugate(s) of the present disclosure", as used herein, mean a conjugate as defined herein, in any form, i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including nonsolid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemihydrates)), and mixtures of various forms.

[0116] Accordingly, included within the present disclosure are the conjugates as disclosure herein, in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present disclosure, it will be understood that the conjugates of the present disclosure, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes.

[0117] As used herein, the expressions "one or more of A, B, or C," ''one or more A, B, or C," "one or more of A, B, and C," "one or more A, B, and C," "selected from the group consisting of A, B, and C", "selected from A, B, and C", and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof unless indicated otherwise.

[0118] It is understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processesUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0119] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0120] When used herein in the context of two or more antibodies, the term "competes with" or "cross-competes with" indicates that the two or more antibodies compete for binding to Wnt2, e.g., compete for Wnt2 binding as described herein. An antibody "blocks" or "cross-blocks" one or more other antibodies from binding to Wnt2 if the antibody competes with the one or more other antibodies 25% or more, with 25%-74% representing "partial block" and 75%-400% representing "full block", preferably as determined herein. For some pairs of antibodies, competition or blocking in an assay described herein is only observed when one antibody is coated on the plate and the other is used to compete, and not vice versa. Unless otherwise defined or negated by context, the terms "competes with", "cross competes with", "blocks" or "cross-blocks" when used herein is also intended to cover such pairs of antibodies.

[0121] Throughout the present disclosure, the numbering of the residues in an immunoglobulin heavy chain and in an immunoglobulin light chain is that as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), expressly incorporated herein by reference.

[0122] As used herein, the term “framework” when used in reference to an antibody variable region is intended to mean all amino acid residues outside the CDR regions within the variable region of an antibody. A variable region framework is generally a discontinuous amino acid sequence between about 100-120 amino acids in length but is intended to reference only those amino acids outside of the CDRs. As used herein, the term “framework region” is intended to mean each domain of the framework that is separated by the CDRs.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0123] A “parent Ig polypeptide” is a polypeptide comprising an amino acid sequence which lacks an aldehyde-tagged constant region as described herein. The parent polypeptide may comprise a native sequence constant region, or may comprise a constant region with pre-existing amino acid sequence modifications (such as additions, deletions and / or substitutions).

[0124] In the context of an Ig polypeptide, the term “constant region” is well understood in the art, and refers to a C-terminal region of an Ig heavy chain, or an Ig light chain. An Ig heavy chain constant region includes CH1, CH2, and CH3 domains (and CH4 domains, where the heavy chain is a μ or an ε heavy chain). In a native Ig heavy chain, the CH1, CH2, CH3 (and, if present, CH4) domains begin immediately after (C-terminal to) the heavy chain variable (VH) region, and are each from about 100 amino acids to about 130 amino acids in length. In a native Ig light chain, the constant region begins immediately after (C-terminal to) the light chain variable (VL) region, and is about 100 amino acids to 120 amino acids in length.

[0125] An “epitope” is a site on an antigen (e.g., a site on Wnt2) to which an antibody binds. Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by folding (e.g., tertiary folding) of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a linear or spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed (1996). Several commercial laboratories offer epitope mapping services. Epitopes bound by an antibody immunoreactive with a membrane associated antigen can reside on the surface of the cell (e.g., in the extracellular region of a transmembrane protein), so that such epitopes are considered cell- surface accessible, solvent accessible, and / or cell-surface exposed.

[0126] By “genetically-encodable” as used in reference to an amino acid sequence of polypeptide, peptide or protein means that the amino acid sequence is composed of amino acid residues that are capable of production by transcription and translation of a nucleic acid encoding the amino acid sequence, where transcription and / or translation may occur in a cell or in a cell- free in vitro transcription / translation system.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0127] The term “control sequences” refers to DNA sequences that facilitate expression of an operably linked coding sequence in a particular expression system, e.g., mammalian cell, bacterial cell, cell-free synthesis, etc. The control sequences that are suitable for prokaryote systems, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cell systems may utilize promoters, polyadenylation signals, and enhancers.

[0128] A nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate the initiation of translation. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. Linking is accomplished by ligation or through amplification reactions. Synthetic oligonucleotide adaptors or linkers may be used for linking sequences in accordance with conventional practice.

[0129] The term “expression cassette” as used herein refers to a segment of nucleic acid, usually DNA, that can be inserted into a nucleic acid (e.g., by use of restriction sites compatible with ligation into a construct of interest or by homologous recombination into a construct of interest or into a host cell genome). In general, the nucleic acid segment comprises a polynucleotide that encodes a polypeptide of interest, and the cassette and restriction sites are designed to facilitate insertion of the cassette in the proper reading frame for transcription and translation. Expression cassettes can also comprise elements that facilitate expression of a polynucleotide encoding a polypeptide of interest in a host cell, e.g., a mammalian host cell. These elements may include, but are not limited to: a promoter, a minimal promoter, an enhancer, a response element, a terminator sequence, a polyadenylation sequence, and the like.

[0130] In certain embodiments, the antibody molecules disclosed herein include a heavy chain comprising a variable heavy chain region as provided herein and a human IgG1 constant region having the amino acid sequence sequence set forth in UniProt: P01857-1, version 1. In certain embodiments, the antibody molecules disclosed herein include a light chain comprising aUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO variable light chain region as provided herein and a human light chain constant region. In certain embodiments, the human light chain constant region is a human kappa light chain constant region having the amino acid set forth in UniProtKB / Swiss-Prot: P01834.2. In certain embodiments, the human IgG1 heavy chain constant region present in the subject antibodies may include mutations, e.g., substitutions to modulate Fc function. For example, the LALAPG effector function mutations (L234A, L235A, and P329G) or the N297A mutation may be introduced to reduce antibody dependent cellular cytotoxicity (ADCC). The numbering of the substitutions is based on the EU numbering system. The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). The “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody.

[0131] The term “chimeric antibodies” refer to antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from antibody variable and constant region genes belonging to different species. For example, the variable segments of the genes from a mouse monoclonal antibody may be joined to human constant segments, such as gamma 1 and gamma 3. An example of a therapeutic chimeric antibody is a hybrid protein composed of the variable or antigen-binding domain from a mouse antibody and the constant or effector domain from a human antibody, although domains from other mammalian species may be used.

[0132] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymeric form of amino acids of any length. Unless specifically indicated otherwise, “polypeptide,” “peptide,” and “protein” can include genetically coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones. The term includes fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusions with heterologous and homologous leader sequences, proteins which contain at least one N-terminal methionine residue (e.g., to facilitate production in a recombinant host cell); immunologically tagged proteins; and the like. In the context of an antibody, it is clear that a chain or a domain comprises a polypeptide.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0133] “Native amino acid sequence” or “parent amino acid sequence” are used interchangeably herein to refer to the amino acid sequence of a polypeptide prior to modification to include a modified amino acid residue.

[0134] The terms “amino acid analog,” “unnatural amino acid,” and the like may be used interchangeably, and include amino acid-like compounds that are similar in structure and / or overall shape to one or more amino acids commonly found in naturally occurring proteins (e.g., Ala or A, Cys or C, Asp or D, Glu or E, Phe or F, Gly or G, His or H, Ile or I, Lys or K, Leu or L, Met or M, Asn or N, Pro or P, Gln or Q, Arg or R, Ser or S, Thr or T, Val or V, Trp or W, Tyr or Y). Amino acid analogs also include natural amino acids with modified side chains or backbones. Amino acid analogs also include amino acid analogs with the same stereochemistry as in the naturally occurring D-form, as well as the L-form of amino acid analogs. In some instances, the amino acid analogs share backbone structures, and / or the side chain structures of one or more natural amino acids, with difference(s) being one or more modified groups in the molecule. Such modification may include, but is not limited to, substitution of an atom (such as N) for a related atom (such as S), addition of a group (such as methyl, or hydroxyl, etc.) or an atom (such as Cl or Br, etc.), deletion of a group, substitution of a covalent bond (single bond for double bond, etc.), or combinations thereof. For example, amino acid analogs may include α- hydroxy acids, and α-amino acids, and the like.

[0135] The terms “amino acid side chain” or “side chain of an amino acid” and the like may be used to refer to the substituent attached to the α-carbon of an amino acid residue, including natural amino acids, unnatural amino acids, and amino acid analogs. An amino acid side chain can also include an amino acid side chain as described in the context of the modified amino acids and / or conjugates described herein.

[0136] The term “conjugated” generally refers to a chemical linkage, either covalent or non- covalent, usually covalent, that proximally associates one molecule of interest with a second molecule of interest. In some embodiments, the agent is selected from a half-life extending moiety, a labeling agent, and a therapeutic agent. For half-life extension, for example, the antibodies of the present disclosure can optionally be modified to provide for improved pharmacokinetic profile (e.g., by PEGylation, hyperglycosylation, and the like). Modifications that can enhance serum half-life are of interest.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0137] The term “carbohydrate” and the like may be used to refer to monomer units and / or polymers of monosaccharides, disaccharides, oligosaccharides, and polysaccharides. The term sugar may be used to refer to the smaller carbohydrates, such as monosaccharides, disaccharides. The term “carbohydrate derivative” includes compounds where one or more functional groups of a carbohydrate of interest are substituted (replaced by any convenient substituent), modified (converted to another group using any convenient chemistry) or absent (e.g., eliminated or replaced by H). A variety of carbohydrates and carbohydrate derivatives are available and may be adapted for use in the subject compounds and conjugates.

[0138] As used herein, the term “substantially purified” refers to a compound that is removed from its natural environment and is at least 60% free, at least 75% free, at least 80% free, at least 85% free, at least 90% free, at least 95% free, at least 98% free, or more than 98% free, from other components with which it is naturally associated.

[0139] The term “physiological conditions” is meant to encompass those conditions compatible with living cells, e.g., predominantly aqueous conditions of a temperature, pH, salinity, etc. that are compatible with living cells.

[0140] By “reactive partner” is meant a molecule or molecular moiety that specifically reacts with another reactive partner to produce a reaction product. Exemplary reactive partners include a cysteine or serine of a sulfatase motif and Formylglycine Generating Enzyme (FGE), which react to form a reaction product of a converted aldehyde tag containing a formylglycine (fGly) in lieu of cysteine or serine in the motif. Other exemplary reactive partners include an aldehyde of an fGly residue of a converted aldehyde tag (e.g., a reactive aldehyde group) and an “aldehyde- reactive reactive partner,” which comprises an aldehyde-reactive group and a moiety of interest, and which reacts to form a reaction product of a polypeptide having the moiety of interest conjugated to the polypeptide through the fGly residue.

[0141] “N-terminus” refers to the terminal amino acid residue of a polypeptide having a free amine group, which amine group in non-N-terminus amino acid residues normally forms part of the covalent backbone of the polypeptide.

[0142] “C-terminus” refers to the terminal amino acid residue of a polypeptide having a free carboxyl group, which carboxyl group in non-C-terminus amino acid residues normally forms part of the covalent backbone of the polypeptide.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0143] By “internal site” as used in referenced to a polypeptide or an amino acid sequence of a polypeptide means a region of the polypeptide that is not at the N-terminus or at the C-terminus.

[0144] As used herein, the terms “treatment,” “treating,” and the like, refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, e.g., arresting its development; and (c) relieving the disease, e.g., causing regression of the disease.

[0145] The terms “individual,” “subject,” “host,” and “patient,” used interchangeably herein, refer to a mammal, including, but not limited to, murines (rats, mice), non-human primates, humans, canines, felines, ungulates (e.g., equines, bovines, ovines, porcines, caprines), etc.

[0146] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0147] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0148] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein canUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0149] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an antibody” includes a plurality of such antibodies and reference to “the CDR” includes reference to one or more CDRs and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0150] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. DETAILED DESCRIPTION I. Introduction

[0151] Provided herein are compositions for inhibiting Wnt2, such as antibodies and antibody- drug conjugates, as well as pharmaceutical compositions including these compositions. Also provided are methods of using these compositions to treat diseases. II. Antibodies

[0152] In one aspect, the invention provides an antibody (e.g. isolated antibody) that specifically binds Wnt2 comprising: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO:5) or IYPGYGSTY (SEQ ID NO:15), and a variable heavy chain complementarity determining region 3 (HCDR3) comprising anUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26). In an exemplary embodiment, the invention provides an antibody (e.g. isolated antibody) that specifically binds Wnt2 comprising: a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO:8), QSLVYGDGNTY (SEQ ID NO:18), QSLVDGDGNTY (SEQ ID NO:28), or QSLLDSDGKTY (SEQ ID NO:58), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO:9) or QVS (SEQ ID NO:19), and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO:10) or WQGTHFPFT (SEQ ID NO:20). In an exemplary embodiment, the invention provides an antibody (e.g. isolated antibody) that specifically binds Wnt2 comprising: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO:5) or IYPGYGSTY (SEQ ID NO:15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26), a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO:8), QSLVYGDGNTY (SEQ ID NO:18), QSLVDGDGNTY (SEQ ID NO:28), or QSLLDSDGKTY (SEQ ID NO:58), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO:9) or QVS (SEQ ID NO:19), and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO:10) or WQGTHFPFT (SEQ ID NO:20).

[0153] In an exemplary embodiment, the antibody (e.g. isolated antibody) specifically binding Wnt2 comprises: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO:5) or IYPGYGSTY (SEQ ID NO:15), and a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26). In an exemplary embodiment, the antibody (e.g. isolated antibody) specifically binding Wnt2 comprises: aUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYGDGNTY (SEQ ID NO:18), QSLVDGDGNTY (SEQ ID NO:28), or QSLLDSDGKTY (SEQ ID NO:58), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is QVS (SEQ ID NO:19), and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPFT (SEQ ID NO:20). In an exemplary embodiment, the antibody (e.g. isolated antibody) specifically binding Wnt2 comprises: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO:5) or IYPGYGSTY (SEQ ID NO:15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26), a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYGDGNTY (SEQ ID NO:18), QSLVDGDGNTY (SEQ ID NO:28), or QSLLDSDGKTY (SEQ ID NO:58), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is QVS (SEQ ID NO:19), and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPFT (SEQ ID NO:20).

