Anti-CD64 antibodies and antibody-drug conjugates and methods of treating diseases using the same

Abstract

Provided are antibodies that specifically bind CD64 antigen. Also provided are conjugates comprising such antibodies. In some cases, the conjugates comprise an anti-CD64 antibody conjugated through a maleimide based linker to an anthracycline or an anthracycline derivative, such as PNU-159682. Pharmaceutical compositions and kits that comprise the antibodies and conjugates are also provided. Further provided are methods of administering anti-CD64 conjugates described herein to an individual having a cancer, wherein the individual comprises cancer cells that express CD64, and wherein the conjugate is targeted to the cancer cells expressing CD64. In certain embodiments, provided are methods comprising administering anti-CD64 conjugates described herein to an individual having an inflammatory or an autoimmune disease, wherein the individual comprises inflammatory or autoimmune cells that express CD64, and wherein the anti-CD64 conjugate is targeted to the inflammatory or autoimmune cells expressing CD64.

Description

[0001] ANTI-CD64 ANTIBODIES AND ANTIBODY-DRUG CONJUGATES AND METHODS OF T HEATING DISEASES USING THE SAME

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] Pursuant to 35 U.S.C. §119(e), this application claims priority to the filing date of the United States Provisional Patent Application Serial No. 63 / 779,096, filed March 27, 2025, the disclosure of which application is herein incorporated by reference.

[0004] INTRODUCTION GD64 is expressed on the surface of certain immune cells, such as monocytes (including early monocyte precursors to mature monocytes), macrophages, dendritic cells, neutrophils, and eosinophils. CD64 is a high-affinity receptor for immunoglobulin G (IgG). CD64 plays a role in the immune response by binding to IgG-coated pathogens and immune complexes thereby facilitating their phagocytosis by immune cells. Certain cancers involve CD64 expressing cells, including leukemias such as acute myeloid leukemia (AML) with a monocytic component, classified as AML M4 type and AML M5 type by the French-American-British Classification, as well as chronic myelomonocytic leukemia (CMML).

[0005] Moreover, tumor infiltrating macrophages (TAMs) and Tissue Resident Macrophages (TRMs) are macrophages in the solid tumors. TAMs and TRMs also express CD64. Interaction of TAMs or TRMs with neoplastic cells in the tumor microenvironment results in immunosuppression and promotion of tumor growth. The prevalence of TAMs or TRMs within solid tumors is linked with worse overall prognosis.

[0006] Further, certain pro-inflammatory monocytes and macrophages expressing CD64 are involved in the development of certain inflammatory and autoimmune diseases.

[0007] Therefore, targeting CD64 expressing cells may have therapeutic potential in cancer, inflammatory, or autoimmune diseases.

[0008] SU ARY

[0009] Provided herein are antibodies that specifically bind CD64, wherein the antibodies comprise specific sequences, including specific sequences of the complementarity determining regions (CDRs). Also provided herein are conjugates comprising the anti-CD64 antibodies having the specific sequences conjugated to an agent, such as a chemotherapeutic agent, a toxin, acytotoxic agent, a radiation sensitizing agent, a radioactive isotope, a detectable label, and a halflife extending moiety. In certain embodiments, the anti-CD64 antibodies having the specific sequences are conjugated to an anthracycline or an anthracycline derivative, such as PNU-159682. In some cases, an anti-CD64 antibody is conjugated to an anthracycline or an anthracycline derivative via a maleimide based linker. In a specific embodiment, the maleimide based linker is Mal-C2-Gly3-EDA.

[0010] Further provided herein are multi-specific antibodies comprising an anti-CD64 binding domain comprising the specific sequences and a second antigen-binding domain. In some cases, the second antigen-binding domain specifically binds to an antigen other than CD64, such as a tumor antigen. Pharmaceutical compositions and kits that comprise the anti-CD64 antibodies, conjugates thereof, or multi-specific antibodies described herein are also provided.

[0011] Additionally provided herein are antibodies that specifically bind CD64 conjugated to an anthracycline or an anthracycline derivative, such as PNU-159682. In some cases, an anti-CD64 antibody is conjugated to an anthracycline or an anthracycline derivative via a maleimide based linker. In a specific embodiment, the maleimide based linker is Mal-C2-Gly3-EDA.

[0012] Further provided herein are cells that express the anti-CD64 antibodies described herein as well as methods of producing the anti-CD64 antibodies described herein by culturing such