[0154] In an exemplary embodiment, the antibody (e.g. isolated antibody) specifically binding Wnt2 comprises: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGSTY (SEQ ID NO:15), and a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26). In an exemplary embodiment, the antibody (e.g. isolated antibody) specifically binding Wnt2 comprises: a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYGDGNTY (SEQ ID NO:18) or QSLVDGDGNTY (SEQ ID NO:28), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is QVS (SEQ ID NO:19), and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPFTUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO (SEQ ID NO:20). In an exemplary embodiment, the antibody (e.g. isolated antibody) specifically binding Wnt2 comprises: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGSTY (SEQ ID NO:15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26), a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYGDGNTY (SEQ ID NO:18) or QSLVDGDGNTY (SEQ ID NO:28), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is QVS (SEQ ID NO:19), a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPFT (SEQ ID NO:20).

[0155] In an exemplary embodiment, the invention provides an antibody (e.g. isolated antibody) that specifically binds Wnt2 comprising: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGSTY (SEQ ID NO:15), and a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26). In an exemplary embodiment, the invention provides an antibody (e.g. isolated antibody) that specifically binds Wnt2 comprising: a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO:8) or QSLVYGDGNTY (SEQ ID NO:18), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO:9) or QVS (SEQ ID NO:19), and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO:10) or WQGTHFPFT (SEQ ID NO:20). In one aspect, the invention provides an antibody (e.g. isolated antibody) that specifically binds Wnt2 comprising: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33), a variable heavy chain complementarity determining region 2 (HCDR2)UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO comprising an amino acid sequence which is IYPGYGSTY (SEQ ID NO:15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26), a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO:8) or QSLVYGDGNTY (SEQ ID NO:18), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO:9) or QVS (SEQ ID NO:19), a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO:10) or WQGTHFPFT (SEQ ID NO:20).

[0156] In one aspect, the invention provides an antibody (e.g. isolated antibody) that specifically binds Wnt2 comprising: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 4), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO: 5) or IYPGYGSTY (SEQ ID NO: 15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO: 16) or ARWGDSFAY (SEQ ID NO: 26), a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO: 8), QSLVYGDGNTY (SEQ ID NO: 18), or QSLVDGDGNTY (SEQ ID NO: 28), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO: 9) or QVS (SEQ ID NO: 19), a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO: 10) or WQGTHFPFT (SEQ ID NO: 20).

[0157] In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence described herein, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the heavy chain variable sequence described herein. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence which is SEQ ID NO:3, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO amino acid residues from the heavy chain variable sequence which is SEQ ID NO:3, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence which is SEQ ID NO:3. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence which is SEQ ID NO:13, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence which is SEQ ID NO:13, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence which is SEQ ID NO:13. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence which is SEQ ID NO:23, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence which is SEQ ID NO:23, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence which is SEQ ID NO:23. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence which is SEQ ID NO:37, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence which is SEQ ID NO:37, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence which is SEQ ID NO:37. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence which is SEQ ID NO:42, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence which is SEQ ID NO:42, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence which is SEQ ID NO:42. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequenceUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO which is SEQ ID NO:47, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence which is SEQ ID NO:47, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence which is SEQ ID NO:47. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence which is SEQ ID NO:52, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence which is SEQ ID NO:52, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence which is SEQ ID NO:52. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a light chain variable sequence described herein, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the light chain variable sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the light chain variable sequence described herein. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a light chain variable sequence which is SEQ ID NO:7, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the light chain variable sequence which is SEQ ID NO:7, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the light chain variable sequence which is SEQ ID NO:7. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a light chain variable sequence which is SEQ ID NO:17, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the light chain variable sequence which is SEQ ID NO:17, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the light chain variable sequence which is SEQ ID NO:17. In anUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO exemplary embodiment, the antibody (e.g. isolated antibody) comprises a light chain variable sequence which is SEQ ID NO:27, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the light chain variable sequence which is SEQ ID NO:27, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the light chain variable sequence which is SEQ ID NO:27. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a light chain variable sequence which is SEQ ID NO:57, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the light chain variable sequence which is SEQ ID NO:57, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the light chain variable sequence which is SEQ ID NO:57. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a light chain variable sequence which is SEQ ID NO:62, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the light chain variable sequence which is SEQ ID NO:62, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the light chain variable sequence which is SEQ ID NO:62. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence described herein (such as in this paragraph), or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the heavy chain variable sequence described herein, and a light chain variable sequence described herein (such as in this paragraph), or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the light chain variable sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the lightUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO chain variable sequence described herein. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence and a light chain variable sequence described in Table 14, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence and / or the light chain variable sequence described in Table 14, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the heavy chain variable sequence described herein, and / or the light chain variable sequence described in Table 14.

[0158] In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence comprising an amino acid sequence which is SEQ ID NO: 3, SEQ ID NO: 13, or SEQ ID NO: 23, and a light chain variable sequence comprising an amino acid sequence which is SEQ ID NO: 7, SEQ ID NO: 17, or SEQ ID NO: 27.

[0159] In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence described herein, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full length heavy chain sequence described herein. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence which is SEQ ID NO:1, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequence which is SEQ ID NO:1, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full length heavy chain sequence which is SEQ ID NO:1. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence which is SEQ ID NO:12, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequence which is SEQ ID NO:12, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at leastUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO 97, at least 98, at least 99 or 100% sequence identity with the full length heavy chain sequence which is SEQ ID NO:12. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence which is SEQ ID NO:21, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequence which is SEQ ID NO:21, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full length heavy chain sequence which is SEQ ID NO:21. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence which is SEQ ID NO:31, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequence which is SEQ ID NO:31, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full length heavy chain sequence which is SEQ ID NO:31. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence which is SEQ ID NO:36, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequence which is SEQ ID NO:36, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full length heavy chain sequence which is SEQ ID NO:36. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence which is SEQ ID NO:41, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequence which is SEQ ID NO:41, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full length heavy chain sequence which is SEQ ID NO:41. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence which is SEQ ID NO:46, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequenceUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO which is SEQ ID NO:46, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full length heavy chain sequence which is SEQ ID NO:46. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain sequence which is SEQ ID NO:51, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full length heavy chain sequence which is SEQ ID NO:51, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full length heavy chain sequence which is SEQ ID NO:51. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length light chain sequence described herein, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length light chain sequence described herein. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length light chain sequence which is SEQ ID NO:2, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:2, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:2. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length light chain sequence which is SEQ ID NO:12, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:12, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:12. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length light chain sequence which is SEQ ID NO:22, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6,UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:22, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:22. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length light chain sequence which is SEQ ID NO:56, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:56, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:56. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length light chain sequence which is SEQ ID NO:61, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:61, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:61. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length heavy chain sequence described herein (such as in this paragraph), or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length heavy chain sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length heavy chain sequence described herein, and a full-length light chain sequence described herein (such as in this paragraph), or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence described herein, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length light chain sequence described herein. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length heavy chain sequence which is SEQ ID NO:1, orUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length heavy chain sequence which is SEQ ID NO:1, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length heavy chain sequence which is SEQ ID NO:1, and a full-length light chain sequence which is SEQ ID NO:2, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:2, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:2. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length heavy chain sequence which is SEQ ID NO:11, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length heavy chain sequence which is SEQ ID NO:11, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length heavy chain sequence which is SEQ ID NO:11, and a full-length light chain sequence which is SEQ ID NO:12, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:12, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:12. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length heavy chain sequence which is SEQ ID NO:21, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full- length heavy chain sequence which is SEQ ID NO:21, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length heavy chain sequence which is SEQ ID NO:21, and a full-length light chain sequence which is SEQ ID NO:22, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:22, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:22. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full- length heavy chain sequence which is SEQ ID NO:66, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length heavy chain sequence which is SEQ ID NO:66, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length heavy chain sequence which is SEQ ID NO:66, and a full-length light chain sequence which is SEQ ID NO:67, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:67, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:67. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length heavy chain sequence which is SEQ ID NO:68, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length heavy chain sequence which is SEQ ID NO:68, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length heavy chain sequence which is SEQ ID NO:68, and a full- length light chain sequence which is SEQ ID NO:69, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:69, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:69. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full-length heavy chain sequence which is SEQ ID NO:70, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length heavy chain sequence which is SEQ ID NO:70, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length heavy chain sequence which is SEQ ID NO:70, and a full-length light chain sequence which is SEQ ID NO:71, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the full-length light chain sequence which is SEQ ID NO:71, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the full-length light chain sequence which is SEQ ID NO:71.

[0160] In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 1, SEQ ID NO: 11, or SEQ ID NO: 21, and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 2, SEQ ID NO: 12, or SEQ ID NO: 22.

[0161] In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a Lib1 (mAb1) amino acid sequence described herein. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a Lib11 (mAb2) amino acid sequence described herein. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a Lib6 (mAb3) amino acid sequence described herein.

[0162] In another aspect, the invention provides an antibody (e.g. isolated antibody) that specifically binds Wnt2 comprising a member selected from the group consisting of: a) a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 4), a variable heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGTAY (SEQ ID NO: 5), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSRAY (SEQ ID NO: 6), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVYSDGNTY (SEQ ID NO: 8), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence KVS (SEQ ID NO: 9), a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPWT (SEQ ID NO: 10); b) aUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 14), a variable heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGSTY (SEQ ID NO: 15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSRAY (SEQ ID NO: 16), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVYGDGNTY (SEQ ID NO: 18), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence QVS (SEQ ID NO: 19), a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPFT (SEQ ID NO: 20); or c) a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 24), a variable heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGSTY (SEQ ID NO: 25), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSFAY (SEQ ID NO: 26), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVDGDGNTY (SEQ ID NO: 28), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence QVS (SEQ ID NO: 29), a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPFT (SEQ ID NO: 30). In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a member selected from the group consisting of: a) a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 3, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 7; b) a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 13, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 17; or c) a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 23, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 27. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a member selected from the group consisting of: a) a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 1 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 2; b) a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 11 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 12; or c) a fullUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO length heavy chain comprising an amino acid sequence which is SEQ ID NO: 21 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 22.

[0163] In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 4), a variable heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGTAY (SEQ ID NO: 5), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSRAY (SEQ ID NO: 6), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVYSDGNTY (SEQ ID NO: 8), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence KVS (SEQ ID NO: 9), a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPWT (SEQ ID NO: 10). In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence comprising the amino acid sequence (SEQ ID NO: 3), and a light chain variable sequence comprising the amino acid sequence (SEQ ID NO: 7). In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 1 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 2.

[0164] In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 14), a variable heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGSTY (SEQ ID NO: 15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSRAY (SEQ ID NO: 16), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVYGDGNTY (SEQ ID NO: 18), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence QVS (SEQ ID NO: 19), a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPFT (SEQ ID NO: 20). In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 13, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 17. In an exemplary embodiment,UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO the antibody (e.g. isolated antibody) comprises a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 11 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 12.

[0165] In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 24), a variable heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGSTY (SEQ ID NO: 25), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSFAY (SEQ ID NO: 26), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVDGDGNTY (SEQ ID NO: 28), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence QVS (SEQ ID NO: 29), a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPFT (SEQ ID NO: 30). In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 23, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 27. In an exemplary embodiment, the antibody (e.g. isolated antibody) comprises a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 21 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 22.

[0166] In an exemplary embodiment, the antibody described herein is a full-length antibody. In an exemplary embodiment, the antibody described herein is an intact antibody. In an exemplary embodiment, the antibody described herein is a full-length antibody. In an exemplary embodiment, the antibody (e.g. isolated antibody) described herein is a monoclonal antibody. In an exemplary embodiment, the antibody (e.g. isolated antibody) described herein is a rabbit, mouse, chimeric, humanized or fully human monoclonal antibody. In an exemplary embodiment, the antibody (e.g. isolated antibody) described herein is an IgG isotype. In an exemplary embodiment, the antibody (e.g. isolated antibody) described herein is an IgG1 isotype. In an exemplary embodiment, the antibody (e.g. isolated antibody) described herein competes for specific binding to human Wnt2. In an exemplary embodiment, the antibody (e.g. isolated antibody) described herein competes for specific binding to human Wnt2. In an exemplary embodiment, the antibody described herein is a polyclonal antibody. In an exemplaryUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO embodiment, the antibody described herein is a multispecific antibody. In an exemplary embodiment, the antibody described herein is an antibody fragment. In an exemplary embodiment, the antibody described herein is an antibody fragment which is Fv. In an exemplary embodiment, the antibody described herein is an antibody fragment which is Fab. In an exemplary embodiment, the antibody described herein is an antibody fragment which is Fab'. In an exemplary embodiment, the antibody described herein is an antibody fragment which is Fab'-SH. In an exemplary embodiment, the antibody described herein is an antibody fragment which is F(ab')2. In an exemplary embodiment, the antibody described herein is an antibody fragment which is a diabody. In an exemplary embodiment, the antibody described herein is an antibody fragment which is a linear antibody. In an exemplary embodiment, the antibody described herein is an antibody fragment which is a single-chain antibody molecules (e.g. scFv). In an exemplary embodiment, the antibody described herein is a multispecific antibody formed from antibody fragments. III. Antibody-Drug Conjugates

[0167] In another aspect, the invention provides an antibody-drug conjugate (ADC) comprising a) an antibody described herein; and b) a covalently coupled therapeutic agent. In an exemplary embodiment, the invention provides an antibody-drug conjugate (ADC) comprising a) an antibody described herein; and b) a covalently coupled therapeutic agent described herein. In another aspect, the invention provides an anti-Wnt2 antibody-drug conjugate comprising: a) an anti-Wnt2 antibody described herein; and b) one or more -L-D moieties covalently coupled to the anti-Wnt2 antibody, wherein L is a linker, D is a therapeutic agent, and the L-D moiety is attached to the anti-Wnt2 antibody through the linker. In an exemplary embodiment, the ADC comprises: a) an antibody that specifically binds Wnt2 comprising: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO:5) or IYPGYGSTY (SEQ ID NO:15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26), a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO:8), QSLVYGDGNTY (SEQ ID NO:18), QSLVDGDGNTYUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO (SEQ ID NO:28), or QSLLDSDGKTY (SEQ ID NO:58), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO:9) or QVS (SEQ ID NO:19), and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO:10) or WQGTHFPFT (SEQ ID NO:20); and b) a covalently coupled therapeutic agent. In an exemplary embodiment, the therapeutic agent is a cytotoxin. In an exemplary embodiment, the therapeutic agent is MMAE. In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 4), a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO: 5) or IYPGYGSTY (SEQ ID NO: 15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO: 6) or ARWGDSFAY (SEQ ID NO: 26), a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO: 8), QSLVYGDGNTY (SEQ ID NO: 18), or QSLVDGDGNTY (SEQ ID NO: 28), a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO: 9) or QVS (SEQ ID NO: 19), and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO: 10) or WQGTHFPFT (SEQ ID NO: 20). In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a heavy chain variable sequence comprising an amino acid sequence which is SEQ ID NO: 2, SEQ ID NO: 13, or SEQ ID NO: 23, and a light chain variable sequence comprising an amino acid sequence which is SEQ ID NO: 7, SEQ ID NO: 17, or SEQ ID NO: 27. In an exemplary embodiment, the anti- Wnt2 antibody of the conjugate comprises: a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 1, SEQ ID NO: 11, or SEQ ID NO: 21, and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 2, SEQ ID NO: 12, or SEQ ID NO: 22.

[0168] In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 4), a variable heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGTAY (SEQ IDUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO NO: 5), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSRAY (SEQ ID NO: 6), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVYSDGNTY (SEQ ID NO: 8), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence KVS (SEQ ID NO: 9), and a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPWT (SEQ ID NO: 10). In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a heavy chain variable sequence comprising the amino acid sequence (SEQ ID NO: 3), and a light chain variable sequence comprising the amino acid sequence (SEQ ID NO: 7). In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 1 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 2.

[0169] In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 14), a variable heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGSTY (SEQ ID NO: 15), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSRAY (SEQ ID NO: 16), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVYGDGNTY (SEQ ID NO: 18), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence QVS (SEQ ID NO: 19), and a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPFT (SEQ ID NO: 20). In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 13, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 17. In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 11 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 12.

[0170] In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 24), a variable heavy chain complementarityUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO determining region 2 (HCDR2) comprising the amino acid sequence IYPGYGSTY (SEQ ID NO: 25), a variable heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence ARWGDSFAY (SEQ ID NO: 26), a variable light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence QSLVDGDGNTY (SEQ ID NO: 28), a variable light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence QVS (SEQ ID NO: 29), and a variable light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence WQGTHFPFT (SEQ ID NO: 30). In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 23, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 27. In an exemplary embodiment, the anti-Wnt2 antibody of the conjugate comprises: a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 21 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 22.

[0171] In an exemplary embodiment, the anti-Wnt2 antibody is a monoclonal antibody. In an exemplary embodiment, the anti-Wnt2 antibody is a recombinant antibody or a fusion protein. In an exemplary embodiment, the anti-Wnt2 antibody is a rabbit, mouse, chimeric, humanized or fully human monoclonal antibody. In an exemplary embodiment, the anti-Wnt2 antibody is an IgG isotype. In an exemplary embodiment, the anti-Wnt2 antibody is an IgG1 isotype.

[0172] In an exemplary embodiment, the therapeutic agent is a chemotherapeutic agent. In an exemplary embodiment, the therapeutic agent is a cytotoxin. In an exemplary embodiment, the therapeutic agent is a cytotoxin which is selected from the group consisting of a tubulin stabilizer, a tubulin destabilizer, a DNA alkylator, a DNA minor groove binder, a DNA intercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a gyrase inhibitor, a protein synthesis inhibitor, a proteosome inhibitor, and an anti-metabolite. In an exemplary embodiment, the therapeutic agent is a cytotoxin which is selected from the group consisting of Actinomycin-D, Amonafide, an auristatin, benzophenone, benzothiazole, a calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinafide, Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), a maytansinoid, Methotrexate, Mitoxantrone, Nocodazole, Proteosome Inhibitor 1 (PSI 1), Roridin A, T-2 Toxin (trichothecene analog), Taxol, a tubulysin, Velcade®, and Vincristine. In an exemplary embodiment, the therapeutic agent is a cytotoxin which is an auristatin, a calicheamicin, aUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO maytansinoid, a pyrrolobenzodiazepine (PBD), or a tubulysin. In an exemplary embodiment, the therapeutic agent is a cytotoxin which is monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), calicheamicin y, mertansine, tubulysin T3, or tubulysin T4. In an exemplary embodiment, the therapeutic agent is a cytotoxin which is MMAE or MMAF.

[0173] In an exemplary embodiment, the antibody is covalently coupled to the therapeutic agent through a linker. In an exemplary embodiment, the linker comprises a member selected from the group consisting of valine, citrulline, p-amino benzyl alcohol p-nitrophenyl carbonate, and polyethylene glycol, or a combination thereof.

[0174] In an exemplary embodiment, the antibody-drug conjugate has from 1 to 10 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody- drug conjugate has from 2 to 8 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has from 3 to 7 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has from 4 to 7 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has from 4 to 6 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has from 3 to 6 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has from 4 to 5 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has 3 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has 4 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has 5 covalently coupled therapeutic agents (such as a cytotoxin). In an exemplary embodiment, the antibody-drug conjugate has 6 covalently coupled therapeutic agents (such as a cytotoxin).

[0175] In an exemplary embodiment, the antibody-drug conjugate has between 1 and 10 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has between 2 and 8 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has between 3 and 7 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has between 4 and 7 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has between 4 and 6 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has between 3 and 6 -L-DUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO moieties. In an exemplary embodiment, the antibody-drug conjugate has between 4 and 5 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has from 1 to 10 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has from 2 to 8 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has from 3 to 7 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has from 4 to 7 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has from 4 to 6 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has from 3 to 6 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has from 4 to 5 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has 3 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has 4 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has 5 -L-D moieties. In an exemplary embodiment, the antibody-drug conjugate has 6 -L-D moieties.

[0176] In certain embodiments, the antibody-drug conjugate have an average drug-to-antibody ratio (DAR) (molar ratio) in the range of from 0.1 to 10, from 0.5 to 10, from 1 to 10, from 1 to 9, from 1 to 8, from 2 to 7, from 2 to 6, from 3 to 6, from 3 to 5, from 4 to 6, from 4 to 5, or from 5 to 6. In certain embodiments, the antibody-drug conjugates have an average DAR from 4.1 to 5.6. In certain embodiments, the antibody-drug conjugates have an average DAR of 4.1 to 4.6. In certain embodiments, the antibody-drug conjugates have an average DAR of 4.6 to 5.1. In certain embodiments, the antibody-drug conjugates have an average DAR of 5.1 to 5.6. By average is meant the arithmetic mean. IV. Pharmaceutical Compositions

[0177] In another aspect, the invention provides a pharmaceutical composition comprising: a) an antibody (e.g. isolated antibody) or an antibody-drug conjugate described herein; and b) a pharmaceutically acceptable excipient.

[0178] The pharmaceutical formulations of the invention can take a variety of forms adapted to the chosen route of administration. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutical formulations incorporating an antibody (e.g. isolated antibody) or an antibody-drug conjugate described herein. Those skilled in the art can utilize a reference such as Handbook of PharmaceuticalUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Excipients, 4th Edition, Edited by Raymond Rowe for information on useful pharmaceutical excipients. V. Kits

[0179] In another aspect, the invention provides a kit comprising the antibody described herein; and instructions for use of the kit. In another aspect, the invention provides a kit comprising the antibody-drug conjugate described herein; and instructions for use of the kit. In another aspect, the invention provides a kit comprising the pharmaceutical composition described herein; and instructions for use of the kit. VI. Methods A. Inhibition of Cell Proliferation

[0180] Agents that inhibit Wnt2 signaling, such as the anti-Wnt2 antibodies and anti-Wnt2 antibody-drug conjugates of the invention (e.g. those described herein) may find use in a variety of ways. In a preferred embodiment of this invention a method of inhibiting proliferation of a cell that overexpresses a Wnt2 is provided. The Wnt2 that is overexpressed can be either a Wnt2 protein or a Wnt2 mRNA. This method comprises the step of contacting the cell with an amount of an agent that inhibits Wnt2 signaling effective to inhibit proliferation of the cell. "Proliferation" refers to the growth of a cell, the reproduction or multiplication of a cell or morbid cysts.

[0181] In a preferred embodiment of the present invention, this method is practiced in vitro. As further described herein, the methods of the present invention can also be practiced in vivo.

[0182] In a preferred embodiment of the present invention, the cell being contacted with the agent is a cancer cell. Agents of the present invention are useful for inhibiting proliferation of a cancer cell selected from the group consisting of breast, ovarian, colorectal, gastric, lung, kidney, bladder, prostate, uterine, thyroid, pancreatic, cervical, esophageal, mesothelioma, head and neck, hepatocellular, melanoma, brain, vulval, testicular, sarcoma, intestine, skin, leukemia, and lymphoma cancer cells. A preferred cancer cell is a breast cancer cell, a melanoma cell, a lung cancer cell, a mesothelioma cell, a thyroid cancer cell, a colon cancer cell or a liver cancer cell.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO B. Inducing Apoptosis

[0183] Agents that inhibit Wnt2 signaling, such as the anti-Wnt2 antibodies and anti-Wnt2 antibody-drug conjugates of the invention (e.g. those described herein) may find use in a variety of ways. In another preferred embodiment of this invention a method of inducing apoptosis of a cell that overexpresses a Wnt2 is provided. This method comprises the step of contacting the cell with an amount of an agent that inhibits Wnt2 signaling effective to induce apoptosis of the cell. Agents for use in this method, such as anti-Wnt2 antibodies or conjugates are disclosed herein. C. Inhibiting Wnt2 Signaling

[0184] Agents of the present invention, such as the anti-Wnt2 antibodies and anti-Wnt2 antibody-drug conjugates of the invention (e.g. those described herein) may find use in a variety of ways. In another preferred embodiment of this invention a method of inhibiting Wnt2 signaling in a cell is provided. This method comprises the step of contacting a cell that overexpresses a Wnt2 with an amount of an agent effective to inhibit Wnt2 signaling. Agents for use in this method, such as anti-Wnt2 antibodies or conjugates are disclosed herein. D. Treating a Disease

[0185] Agents of the present invention, such as the anti-Wnt2 antibodies and anti-Wnt2 antibody-drug conjugates of the invention (e.g. those described herein) may find use in a variety of ways. In a preferred embodiment of this invention a method of treating a disease associated with Wnt2 signaling is provided. This method comprises the step of administering to a subject, preferably to a subject in need of such treatment, an amount of an agent that inhibits Wnt2 signaling effective to treat the disease. Preferably, the subject is a human. Agents for use in this method, such as anti-Wnt2 antibodies or conjugates are disclosed herein.

[0186] In a preferred embodiment the disease is a cancer. Agents of the present invention are useful for treating a cancer selected from the group consisting of breast, ovarian, colorectal, gastric, lung, kidney, bladder, prostate, uterine, thyroid, pancreatic, cervical, esophageal, mesothelioma, head and neck, hepatocellular, melanoma, brain, vulval, testicular, sarcoma, intestine, skin, leukemia, and lymphoma cancer. A preferred cancer is breast cancer, melanoma, lung cancer, mesothelioma, thyroid cancer, colon cancer or liver cancer.

[0187] As used herein, the terms "treat", "treating", and "treatment" include: (1) preventing a disease, such as cancer, i.e. causing the clinical symptoms of the disease not to develop in aUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO subject that may be predisposed to the disease but does not yet experience any symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms. Preferably, the subject in need of such treatment is a mammal, more preferable a human.

[0188] This invention also provides a method of treating a cancer that overexpresses Wnt2. This method comprises the step of administering to a subject in need of such treatment an amount of an agent effective to treat the cancer. Agents for use in this method, such as the anti-Wnt2 antibodies and anti-Wnt2 antibody-drug conjugates of the invention (e.g. those described herein).

[0189] Wnt2 antibodies are generated, for example, using the methods described in the Examples provided herein. Alternatively, or in addition, various procedures known within the art may be used for the production of monoclonal antibodies directed against Wnt2, or against derivatives, fragments, analogs homologs or orthologs thereof. (See, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Kozbor, et al., 1983 Immunol Today 4: 72); Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R Liss, Inc., pp. 77-96; Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030; each of which are incorporated herein by reference in their entirety).

[0190] Monoclonal antibodies disclosed herein include fully human antibodies or humanized antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. A humanized or fully human Wnt2 antibody is developed, for example, using phage-display methods using antibodies containing only human sequences. Such approaches are well-known in the art, e.g., in WO092 / 01047 and US. Pat. No. 6,521,404, which are hereby incorporated by reference.

[0191] Antibodies are purified by well-known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, forUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 (April 17, 2000), pp. 25-28; incorporated herein by reference).

[0192] The invention also includes Fv, Fab, Fab' and F(ab')2 anti-Wnt2 fragments or anti-Wnt2 fragments, single chain anti-Wnt2 antibodies, multispecific antibodies in which at least one arm binds Wnt2, and heteroconjugate anti-Wnt2 antibodies.

[0193] Bispecific antibodies are antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for Wnt2. The second binding target is any other antigen, including a cell-surface protein or receptor or receptor subunit. VII. Nucleic Acids

[0194] The present disclosure also features nucleic acids comprising nucleic acid sequences that encode the antibodies (e.g., CDRs, heavy and light chain variable regions, full length heavy and light chains of the antibodies), antibody-drug conjugates (e.g., CDRs, heavy and light chain variable regions, full length heavy and light chains of the antibody in the antibody-drug conjugates), or other peptides described herein. For example, the present disclosure provides nucleic acids that encode CDRs, heavy and light chain variable regions, and full length heavy and light chains of an antibody described herein. In an exemplary embodiment, the invention provides a nucleic acid sequence comprising a nucleic acid sequence (e.g. nucleic acid sequence described herein) which can encode any of the amino acid sequences described herein, or a nucleic acid sequence substantially identical thereto (nucleic acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 nucleic acids from the nucleic acid sequence of interest, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, or 100% sequence identity with the nucleic acid sequence of interest).

[0195] The nucleic acids disclosed herein include deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. TheUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a nonnatural arrangement.

[0196] In some aspects, the application features cells (e.g. host cells) and vectors containing the nucleic acids described herein. The nucleic acids may be present in a single vector or separate vectors present in the same host cell or separate host cell, as described in more detail below.

[0197] Nucleic acid sequences are provided below:

[0198] Nucleic Acid Sequence for Full Length Heavy Chain 1 (SEQ ID NO:77) atggattggacctggcgcttcctctttgtagtggctgccgccactggcgtccagagtcaagtacagttggtacagtctggcgcagaggttaaaa aacccggtgcctcagtgaaggtttcctgtaaagcctctggctacaccttcactacttttgtagtttcctgggttcgacaagcacccggacagggtc tcgagtggatgggagaaatataccctggttacggtaccgcctattataaccaaaaattcaaaggtcgagtaactatgacagccgataaggtcact agcactgcatatatggaagtatcctcacttacctctgaggacactgctgtgtactattgcgctcgttggggagacagtagggcttactggggaca ggggacactcgtcaccgtatcaagcgctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcaca gcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacacct tcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaa cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagca cctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtg gtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgg gaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaagg tctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgccccc atcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagc aatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaa gagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctcc gggtaaa

[0199] Nucleic Acid Sequence for VH1 (Variable Heavy 1) (SEQ ID NO:78) atggattggacctggcgcttcctctttgtagtggctgccgccactggcgtccagagtcaagtacagttggtacagtctggcgcagaggttaaaa aacccggtgcctcagtgaaggtttcctgtaaagcctctggctacaccttcactacttttgtagtttcctgggttcgacaagcacccggacagggtc tcgagtggatgggagaaatataccctggttacggtaccgcctattataaccaaaaattcaaaggtcgagtaactatgacagccgataaggtcactUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO agcactgcatatatggaagtatcctcacttacctctgaggacactgctgtgtactattgcgctcgttggggagacagtagggcttactggggaca ggggacactcgtcaccgtatcaagc

[0200] Nucleic Acid Sequence for CDR1 Heavy Chain 1 (H1CDR1) (SEQ ID NO:79) ggctacaccttcactacttttgta

[0201] Nucleic Acid Sequence for CDR2 Heavy Chain 1 (H1CDR2) (SEQ ID NO:80) atataccctggttacggtaccgcctat

[0202] Nucleic Acid Sequence for CDR3 Heavy Chain 1 (H1CDR3) (SEQ ID NO:81) gctcgttggggagacagtagggcttac

[0203] Nucleic Acid Sequence for Full Length Heavy Chain 2 (SEQ ID NO:82) atggattggacctggagagtgttttgtctgttggctgtcgctcccggagctcacagtcaggtgcagttggtgcaaagcggagcagaagtgaa aaagccaggcgcaagcgttaaagtatcttgcaaggcctctggatatacttttaccacctttgtcgtatcctgggtacggcaagcaccaggtca gggtttggagtggatgggagagatatatcctggatacggctcaacctactataatgaaaaatttaaaggaagagtcacaatgaccgctgata aggtaacctcaacagcttatatggaggtttccagcctcacctctgaggacacagcagtttactattgcgctcgctggggcgacagtcgtgctt actggggtcagggaaccctcgtcacagttagcagcgctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacct ctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagc ggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcaccc agacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacat gcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggac ccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataa tgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatg gcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgaga accacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccag cgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttct tcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtaaa

[0204] Nucleic Acid Sequence for VH2 (Variable Heavy 2) (SEQ ID NO:83) atggattggacctggagagtgttttgtctgttggctgtcgctcccggagctcacagtcaggtgcagttggtgcaaagcggagcagaagtgaaaa agccaggcgcaagcgttaaagtatcttgcaaggcctctggatatacttttaccacctttgtcgtatcctgggtacggcaagcaccaggtcagggt ttggagtggatgggagagatatatcctggatacggctcaacctactataatgaaaaatttaaaggaagagtcacaatgaccgctgataaggtaaUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO cctcaacagcttatatggaggtttccagcctcacctctgaggacacagcagtttactattgcgctcgctggggcgacagtcgtgcttactggggt cagggaaccctcgtcacagttagcagc

[0205] Nucleic Acid Sequence for CDR1 Heavy Chain 2 (H2CDR1) (SEQ ID NO:84) ggatatacttttaccacctttgtc

[0206] Nucleic Acid Sequence for CDR2 Heavy Chain 2 (H2CDR2) (SEQ ID NO:85) atatatcctggatacggctcaacctac

[0207] Nucleic Acid Sequence for CDR3 Heavy Chain 2 (H2CDR3) (SEQ ID NO:86) gctcgctggggcgacagtcgtgcttac

[0208] Nucleic Acid Sequence for Full Length Heavy Chain 3 (SEQ ID NO:87) atggactggacttggcgggtattttgtttgctcgctgtagctcctggtgctcattcacaggtccaactcgtacaatccggcgcagaggtaaaaaaa ccaggtgcaagcgtcaaagtttcctgcaaggcatccggatacactttcactacttttgtagtgagctgggtccgacaagcaccaggtcaaggatt ggagtggatgggtgaaatatatcctggttatggttccacctactacaatgaaaaattcaagggccgagtaacaatgacagcagacaaagtaaca agcactgcctacatggaagtaagttcactcacctcagaggatacagccgtttactactgcgcccgctggggggacagctttgcttactggggac aaggtacattggtcactgtaagctcagctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacag cggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacacctt cccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaa cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagca cctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtg gtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgg gaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaagg tctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgccccc atcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagc aatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaa gagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctcc gggtaaa

[0209] Nucleic Acid Sequence for VH3 (Variable Heavy 3) (SEQ ID NO:88) atggactggacttggcgggtattttgtttgctcgctgtagctcctggtgctcattcacaggtccaactcgtacaatccggcgcagaggtaaaaaaa ccaggtgcaagcgtcaaagtttcctgcaaggcatccggatacactttcactacttttgtagtgagctgggtccgacaagcaccaggtcaaggatt ggagtggatgggtgaaatatatcctggttatggttccacctactacaatgaaaaattcaagggccgagtaacaatgacagcagacaaagtaacaUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO agcactgcctacatggaagtaagttcactcacctcagaggatacagccgtttactactgcgcccgctggggggacagctttgcttactggggac aaggtacattggtcactgtaagctca

[0210] Nucleic Acid Sequence for CDR1 Heavy Chain 3 (H3CDR1) (SEQ ID NO:89) ggatacactttcactacttttgta

[0211] Nucleic Acid Sequence for CDR2 Heavy Chain 3 (H3CDR2) (SEQ ID NO:90) atatatcctggttatggttccacctac

[0212] Nucleic Acid Sequence for CDR3 Heavy Chain 3 (H3CDR3) (SEQ ID NO:91) gcccgctggggggacagctttgcttac

[0213] Nucleic Acid Sequence for Full Length Heavy Chain 4 (SEQ ID NO:92) atggactggacctggagggtcttctgcttgctggctgtagctccaggtgctcactcccaagtacagcttgtgcaatcaggggccgaggtcaaga agcccggagcatctgtgaaagtaagttgtaaggcctccgggtacacctttaccgactacgttttgagctgggtccggcaagcacccggacaag ggttggaatggatgggggaaatttatcccggctatggcagtacctattacaacgaaaaatttaagggtcgtgtcactatgactcgggataccagc acatccacagtctatatggagctcagtagtctgaggagcgaagacacagccgtctactattgcgctcgctggggtgattctagggcttactggg gacaaggaacacttgtgactgtatcctctgctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggca cagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacac cttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgc aacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccag cacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcg tggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcg ggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaag gtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgccc ccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggaga gcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggac aagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtct ccgggtaaa

[0214] Nucleic Acid Sequence for VH 4 (Variable Heavy 4) (SEQ ID NO:93) atggactggacctggagggtcttctgcttgctggctgtagctccaggtgctcactcccaagtacagcttgtgcaatcaggggccgaggtcaaga agcccggagcatctgtgaaagtaagttgtaaggcctccgggtacacctttaccgactacgttttgagctgggtccggcaagcacccggacaag ggttggaatggatgggggaaatttatcccggctatggcagtacctattacaacgaaaaatttaagggtcgtgtcactatgactcgggataccagcUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO acatccacagtctatatggagctcagtagtctgaggagcgaagacacagccgtctactattgcgctcgctggggtgattctagggcttactggg gacaaggaacacttgtgactgtatcctct

[0215] Nucleic Acid Sequence for CDR1 Heavy Chain 4 (H4CDR1) (SEQ ID NO:94) gggtacacctttaccgactacgtt

[0216] Nucleic Acid Sequence for CDR2 Heavy Chain 4 (H4CDR2) (SEQ ID NO:95) atttatcccggctatggcagtacctat

[0217] Nucleic Acid Sequence for CDR3 Heavy Chain 4 (H4CDR3) (SEQ ID NO:96) gctcgctggggtgattctagggcttac

[0218] Nucleic Acid Sequence for Full Length Heavy Chain 5 (SEQ ID NO:97) atggactggacctggagggtcttctgcttgctggctgtagctccaggtgctcactcccaagtacagctggtacagagtggacccgaggttaaaa aacctggtgcatctgtaaaggtgtcttgcaaggcatcaggttatacatttaccgattatgtcttgagttgggtccgtcaagcccctggtcagggtctt gagtggatgggcgaaatctaccctggctatggtagtacctactataatgagaaattcaaggggagggtgactcttactgccgacaagtccacca ataccgcctatatggaactctcttcactcacatccgaggataccgcagtttatttctgtgctagatggggcgatagcagagcctactggggtcag gggacactcgtcaccgttagctcagctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagc ggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac gtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcac ctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggt ggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcggga ggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtct ccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccat cccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagca atgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccg ggtaaa

[0219] Nucleic Acid Sequence for VH 5 (Variable Heavy 5) (SEQ ID NO:98) atggactggacctggagggtcttctgcttgctggctgtagctccaggtgctcactcccaagtacagctggtacagagtggacccgaggttaaaa aacctggtgcatctgtaaaggtgtcttgcaaggcatcaggttatacatttaccgattatgtcttgagttgggtccgtcaagcccctggtcagggtctt gagtggatgggcgaaatctaccctggctatggtagtacctactataatgagaaattcaaggggagggtgactcttactgccgacaagtccaccaUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO ataccgcctatatggaactctcttcactcacatccgaggataccgcagtttatttctgtgctagatggggcgatagcagagcctactggggtcag gggacactcgtcaccgttagctca

[0220] Nucleic Acid Sequence for CDR1 Heavy Chain 5 (H5CDR1) (SEQ ID NO:99) ggttatacatttaccgattatgtc

[0221] Nucleic Acid Sequence for CDR2 Heavy Chain 5 (H5CDR2) (SEQ ID NO:100) atctaccctggctatggtagtacctac

[0222] Nucleic Acid Sequence for CDR3 Heavy Chain 5 (H5CDR3) (SEQ ID NO:101) gctagatggggcgatagcagagcctac

[0223] Nucleic Acid Sequence for Full Length Heavy Chain 6 (SEQ ID NO:102) atggattggacctggcgcttcctctttgtagtggctgccgccactggcgtccagagtcaggtgcaattggtacagagcggcgcagaagtga aaaagcccggggcatcagtcaaggtgagctgtaaagccagtggctatactttcacaacattcgtggtgagctgggttcgccaggccccagg tcagggcctggagtggatgggcgagatatatccaggatacgggagcacttactataatcaaaaattcaaggggcgagtaactatgacagcc gacaaggtgacttccacagcatacatggaggtttcaagtcttacaagtgaggatacagcagtttactattgcgcccggtggggggattcacg agcttactgggggcaaggcaccctcgtaactgtttcctccgctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagca cctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccag cggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcaccca gacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcc caccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctg aggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaa gacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagga gtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggt gtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgcc gtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagca agctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaa gagcctctccctgtctccgggtaaa

[0224] Nucleic Acid Sequence for VH 6 (Variable Heavy 6) (SEQ ID NO:103) atggattggacctggcgcttcctctttgtagtggctgccgccactggcgtccagagtcaggtgcaattggtacagagcggcgcagaagtga aaaagcccggggcatcagtcaaggtgagctgtaaagccagtggctatactttcacaacattcgtggtgagctgggttcgccaggccccagg tcagggcctggagtggatgggcgagatatatccaggatacgggagcacttactataatcaaaaattcaaggggcgagtaactatgacagccUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO gacaaggtgacttccacagcatacatggaggtttcaagtcttacaagtgaggatacagcagtttactattgcgcccggtggggggattcacg agcttactgggggcaaggcaccctcgtaactgtttcctcc

[0225] Nucleic Acid Sequence for CDR1 Heavy Chain 6 (H6CDR1) (SEQ ID NO:104) ggctatactttcacaacattcgtg

[0226] Nucleic Acid Sequence for CDR2 Heavy Chain 6 (H6CDR2) (SEQ ID NO:105) atatatccaggatacgggagcacttac

[0227] Nucleic Acid Sequence for CDR3 Heavy Chain 6 (H6CDR3) (SEQ ID NO:106) gcccggtggggggattcacgagcttac

[0228] Nucleic Acid Sequence for Full Length Heavy Chain 7 (SEQ ID NO:107) atggattggacctggcgcttcctctttgtagtggctgccgccactggcgtccagagtcaagtccaactcgtccagagtggcgcagaggtgaa aaagcccggagccagcgtcaaggtttcatgcaaagcctctggttacaccttcaccacattcgttgtaagctgggttaggcaggctccaggac aaggcttggagtggatgggcgaaatttatcctggctatggaacagcttactacaaccaaaaatttaaaggccgtgtcacaatgacagccgac aaggttacatccactgcttacatggaagtaagttcacttacaagcgaggacactgccgtgtattactgcgctagatggggggactccttcgcc tactggggacaggggactctggtaactgtgtctagcgctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctct gggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggc gtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccacc gtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagaca aagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtac aagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtac accctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtgg agtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcc tctccctgtctccgggtaaa

[0229] Nucleic Acid Sequence for VH 7 (Variable Heavy 7) (SEQ ID NO:108) atggattggacctggcgcttcctctttgtagtggctgccgccactggcgtccagagtcaagtccaactcgtccagagtggcgcagaggtgaa aaagcccggagccagcgtcaaggtttcatgcaaagcctctggttacaccttcaccacattcgttgtaagctgggttaggcaggctccaggac aaggcttggagtggatgggcgaaatttatcctggctatggaacagcttactacaaccaaaaatttaaaggccgtgtcacaatgacagccgacUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO aaggttacatccactgcttacatggaagtaagttcacttacaagcgaggacactgccgtgtattactgcgctagatggggggactccttcgcc tactggggacaggggactctggtaactgtgtctagc

[0230] Nucleic Acid Sequence for CDR1 Heavy Chain 7 (H7CDR1) (SEQ ID NO:109) ggttacaccttcaccacattcgtt

[0231] Nucleic Acid Sequence for CDR2 Heavy Chain 7 (H7CDR2) (SEQ ID NO:110) atttatcctggctatggaacagcttac

[0232] Nucleic Acid Sequence for CDR3 Heavy Chain 7 (H7CDR3) (SEQ ID NO:111) gctagatggggggactccttcgcctac

[0233] Nucleic Acid Sequence for Full Length Heavy Chain 8 (SEQ ID NO:112) atggattggacctggcgcttcctctttgtagtggctgccgccactggcgtccagagtcaggttcagctcgtgcaaagtggtgctgaggttaaa aaacccggcgcctctgtgaaggtaagctgcaaggcttccggctacacttttactacctttgtggtcagctgggttaggcaagctcctggacaa ggattggaatggatgggtgaaatatacccaggctatggtagcacttactacaaccaaaagttcaagggtcgtgttacaatgacagctgataaa gtgacctccactgcatatatggaggtgtcatctcttacttcagaggatacagcagtctattattgtgccaggtggggggatagctttgcttactg ggggcagggtactttggtaactgtctcttccgctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggggg cacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcac accttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatct gcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccc agcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatg cgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccg cgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgca aggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggga gagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtgg acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctg tctccgggtaaa

[0234] Nucleic Acid Sequence for VH 8 (Variable Heavy 8) (SEQ ID NO:113) atggattggacctggcgcttcctctttgtagtggctgccgccactggcgtccagagtcaggttcagctcgtgcaaagtggtgctgaggttaaa aaacccggcgcctctgtgaaggtaagctgcaaggcttccggctacacttttactacctttgtggtcagctgggttaggcaagctcctggacaa ggattggaatggatgggtgaaatatacccaggctatggtagcacttactacaaccaaaagttcaagggtcgtgttacaatgacagctgataaaUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO gtgacctccactgcatatatggaggtgtcatctcttacttcagaggatacagcagtctattattgtgccaggtggggggatagctttgcttactg ggggcagggtactttggtaactgtctcttcc

[0235] Nucleic Acid Sequence for CDR1 Heavy Chain 8 (H8CDR1) (SEQ ID NO:114) ggctacacttttactacctttgtg

[0236] Nucleic Acid Sequence for CDR2 Heavy Chain 8 (H8CDR2) (SEQ ID NO:115) atatacccaggctatggtagcacttac

[0237] Nucleic Acid Sequence for CDR3 Heavy Chain 8 (H8CDR3) (SEQ ID NO:116) gccaggtggggggatagctttgcttac

[0238] Nucleic Acid Sequence for Full Length Light Chain A (SEQ ID NO:117) atgcggctcccagcccaactcctcggtctcctcatgctttgggtccccggctctagcggagacatagtgatgactcagagtcctcttagtcttcca gtgaccttgggccagcctgcctctatctcctgccggtcatctcaaagtctggtatatagtgacggcaacacatatctgaattggatacagcaacg gcctggacagtcaccaagatgcttgatatacaaggtgtcaaagagagattcaggcgtgcccgacagattttcaggttcaggctctgggacaga cttcactcttaaaatttcacgcgtagaagcagaggatgtaggcgtgtattattgttggcaaggtactcatttcccctggaccttcgggcagggcac caagctcgagatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtg cctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacag agcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgc gaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt

[0239] Nucleic Acid Sequence for VK A (Variable Kappa Light A) (SEQ ID NO:118) atgcggctcccagcccaactcctcggtctcctcatgctttgggtccccggctctagcggagacatagtgatgactcagagtcctcttagtcttcca gtgaccttgggccagcctgcctctatctcctgccggtcatctcaaagtctggtatatagtgacggcaacacatatctgaattggatacagcaacg gcctggacagtcaccaagatgcttgatatacaaggtgtcaaagagagattcaggcgtgcccgacagattttcaggttcaggctctgggacaga cttcactcttaaaatttcacgcgtagaagcagaggatgtaggcgtgtattattgttggcaaggtactcatttcccctggaccttcgggcagggcac caagctcgagatcaaa

[0240] Nucleic Acid Sequence for CDR1 Light Chain A (LACDR1) (SEQ ID NO:119) caaagtctggtatatagtgacggcaacacatat

[0241] Nucleic Acid Sequence for CDR2 Light Chain A (LACDR2) (SEQ ID NO:120) aaggtgtca

[0242] Nucleic Acid Sequence for CDR3 Light Chain A (LACDR3) (SEQ ID NO:121) tggcaaggtactcatttcccctggaccUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0243] Nucleic Acid Sequence for Full Length Light Chain B (SEQ ID NO:122) atgagactcccagcccaactgctcggtctcctgatgctttgggttcctggatcttccggtgatatagtgatgacacaaacaccactctctcttcccg ttactcccggcgaaccagcaagcataagctgcaggtcaagccaatccctggtttacggagacgggaacacttacctcaactggattcagcagc gtcctggtcaatcaccacgccgcttgatttatcaggtctcaaaacgggattcaggcgtaccagatcgcttttcaggatccggtagcgggacaga cttcaccctcaaaatcagtcgggttgaggcagaagacgttggagtgtattactgctggcagggaacccacttcccatttactttcggagggggc accaaattggaaatcaagcgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgt gcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcaca gagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctg cgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt

[0244] Nucleic Acid Sequence for VK B (Variable Kappa Light B) (SEQ ID NO:123) atgagactcccagcccaactgctcggtctcctgatgctttgggttcctggatcttccggtgatatagtgatgacacaaacaccactctctcttcccg ttactcccggcgaaccagcaagcataagctgcaggtcaagccaatccctggtttacggagacgggaacacttacctcaactggattcagcagc gtcctggtcaatcaccacgccgcttgatttatcaggtctcaaaacgggattcaggcgtaccagatcgcttttcaggatccggtagcgggacaga cttcaccctcaaaatcagtcgggttgaggcagaagacgttggagtgtattactgctggcagggaacccacttcccatttactttcggagggggc accaaattggaaatcaag

[0245] Nucleic Acid Sequence for CDR1 Light Chain B (LBCDR1) (SEQ ID NO:124) caatccctggtttacggagacgggaacacttac

[0246] Nucleic Acid Sequence for CDR2 Light Chain B (LBCDR2) (SEQ ID NO:125) caggtctca

[0247] Nucleic Acid Sequence for CDR3 Light Chain B (LBCDR3) (SEQ ID NO:126) tggcagggaacccacttcccatttact

[0248] Nucleic Acid Sequence for Full Length Light Chain C (SEQ ID NO:127) atgcgtctgcccgcccagttgttgggcctgctgatgctttgggttccaggaagcagtggcgatattgtaatgactcagaccccactgtcactgcc agttacaccaggagagccagccagcattagttgtcgttccagccagtcactcgtagatggagatggcaatacctacctgaactggattcaacaa agaccaggacaatctcccagaagattgatctaccaagtgtcaaaacgcgactctggcgttcccgaccgcttttccgggagtggatccggaaca gactttaccctcaaaatatcaagagtagaggctgaagacgtaggagtatactactgttggcaaggaacccattttcctttcaccttcggaggtggc accaaacttgagataaagcgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgt gcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcaca gagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctg cgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0249] Nucleic Acid Sequence for VK C (Variable Kappa Light C) (SEQ ID NO:128) atgcgtctgcccgcccagttgttgggcctgctgatgctttgggttccaggaagcagtggcgatattgtaatgactcagaccccactgtcactgcc agttacaccaggagagccagccagcattagttgtcgttccagccagtcactcgtagatggagatggcaatacctacctgaactggattcaacaa agaccaggacaatctcccagaagattgatctaccaagtgtcaaaacgcgactctggcgttcccgaccgcttttccgggagtggatccggaaca gactttaccctcaaaatatcaagagtagaggctgaagacgtaggagtatactactgttggcaaggaacccattttcctttcaccttcggaggtggc accaaacttgagataaag

[0250] Nucleic Acid Sequence for CDR1 Light Chain C (LCCDR1) (SEQ ID NO:129) cagtcactcgtagatggagatggcaatacctac

[0251] Nucleic Acid Sequence for CDR2 Light Chain C (LCCDR2) (SEQ ID NO:130) caagtgtca

[0252] Nucleic Acid Sequence for CDR3 Light Chain C (LCCDR3) (SEQ ID NO:131) tggcaaggaacccattttcctttcacc

[0253] Nucleic Acid Sequence for Full Length Light Chain D (SEQ ID NO:132) atgagactcccagcccaactgctcggtctcctgatgctttgggttcctggatcttccggtgacgtggtgatgactcaatcccccctttcattgcc cgtgacacttggacagcccgcatctatatcctgcaaaagtagtcagagtcttctcgatagtgacggtaagacatatctgaattggttccaacaa cgcccaggacagtcacctcggcgattgatatatcaggtatctaagttggatagtggggttcccgaccgtttttccggctccgggtccggcacc gattttacactcaaaattagtagggtggaagcagaggacgttggtgtctactactgttggcaagggacccacttcccattcacttttggacaag gaaccaaggtagagattaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttg tgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtca cagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt

[0254] Nucleic Acid Sequence for VK D (Variable Kappa Light D) (SEQ ID NO:133) atgagactcccagcccaactgctcggtctcctgatgctttgggttcctggatcttccggtgacgtggtgatgactcaatcccccctttcattgcc cgtgacacttggacagcccgcatctatatcctgcaaaagtagtcagagtcttctcgatagtgacggtaagacatatctgaattggttccaacaa cgcccaggacagtcacctcggcgattgatatatcaggtatctaagttggatagtggggttcccgaccgtttttccggctccgggtccggcacc gattttacactcaaaattagtagggtggaagcagaggacgttggtgtctactactgttggcaagggacccacttcccattcacttttggacaag gaaccaaggtagagattaaa

[0255] Nucleic Acid Sequence for CDR1 Light Chain D (LDCDR1) (SEQ ID NO:134) cagagtcttctcgatagtgacggtaagacatat

[0256] Nucleic Acid Sequence for CDR2 Light Chain D (LDCDR2) (SEQ ID NO:135) caggtatctUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0257] Nucleic Acid Sequence for CDR3 Light Chain D (LDCDR3) (SEQ ID NO:136) tggcaagggacccacttcccattcact

[0258] Nucleic Acid Sequence for Full Length Light Chain E (SEQ ID NO:137) atgagactcccagcccaactgctcggtctcctgatgctttgggttcctggatcttccggtgatgttgtaatgacacaaagcccactctctctgcc agtgaccccaggccaaccagcaagcattagctgcaaatcctcacaaagtttggtatacggagatggcaacacttacttgaactggttccaac agcggcccggacagtcacctcgcaggcttatctatcaggtgagtaaacttgattctggtgtccctgaccgattttctggatcaggctccggtac agactttacacttaaaataagccgagtcgaggctgaggacgtgggggtatactactgttggcagggaacacattttcccttcacctttgggca aggcaccaaattggaaataaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctg ttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgt cacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacg cctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt

[0259] Nucleic Acid Sequence for VK E (Variable Kappa Light E) (SEQ ID NO:138) atgagactcccagcccaactgctcggtctcctgatgctttgggttcctggatcttccggtgatgttgtaatgacacaaagcccactctctctgcc agtgaccccaggccaaccagcaagcattagctgcaaatcctcacaaagtttggtatacggagatggcaacacttacttgaactggttccaac agcggcccggacagtcacctcgcaggcttatctatcaggtgagtaaacttgattctggtgtccctgaccgattttctggatcaggctccggtac agactttacacttaaaataagccgagtcgaggctgaggacgtgggggtatactactgttggcagggaacacattttcccttcacctttgggca aggcaccaaattggaaataaaa

[0260] Nucleic Acid Sequence for CDR1 Light Chain E (LECDR1) (SEQ ID NO:139) caaagtttggtatacggagatggcaacacttac

[0261] Nucleic Acid Sequence for CDR2 Light Chain E (LECDR2) (SEQ ID NO:140) caggtgagt

[0262] Nucleic Acid Sequence for CDR3 Light Chain E (LECDR3) (SEQ ID NO:141) tggcagggaacacattttcccttcacc VIII. Vectors

[0263] In an exemplary embodiment, the invention further provides vectors that comprise nucleic acid sequences encoding an antibody described herein, antibody-drug conjugate (ADC) described herein, or another peptide described herein. In an embodiment, the vector comprises nucleic acids encoding an antibody described herein. In an embodiment, the vector comprise the nucleic acid sequences described herein. The vectors include, but are not limited to, a virus, plasmid, cosmid, lambda phage or a yeast artificial chromosome (YAC).UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0264] Numerous vector systems can be employed. For example, one class of vectors utilizes DNA elements which are derived from animal viruses such as, for example, bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retroviruses (Rous Sarcoma Virus, MMTV or MOMLV) or SV40 virus. Another class of vectors utilizes RNA elements derived from RNA viruses such as Semliki Forest virus, Eastern Equine Encephalitis virus and Flaviviruses.

[0265] Additionally, cells which have stably integrated the DNA into their chromosomes may be selected by introducing one or more markers which allow for the selection of transfected host cells. The marker may provide, for example, prototropy to an auxotrophic host, biocide resistance (e.g., antibiotics), or resistance to heavy metals such as copper, or the like. The selectable marker gene can be either directly linked to the DNA sequences to be expressed, or introduced into the same cell by cotransformation. Additional elements may also be needed for optimal synthesis of mRNA. These elements may include splice signals, as well as transcriptional promoters, enhancers, and termination signals.

[0266] Once the expression vector or DNA sequence containing the constructs has been prepared for expression, the expression vectors may be transfected or introduced into an appropriate host cell. Various techniques may be employed to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid based transfection or other conventional techniques. In the case of protoplast fusion, the cells are grown in media and screened for the appropriate activity.

[0267] Methods and conditions for culturing the resulting transfected cells and for recovering the antibody, or antibody-drug conjugate produced are known to those skilled in the art, and may be varied or optimized depending upon the specific expression vector and mammalian host cell employed, based upon the present description. IX. Cells

[0268] The present disclosure also provides cells (e.g. host cells) comprising a nucleic acid sequence encoding an antibody described herein or antibody-drug conjugate described herein. For example, the cell (e.g. host cell) may comprise a nucleic acid sequence described herein, or a portion of one of the nucleic acid sequences described herein. In an exemplary embodiment, the cell (e.g. host cell) are genetically engineered to comprise nucleic acid sequences encoding theUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO antibody molecule, ADC, or antimicrobial peptide. In an exemplary embodiment, the cell (e.g. host cell) is genetically engineered by using an expression cassette. The phrase "expression cassette," refers to nucleic acid sequences, which are capable of affecting expression of a gene in hosts compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without introns, and a termination signal. Additional factors necessary or helpful in effecting expression may also be used, such as, for example, an inducible promoter. The disclosure also provides host cells comprising the vectors described herein. The cell can be, but is not limited to, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells.

[0269] In an exemplary embodiment, the invention can be described according to the following clauses (alone or in combination): Clause 1. An antibody that specifically binds Wnt2 described herein, such as one comprising: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33); a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO:5) or IYPGYGSTY (SEQ ID NO:15); a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26); a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO:8), QSLVYGDGNTY (SEQ ID NO:18), QSLVDGDGNTY (SEQ ID NO:28), or QSLLDSDGKTY (SEQ ID NO:58); a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO:9) or QVS (SEQ ID NO:19); and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO:10) or WQGTHFPFT (SEQ ID NO:20. Clause 2. An anti-Wnt2 antibody-drug conjugate comprising: a) the antibody of clause 1; and b) a covalently coupled therapeutic agent.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Clause 3. An anti-Wnt2 antibody-drug conjugate comprising: a) the antibody of clause 1; and b) one or more -L-D moieties covalently coupled to the anti-Wnt2 antibody, wherein L is a linker, D is a therapeutic agent, and the L-D moiety is attached to the anti-Wnt2 antibody through the linker. Clause 4. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the antibody comprises: a heavy chain variable sequence comprising an amino acid sequence which is SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:32, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:47, or SEQ ID NO:52, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence; and a light chain variable sequence comprising an amino acid sequence which is SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:57, or SEQ ID NO: 62, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the light chain variable sequence, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the light chain variable sequence. Clause 5. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the anti-Wnt2 antibody comprises: a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 4), a variable heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO: 5) or IYPGYGSTY (SEQ ID NO: 15), a variable heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO: 6) or ARWGDSFAY (SEQ ID NO: 26), a variable light chain complementarity determining region l (CDRL1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO: 8), QSLVYGDGNTY (SEQ ID NO: 18), or QSLVDGDGNTY (SEQ ID NO: 28), a variable light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence which is KVS (SEQ ID NO: 9) or QVS (SEQ ID NO: 19), and a variable light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO: 10) or WQGTHFPFT (SEQ ID NO: 20).UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Clause 6. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the anti-Wnt2 antibody comprises: a heavy chain variable sequence comprising an amino acid sequence which is SEQ ID NO: 3, SEQ ID NO: 13, or SEQ ID NO: 23, and a light chain variable sequence comprising an amino acid sequence which is SEQ ID NO: 7, SEQ ID NO: 17, or SEQ ID NO: 27. Clause 7. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the anti-Wnt2 antibody comprises: a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 1, SEQ ID NO: 11, or SEQ ID NO: 21, and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 2, SEQ ID NO: 12, or SEQ ID NO: 22. Clause 8. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the anti-Wnt2 antibody comprises a member selected from the group consisting of: a) a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 4), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYPGYGTAY (SEQ ID NO: 5), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARWGDSRAY (SEQ ID NO: 6), a variable light chain complementarity determining region l (CDRL1) comprising the amino acid sequence QSLVYSDGNTY (SEQ ID NO: 8), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence KVS (SEQ ID NO: 9), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence WQGTHFPWT (SEQ ID NO: 10); b) a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 14), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYPGYGSTY (SEQ ID NO: 15), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARWGDSRAY (SEQ ID NO: 16), a variable light chain complementarity determining region l (CDRL1) comprising the amino acid sequence QSLVYGDGNTY (SEQ ID NO: 18), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence QVS (SEQ ID NO: 19), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence WQGTHFPFT (SEQ ID NO: 20); or c) a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO: 24), a variable heavy chainUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYPGYGSTY (SEQ ID NO: 25), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARWGDSFAY (SEQ ID NO: 26), a variable light chain complementarity determining region l (CDRL1) comprising the amino acid sequence QSLVDGDGNTY (SEQ ID NO: 28), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence QVS (SEQ ID NO: 29), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence WQGTHFPFT (SEQ ID NO: 30). Clause 9. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the anti-Wnt2 antibody comprises a member selected from the group consisting of: a) a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 3, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 7; b) a heavy chain variable sequence comprising the amino acid sequence SEQ ID NO: 13, and a light chain variable sequence comprising the amino acid sequence SEQ ID NO: 17; or c) a heavy chain variable sequence comprising the amino acid sequence (SEQ ID NO: 23), and a light chain variable sequence comprising the amino acid sequence (SEQ ID NO: 27). Clause 10. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the anti-Wnt2 antibody comprises a member selected from the group consisting of: a) a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 1 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 2; b) a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 11 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 12; or c) a full length heavy chain comprising an amino acid sequence which is SEQ ID NO: 21 and a full length light chain comprising an amino acid sequence which is SEQ ID NO: 22. Clause 11. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the antibody is a monoclonal antibody. Clause 12. The conjugate of a preceding claim, wherein the anti-Wnt2 antibody is a recombinant antibody or a fusion protein. Clause 13. The conjugate of a preceding claim, wherein the anti-Wnt2 antibody is a rabbit, mouse, chimeric, humanized or fully human monoclonal antibody.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Clause 14. The conjugate of a preceding claim, wherein the anti-Wnt2 antibody is an IgG isotype. Clause 15. The conjugate of a preceding claim, wherein the anti-Wnt2 antibody is an IgG1 isotype. Clause 16. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the therapeutic agent is a chemotherapeutic agent. Clause 17. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the therapeutic agent is a cytotoxin. Clause 18. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the cytotoxin is selected from the group consisting of a tubulin stabilizer, a tubulin destabilizer, a DNA alkylator, a DNA minor groove binder, a DNA intercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a gyrase inhibitor, a protein synthesis inhibitor, a proteosome inhibitor, and an anti-metabolite. Clause 19. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the cytotoxin is selected from the group consisting of Actinomycin-D, Amonafide, an auristatin, benzophenone, benzothiazole, a calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinafide, Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), a maytansinoid, Methotrexate, Mitoxantrone, Nocodazole, Proteosome Inhibitor 1 (PSI 1), Roridin A, T-2 Toxin (trichothecene analog), Taxol, a tubulysin, Velcade®, and Vincristine. Clause 20. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the cytotoxin is an auristatin, a calicheamicin, a maytansinoid, a pyrrolobenzodiazepine (PBD), or a tubulysin. Clause 21. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the cytotoxin is monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), calicheamicin y, mertansine, tubulysin T3, or tubulysin T4. Clause 22. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the cytotoxin is MMAE or MMAF. Clause 23. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein the therapeutic agent is covalently coupled to the antibody by a linker.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Clause 24. The conjugate of a preceding claim, wherein the linker comprises a member selected from the group consisting of valine, citrulline, p-aminobenzyl alcohol p-nitrophenyl benzoate, and polyethylene glycol, or a combination thereof. Clause 25. The conjugate of a preceding claim, wherein the anti-Wnt2 antibody comprises a lysine moiety, and the linker forms a covalent bond with the lysine moiety of the anti-Wnt2 antibody. Clause 26. The conjugate of a preceding claim, wherein there are between 1 and 10 -L-D moieties. Clause 27. The conjugate of a preceding claim, wherein there are between 2 and 8 -L-D moieties. Clause 28. The conjugate of a preceding claim, wherein there are 4 or 5 -L-D moieties. Clause 29. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein from 1 to 10 therapeutic agents are covalently coupled to the antibody. Clause 30. The anti-Wnt2 antibody-drug conjugate of a preceding clause, wherein from 3 to 6 therapeutic agents are covalently coupled to the antibody. Clause 31. A pharmaceutical composition comprising: a) the anti-Wnt2 antibody-drug conjugate of a preceding clause; and b) a pharmaceutically acceptable excipient. Clause 32. A kit comprising the anti-Wnt2 antibody-drug conjugate of a preceding clause; and instructions for use of the kit. Clause 33. A kit comprising the pharmaceutical composition of a preceding clause; and instructions for use of the kit. Clause 34. A method of inhibiting Wnt2 signaling in a cell, comprising contacting a cell that overexpresses a Wnt2 with a therapeutically effective amount of the anti-Wnt2 antibody-drug conjugate of a preceding clause, the pharmaceutical composition of a preceding clause, or the kit of a preceding clause, thereby inhibiting Wnt2 signaling. Clause 35. A method of treating a disease associated with Wnt2 signaling, comprising administering to a subject in need of such treatment a therapeutically effective amount of theUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO anti-Wnt2 antibody-drug conjugate of a preceding clause, the pharmaceutical composition of a preceding clause, or the kit of a preceding clause, thereby treating the disease. Clause 36. A method of treating, preventing or alleviating one or more symptoms of a disease comprising administering an effective amount of the anti-Wnt2 antibody-drug conjugate of any of claims 2-14, the pharmaceutical composition of a preceding clause, or the kit of a preceding clause to a subject, thereby treating, preventing or alleviating one or more symptoms of the disease. Clause 37. The method of a preceding clause, wherein the disease is cancer. Clause 38. The method of a preceding clause, wherein the cancer is selected from the group consisting of breast, ovarian, colorectal, gastric, lung, kidney, bladder, prostate, uterine, thyroid, pancreatic, cervical, esophageal, mesothelioma, head and neck, hepatocellular, melanoma, brain, vulval, testicular, sarcoma, intestine, skin, leukemia, and lymphoma. Clause 39. A method of treating cancer that overexpresses Wnt2, comprising administering to a subject a therapeutically effective amount of the anti-Wnt2 antibody-drug conjugate of a preceding clause, the pharmaceutical composition of a preceding clause, or the kit of a preceding clause, thereby treating the cancer that overexpresses Wnt2.

[0270] All publications and patent applications mentioned in this disclosure are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0271] No admission is made that any reference cited herein constitutes prior art. The discussion of the references states what their authors assert, and the Applicant reserves the right to challenge the accuracy and pertinence of the cited documents. It will be clearly understood that, although a number of information sources, including scientific journal articles, patent documents, and textbooks, are referred to herein; this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0272] The discussion of the general methods given herein is intended for illustrative purposes only. Other alternative methods and alternatives will be apparent to those of skill in the art upon review of this disclosure, and are to be included within the spirit and purview of this application.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0273] Additional embodiments are disclosed in further detail in the following examples, which are provided by way of illustration and are not in any way intended to limit the scope of this disclosure or the claims. EXAMPLES

[0274] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, cell biology, biochemistry, nucleic acid chemistry, and immunology, which are well known to those skilled in the art. Such techniques are explained fully in the literature, such as Sambrook, J., & Russell, D. W. (2012). Molecular Cloning: A Laboratory Manual (4th ed.). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory and Sambrook, J., & Russel, D. W. (2001). Molecular Cloning: A Laboratory Manual (3rd ed.). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory (jointly referred to herein as “Sambrook”); Ausubel, F. M. (1987). Current Protocols in Molecular Biology. New York, NY: Wiley (including supplements through 2014); Bollag, D. M. et al. (1996). Protein Methods. New York, NY: Wiley-Liss; Huang, L. et al. (2005). Nonviral Vectors for Gene Therapy. San Diego: Academic Press; Kaplitt, M. G. et al. (1995). Viral Vectors: Gene Therapy and Neuroscience Applications. San Diego, CA: Academic Press; Lefkovits, I. (1997). The Immunology Methods Manual: The Comprehensive Sourcebook of Techniques. San Diego, CA: Academic Press; Doyle, A. et al. (1998). Cell and Tissue Culture: Laboratory Procedures in Biotechnology. New York, NY: Wiley; Mullis, K. B., Ferré, F. & Gibbs, R. (1994). PCR: The Polymerase Chain Reaction. Boston: Birkhauser Publisher; Greenfield, E. A. (2014). Antibodies: A Laboratory Manual (2nd ed.). New York, NY: Cold Spring Harbor Laboratory Press; Beaucage, S. L. et al. (2000). Current Protocols in Nucleic Acid Chemistry. New York, NY: Wiley, (including supplements through 2014); and Makrides, S. C. (2003). Gene Transfer and Expression in Mammalian Cells. Amsterdam, NL: Elsevier Sciences B.V., the disclosures of which are incorporated herein by reference.

[0275] Additional embodiments are disclosed in further detail in the following examples, which are provided by way of illustration and are not in any way intended to limit the scope of this disclosure or the claims.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO METHODS Isolated Antibodies

[0276] To produce each antibody recombinantly, variable sequences were cloned into Human IgG heavy chain and light chain expression vectors and plasmid DNA was generated for each construct. Plasmids for each heavy and light chain construct were transfected into CHO cells and recombinant antibody was secreted. Subsequently each antibody was purified by Protein A chromatography. Total purified protein concentration was determined by Absorbance measurement at 280nm, and purity of each antibody was determined by SDS gel microcapillary electrophoresis analysis under reducing conditions. Purified antibodies for Lib1 (mAb1) & Lib11 (mAb2) showed characteristic single bands for heavy and light chain by SDS gel with purity ≥ 96%. Flow Cytometry Cell Binding assay

[0277] For flow cytometry cell binding assays, each antibody was prepared with equimolar WNT-2 / sFRP1 protein (R&D Systems), then a dilution series of each premixed antibody / WNT-2 preparation was incubated with either CACO2, A549, or HCT116 cells. After this primary incubation, cells were washed and then incubated with FITC-conjugated secondary antibody specific to the respective antibody species, then washed and resuspended to assess antibody binding for each condition by flow cytometry. All incubations were performed with cells and antibodies prepared in PBS-1X buffer containing 0.1% BSA and NaN3 (sodium azide) to prevent internalization. Cell Internalization assay

[0278] For cell internalization assays, a dilution series of each antibody was prepared with a species-specific secondary Fab fragment conjugated to pH-sensitive fluorescent dye (Zenon pHrodo iFL Green, ThermoFisher). Each antibody- pHrodo dye complex was then incubated overnight (37C) with either A549, LP9, CAF115, CAF117, or H23 cell cultures. Upon internalization and exposure to intracellular pH (pH ~5.5), the pHrodo dye is activated. The following day, cells were evaluated by flow cytometry to determine the extent of internalization for each antibody-pHrodo dye complex.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Direct ELISA assay for WNT2 Binding

[0279] Purified antibodies were evaluated by Direct ELISA to characterize binding to WNT2 antigen and by Flow Cytometry to characterize binding and internalization activity with multiple cell lines. Direct ELISA assays were performed following traditional methods. In short, 96-well polystyrene EIA / RIA plates were coated via direct absorption with serial dilutions of either WNT2 peptide (amino acid sequence SSQRQLCHRHPDVMRC) or recombinant WNT- 2 / sFRP1 protein (R&D Systems) prepared in PBS, blocked with casein, followed by incubations with each antibody, then incubated with HRP-conjugated secondary antibody specific to the respective antibody species. Plates were washed 4x between each incubation step, and finally developed with TMB substrate and absorbance read at 450nm. Relative affinity of each mAb was determined based on EC50 and endpoint sensitivity against a serial dilution series (decreasing concentration) of WNT2 peptide antigen. Ig secretion assay

[0280] To quantify and measure secretion of IgG, IgG titers in CHO supernatant harvests were quantified by Biolayer Interferometry utilizing a ForteBio Octet and Anti-Human Fc biosensors to measure antibody secretion compared to Human IgG control standards. In short, dilution series of each recombinant antibody CHO supernatant were assessed based on binding rate and equilibrium response. IgG concentration were calculated utilizing ForteBio Data Analysis software and 4-Parameter Logistic Fitting with Human IgG standards. PK ELISA assay

[0281] Serum samples provided by Metkine / UCSF from Lib11-MMAE dosing study were analyzed to quantify Human IgG levels in serum at each time point following a 10 mg / kg dose at Time 0hr.

[0282] Serum was evaluated by Sandwich ELISA utilizing Human IgG, Kappa Capture and Detector Pair AS75 / AS76-B (Antibody Solutions). In short, 96-well polystyrene EIA / RIA plates were coated via direct absorption with AS75 Anti-Human IgG, Kappa monoclonal antibody. After blocking with PBS-Casein buffer, dilutions of each PK study mouse serum time point were added to wells simultaneously with AS76-B, Biotinylated Anti-Human IgG, Kappa monoclonal antibody. Plates were washed 4x between each sample incubation step. Detection was performed using Streptavidin-HRP (Jackson ImmunoResearch) and TMB (Moss Substrates)UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO and absorbance read at 450nm. Samples were analyzed with Perkin Elmer Enspire plat reader and IgG levels were calculated using a Human IgG, Kappa standard curve.

[0283] Based on results and curve fitting values to Human IgG standards, the half-life of Lib11- MMAE in mice was estimated at 25 hours. EXAMPLE 1 a) Antibody sequences

[0284] Antibodies were generated from combinations of the following sequences: Heavy Chain Sequences: Table 1 Heavy Chain 1: Sequence: GL ED SG S CP W C L KS G Ssequence described herein, such as: MDWTWRFLFVVAAATGVQS (SEQ ID NO:74).UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Table 2 Heavy Chain 2: Sequence: Full Len th QVQLVQSGAEVKKPGASVKVSCKASGYTFTTFVVSWVRQAPGQGL D SG S CP W C L KS Gsequence described herein, such as MDWTWRVFCLLAVAPGAHS (SEQ ID NO:75). Table 3 Heavy Chain 3: Sequence: GL D SG S CP W C L KS GUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO CDR1 Heavy Chain GYTFTTFV SEQ ID NO:24 3 (H3CDR1), . Table 4 Heavy Chain 4: Sequence: G E T S PP F EY T VD 31 Isequence described herein, such as MDWTWRVFCLLAVAPGAHS (SEQ ID NO:75).UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Table 5 Heavy Chain 5: Sequence: Full Len th QVQLVQSGPEVKKPGASVKVSCKASGYTFTDYVLSWVRQAPGQG E TS SL PC N K C D 36sequence described herein, such as MDWTWRVFCLLAVAPGAHS (SEQ ID NO:75). Table 6 Heavy Chain 6 Sequence: GL ED SG SS A Y K V R G SEUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO CDR1 Heavy Chain GYTFTTFV SEQ ID NO:43 6 (H6CDR1), . Table 7 Heavy Chain 7 Sequence: GL E TS L C N K CL KS GL Esequence described herein, such as MDWTWRVFCLLAVAPGAHS (SEQ ID NO:75).UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Table 8 Heavy Chain 8 Sequence: Full Len th Heav QVQLVQSGAEVKKPGASVKVSCKASGYTFTTFVVSWVRQAPGQGL E TS L C N K CL KS GL EDsequence described herein, such as MDWTWRVFCLLAVAPGAHS (SEQ ID NO:75). Light Chain Sequences: Table 9 Light Chain A: Sequence: QS Q N A QSUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO CDR1 Light Chain QSLVYSDGNTY SEQ ID NO:8 A (LACDR1), . Table 10 Light Chain B: Sequence: Q Ssequence described herein, such as MRLPAQLLGLLMLWVPGSSG (SEQ ID NO:76). Table 11 Light Chain C: Sequence: S Q NF D SUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO CDR1 Light QSLVDGDGNTY SEQ ID NO:28 Chain Cq , . Table 12 Light Chain D: Sequence: GQ W N A Q Wsequence described herein, such as MRLPAQLLGLLMLWVPGSSG (SEQ ID NO:76).UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Table 13 Light Chain E: Sequence: Full Len th DVVMTQSPLSLPVTPGQPASISCKSSQSLVYGDGNTYLNWFQQRPG C L SK G Csequence described herein, such as MRLPAQLLGLLMLWVPGSSG (SEQ ID NO:76).

[0285] The following Lib table (Table 14) presents the variable heavy and variable light sequences of 28 antibodies generated: Name VH VKUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Name VH VK Lib12 2 A Key: 1 = SEQ ID NOD NO:7; 2 = SEQ ID NO:13; B = SEQ ID NO:17; 3 = SEQ ID NO:23; C = SEQ ID NO:27; 4 = SEQ ID NO:32; D = SEQ ID NO:57; 5 = SEQ ID NO:37; E = SEQ ID NO:62; 6 = SEQ ID NO:42; 7 = SEQ ID NO:47; 8 = SEQ ID NO:52;

[0286] The sequences of Lib1 are provided below (Table 15): Lib1 Sequence: QUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Lib1 Sequence: K V T L P K A Y Q

[0287] The sequences of Lib11 are provided below (Table 16): Lib11 Sequence: T S S DUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Lib11 Sequence: G Y V G Y

[0288] The sequences of Lib6 are provided below (Table 17): Lib6 Sequence: G P F K V P H S KUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Lib6 Sequence: G [Lib3 Sequence: GL ED SG S CP W C L KS C L G SUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO Lib3 VK (Variable DIVMTQTPLSLPVTPGEPASISCRSSQSLVYGDGNTYLNWIQQRPGQ Kappa Light Chain) SPRRLIYQVSKRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCW [Lib5 Sequence: GL ED SG S CP W C L KS P Y S G S PG YUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0291] The sequences of Lib26 are provided below (Table 20): Lib26 Sequence: Lib26 QVQLVQSGAEVKKPGASVKVSCKASGYTFTTFVVSWVRQAPGQG S S Y CP KF EY T VD C L G S QUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0292] A human IgG antibody was utilized as a negative control herein. The 28 antibodies described herein as well as the human IgG negative control were expressed with the canonical human IgG1 and Kappa constant region sequences shown below: Human IgG1: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:72 Kappa Light Chain: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:73

[0293] An anti-Wnt2 murine antibody was also utilized herein. The sequence of this antibody was previously described in US 7,959,923, the amino acid and nucleotide sequences of which are herein incorporated by reference for all purposes, and in particular SEQ ID NOs: 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 92, 93, 94, 103, 104, 105, 106, 110, 112, 113, 115, 116, 120, 137, 138, 139, 140, 141, 142, 143, 144, 145, 153, 154, 159, and 160. EXAMPLE 2 Antibody-Drug Conjugate Production

[0294] To produce ADCs (antibody-drug conjugates), each purified antibody was conjugated via random lysine primary amine side chains to NHS-PEG4-VC-PAB-MMAE (N- hydroxysuccinimide ester–polyethylene-glycol–4–valine–citrulline–p-aminobenzoyloxy carbonyl-monomethyl auristatin E), sourced from Broadpharm (Cat# BP-25503).UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WOpH 8.3. Following the conjugation reaction, excess unconjugated linker payload was removed via PBS pH 7.4 buffer exchange using an Amicon Ultra centrifugation device with 30K MWCO. Average DAR (Drug:Antibody Ratio) was determined for each ADC by measuring the Absorbance at 280nm (A280 for total protein) and 248nm (A248 for total MMAE) and calculating DAR using the formulas below: After conjugation of each purified(Drug:Antibody Ratio) was determined for each ADC by measuring the Absorbance at 280nm (A280 for total protein) and 248nm (A248 for total MMAE) as described herein. Example results are shown below: DAR Calculations Post Conjugation 6- E -3EXAMPLE 3 Xenograft mouse models

[0295] The CaCo2 xenograft models were created by subcutaneous injection of 5 x 106cells in PBS into the flank of 12 NSG mice (NOD scid gamma mice) (male and female, 12 weeks orUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO older). Mice were randomized into 3 groups after tumor growth was established. G7-MMAE (10mg / kg once a week,G7:murine wnt2 antibody), Lib11-MMAE (10 mg / kg once a week) were administered through IV. Tumor dimension (using standard calipers) and body weight of mice were measured twice a week and tumor volume was calculated [volume = length x width x width]. For humane reasons, mice were sacrificed when tumor volume reached 2000 mm3. Tumor xenografts were collected one week after the third injection.

[0296] Results are provided in FIG 1A and 1B.

[0297] The CaCo2+CAF115 xenograft models were created by subcutaneous injection of 5 x 106CaCo2 cells and 5 x 105CAF115 cells in PBS into the flank of 12 NSG mice (NOD scid gamma mice) (male and female, 12 weeks or older). Mice were randomized into 3 groups after tumor growth was established. G7-MMAE (10mg / kg once a week), Lib11-MMAE (10 mg / kg once a week) were administered through IV. Tumor dimension (using standard calipers) and body weight of mice were measured twice a week and tumor volume was calculated [volume = length x width x width]. For humane reasons, mice were sacrificed when tumor volume reached 2000 mm3. Tumor xenografts were collected one week after the third injection.

[0298] Results are provided in FIG 2A and 2B.

[0299] Complete inhibition of tumor growth in various models including CaCo2 and CaCo2+CAF115 was observed for both Lib11-MMAE and G7-MMAE, while the weights of mice in treated groups suffered only a minimal change.

[0300] The A549 xenograft models were created by subcutaneous injection of 107cells in PBS into the flank of 10 NU / NU Nude mice (female, 12 weeks) from Charles River laboratories. Mice were randomized into 2 groups after tumor growth was established. Lib11-MMAE (10 mg / kg once a week) was administered through IV. Tumor dimension (using standard calipers) and body weight of mice were measured twice a week and tumor volume was calculated [volume = length x width x width]. For humane reasons, mice were sacrificed when tumor volume reached 2000 mm3. Tumor xenografts were collected one week after the third injection.

[0301] Results are provided in FIG 3A and 3B.

[0302] The A549+CAF117 xenograft models were created by subcutaneous injection of 107A549 cells and 106CAF117cells in PBS into the flank of 10 NU / NU Nude mice (female, 12UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO weeks) from Charles River laboratories. Mice were randomized into 2 groups after tumor growth was established. Lib11-MMAE (10 mg / kg once a week) was administered through IV. Tumor dimension (using standard calipers) and body weight of mice were measured twice a week and tumor volume was calculated [volume = length x width x width]. For humane reasons, mice were sacrificed when tumor volume reached 2000 mm3. Tumor xenografts were collected one week after the third injection.

[0303] Results are provided in FIG 4A and 4B.

[0304] The 211H xenograft models were created by subcutaneous injection of 107cells in PBS into the flank of 10 NSG mice (NOD scid gamma mice) (male and female, 12 weeks or older). Mice were randomized into 2 groups after tumor growth was established. Lib11-MMAE (10 mg / kg once a week) was administered through IV. Tumor dimension (using standard calipers) and body weight of mice were measured twice a week and tumor volume was calculated [volume = length x width x height]. For humane reasons, mice were sacrificed when tumor volume reached 2000 mm3. Tumor xenografts were collected one week after the third injection.

[0305] Results are provided in FIG 5A and 5B.

[0306] The 211H+CAF117 xenograft models were created by subcutaneous injection of 107211H cells and 106CAF117 cells in PBS into the flank of 1010 NSG mice (NOD scid gamma mice) (male and female, 12 weeks or older). Mice were randomized into 2 groups after tumor growth was established. Lib11-MMAE (10 mg / kg once a week) was administered through IV. Tumor dimension (using standard calipers) and body weight of mice were measured twice a week and tumor volume was calculated [volume = length x width x height]. For humane reasons, mice were sacrificed when tumor volume reached 2000 mm3. Tumor xenografts were collected one week after the third injection.

[0307] Results are provided in FIG 6A and 6B.

[0308] Significant inhibition of tumor growth in A549; A549+CAF117; 211H; 211H+CAF117 were also suggested for Lib11-MMAE, again the body weights of the mice in treatment groups barely changed after the injections suggesting optimal therapeutic window for Lib11-MMAE.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO EXAMPLE 4 Real-time PCR

[0309] Total RNA from the various cell lines and SCLC tissue was isolated using the RNeasy extraction method (Qiagen, Valencia, CA, USA). First-strand cDNA was synthesized from total RNA by iScript cDNA synthesis (Bio-Rad, Hercules, CA, USA) according to the manufacturer’s instructions. Taqman RT–PCR analysis was performed on cDNA in a 384-well plate, using a Prism 7900HT Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). Taqman probes were purchased from Applied Biosystems. The expression of Wnt2 gene in each sample was assayed in triplicate and normalized to human GUSB for mRNA expression analysis. Note: 352T, 763T, 784T, 1226T, 1975T, 2058T, 2492T, 2634T and 2758T are all SCLC tumors from different patients. A549 is used as expression level control.

[0310] Results are provided in FIG 7. This study identified WNT2 as a highly expressed gene in human tumor tissues of small cell lung cancer (SCLC) through PCR-based analysis. This overexpression points to a possible oncogenic role of WNT2 in SCLC pathobiology. Clinically, the elevated expression of WNT2 may serve as a valuable biomarker for diagnosis, prognosis, or patient stratification and may represent a potential therapeutic target, and its inhibition could complement or enhance current SCLC treatment regimens. EXAMPLE 5 Wnt2 Binding Affinity of antibodies to Wnt2 peptide & Ig Secretion data:

[0311] The following table presents OD by ELISA vs WNT2 and IgG secretion data for 28 antibodies: O.D. by IgGUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO O.D. by IgG Name ELISA vs. Secretion Key: ++++ = >7.5; +++ om 2.5 to 0. **** = >3; *** =from 3 to 2; = from 2 to 1; = from 1 to 0

[0312] Based in part on this data, five antibodies (Lib3, 5, 6, 7, and 9) were selected to be conjugated with MMAE for further study. Lib11-MMAE was also included in the further studies.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO EXAMPLE 6 Cell viability study of Lib-MMAEs:

[0313] All cells were obtained from the UCSF Cell and Genome Engineering Core and plated in 96-well plates in triplicate at a density of 1,000 cells per well for testing (n=3) with ADC. Cells were treated for 3, 5, 6, or 7 days. The CellTiter-Glo Luminescent Cell Viability Assay (Promega) was used to assess the response. Two independent experiments were conducted to evaluate cell viability.

[0314] Five antibodies (Lib 3, 5, 6, 7, and 9) were selected from the 28 variants for a cell viability study, and then conjugated with MMAE to evaluate their cytotoxic effects as Lib-MMAEs. We tested in a Wnt2-negative cell line (C57mg), a Wnt2-positive cell line (C57Wnt2), and cancer cell lines with high Wnt2 expression, including mesothelioma (211H; H2052), lung cancer (A549), colon cancer (H116), and pancreatic cancer (Panc1, ASPC1, CFPAC1, and Capan1). DNP-MMAE was used as a negative ADC control, while Lib11-MMAE served as the positive ADC control.

[0315] In the Wnt2-negative cell line C57mg, cells were treated for 3 (FIG 8A) and 6 (FIG 8B) days. The results indicated that after both treatment durations, DNP-MMAE, Lib11-MMAE, Lib3-MMAE, Lib5-MMAE, and Lib6-MMAE did not exhibit significant inhibition of cell proliferation.

[0316] In the Wnt2-positive cell line C57Wnt2, cells were treated for 3 (FIG 8C) and 6 (FIG 8D) days. While DNP-MMAE exhibited no cytotoxicity at either time point, Lib11-MMAE and other tested Lib-MMAEs demonstrated varying degrees of cytotoxicity, with Lib3-MMAE showing the most potent inhibition.

[0317] Next, the Lib-MMAEs were tested in the mesothelioma cell lines 211H for 3 (FIG 8E) or 5 (FIG 8F) days and H2052 for 3 days (FIG 8G). IgG-MMAE was used as negative control in the assay. The results indicated that under all treatment conditions, the Lib-MMAEs exhibited varying degrees of cytotoxicity, with Lib3-MMAE demonstrating the most potent inhibition.

[0318] In addition, the colon cancer cell line (H116) (FIG 8H), lung cancer cell line (A549) (FIG 8I & 8J), and pancreatic cancer cell lines (Panc1, ASPC1, CFPAC1, and Capan1) (FIGUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO 8K, 8L, 8M, 8N, 8O, 8P, 8Q, & 8R) were treated with Lib-MMAEs for varying durations. Once again, Lib-MMAEs exhibited varying degrees of cellular activity. EXAMPLE7 In vivo mesothelioma study of Lib3-MMAE, Lib5-MMAE, and Lib6-MMAE:

[0319] The 211H xenograft models were established by subcutaneously injecting 107cells in PBS into the flank of 10 NSG (NOD scid gamma) mice (male and female, 12 weeks or older). Once tumor growth was established, mice were randomized into two groups. In separate experiments, Lib3-MMAE, Lib5-MMAE, and Lib6-MMAE (10 mg / kg) were administered intravenously once per week for three weeks. Tumor dimensions (measured using standard calipers) and body weight were recorded twice weekly, and tumor volume was calculated using the formula: volume = length × width × height. For ethical considerations, mice were sacrificed when tumor volume reached 2000 mm³. Tumor xenografts were collected one week after the third injection.

[0320] The in vivo efficacy and toxicity of Lib3-MMAE, Lib5-MMAE, and Lib6-MMAE were evaluated using the 211H xenograft mouse model. Tumor volumes and mouse body weights were measured as described in the Methods section.

[0321] The results indicated that Lib3-MMAE inhibited tumor growth in the treatment group by approximately 50% compared to the control group (P = 0.0007) (FIG 9A). Additionally, the average body weight of mice in the treatment group decreased by approximately 10% (FIG 9B).

[0322] In the Lib5-MMAE group, tumor growth inhibition was also around 50% compared to the control group (P = 0.0009) (FIG 9C), while the average body weight reduction in the treatment group was less than 10% (FIG 9D).

[0323] In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO

[0324] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms,UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0325] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0326] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0327] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

[0328] Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalentsUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims.

[0329] The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims. In the claims, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) is expressly defined as being invoked for a limitation in the claim only when the exact phrase "means for" or the exact phrase "step for" is recited at the beginning of such limitation in the claim; if such exact phrase is not used in a limitation in the claim, then 35 U.S.C. § 112 (f) or 35 U.S.C. §112(6) is not invoked.

Claims

UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO WHAT IS CLAIMED IS:

1. An antibody that specifically binds Wnt2 comprising: a variable heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence GYTFTTFV (SEQ ID NO:4) or GYTFTDYV (SEQ ID NO:33); a variable heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence which is IYPGYGTAY (SEQ ID NO:5) or IYPGYGSTY (SEQ ID NO:15); a variable heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence which is ARWGDSRAY (SEQ ID NO:6) or ARWGDSFAY (SEQ ID NO:26); a variable light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence which is QSLVYSDGNTY (SEQ ID NO:8), QSLVYGDGNTY (SEQ ID NO:18), QSLVDGDGNTY (SEQ ID NO:28), or QSLLDSDGKTY (SEQ ID NO:58); a variable light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence which is KVS (SEQ ID NO:9) or QVS (SEQ ID NO:19); and a variable light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence which is WQGTHFPWT (SEQ ID NO:10) or WQGTHFPFT (SEQ ID NO:

20.

2. An anti-Wnt2 antibody-drug conjugate comprising: a) the antibody of claim 1; b) a covalently coupled therapeutic agent.

3. The anti-Wnt2 antibody-drug conjugate of claim 1, wherein the anti-Wnt2 antibody comprises: a heavy chain variable sequence comprising an amino acid sequence which is SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:32, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:47, or SEQ ID NO:52, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues from the heavy chain variable sequence, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the heavy chain variable sequence; and a light chain variable sequence comprising an amino acid sequence which is SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:57, or SEQ ID NO: 62, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acidUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO residues from the light chain variable sequence, or has at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99 or 100% sequence identity with the light chain variable sequence.

4. The anti-Wnt2 antibody-drug conjugate of claim 2 or 3, wherein the antibody is a monoclonal antibody.

5. The anti-Wnt2 antibody-drug conjugate of claims 2-4, wherein the therapeutic agent is a chemotherapeutic agent.

6. The anti-Wnt2 antibody-drug conjugate of claims 2-4, wherein the therapeutic agent is a cytotoxin.

7. The anti-Wnt2 antibody-drug conjugate of claim 6, wherein the cytotoxin is selected from the group consisting of a tubulin stabilizer, a tubulin destabilizer, a DNA alkylator, a DNA minor groove binder, a DNA intercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a gyrase inhibitor, a protein synthesis inhibitor, a proteosome inhibitor, and an anti- metabolite.

8. The anti-Wnt2 antibody-drug conjugate of claim 7, wherein the cytotoxin is selected from the group consisting of Actinomycin-D, Amonafide, an auristatin, benzophenone, benzothiazole, a calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinafide, Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), a maytansinoid, Methotrexate, Mitoxantrone, Nocodazole, Proteosome Inhibitor 1 (PSI 1), Roridin A, T-2 Toxin (trichothecene analog), Taxol, a tubulysin, Velcade®, and Vincristine.

9. The anti-Wnt2 antibody-drug conjugate of claim 7, wherein the cytotoxin is an auristatin, a calicheamicin, a maytansinoid, a pyrrolobenzodiazepine (PBD), or a tubulysin.

10. The anti-Wnt2 antibody-drug conjugate of claim 7, wherein the cytotoxin is monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), calicheamicin y, mertansine, tubulysin T3, or tubulysin T4.UCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO 11. The anti-Wnt2 antibody-drug conjugate of claim 7, wherein the cytotoxin is MMAE or MMAF.

12. The anti-Wnt2 antibody-drug conjugate of claims 2-11, wherein the therapeutic agent is covalently coupled to the antibody by a linker.

13. The anti-Wnt2 antibody-drug conjugate of claims 2-12, wherein from 1 to 10 therapeutic agents are covalently coupled to the antibody.

14. The anti-Wnt2 antibody-drug conjugate of claims 2-12, wherein from 3 to 6 therapeutic agents are covalently coupled to the antibody.

15. A pharmaceutical composition comprising: a) the anti-Wnt2 antibody-drug conjugate of claims 2-14; and b) a pharmaceutically acceptable excipient.

16. A kit comprising the anti-Wnt2 antibody-drug conjugate of claims 2-14; and instructions for use of the kit.

17. A kit comprising the pharmaceutical composition of claim 15; and instructions for use of the kit.

18. A method of inhibiting Wnt2 signaling in a cell, comprising contacting a cell that overexpresses a Wnt2 with a therapeutically effective amount of the anti-Wnt2 antibody-drug conjugate of any of claims 2-14, the pharmaceutical composition of claim 15, or the kit of claim 16 or 17, thereby inhibiting Wnt2 signaling.

19. A method of treating a disease associated with Wnt2 signaling, comprising administering to a subject in need of such treatment a therapeutically effective amount of the anti-Wnt2 antibody-drug conjugate of any of claims 2-14, the pharmaceutical composition of claim 15, or the kit of claim 16 or 17, thereby treating the disease.

20. A method of treating, preventing or alleviating one or more symptoms of a disease comprising administering an effective amount of the anti-Wnt2 antibody-drug conjugate of anyUCSF Ref No: SF2022-222-2-PCT BFF Ref No: UCSF-764WO of claims 2-14, the pharmaceutical composition of claim 15, or the kit of claim 16 or 17 to a subject, thereby treating, preventing or alleviating one or more symptoms of the disease.

21. The method of claim 19 or 20, wherein the disease is cancer.

22. The method of claim 21, wherein the cancer is selected from the group consisting of breast, ovarian, colorectal, gastric, lung, kidney, bladder, prostate, uterine, thyroid, pancreatic, cervical, esophageal, mesothelioma, head and neck, hepatocellular, melanoma, brain, vulval, testicular, sarcoma, intestine, skin, leukemia, and lymphoma.

23. A method of treating cancer that overexpresses Wnt2, comprising administering to a subject a therapeutically effective amount of the anti-Wnt2 antibody-drug conjugate of any of claims 2-14, the pharmaceutical composition of claim 15, or the kit of claim 16 or 17, thereby treating the cancer that overexpresses Wnt2.

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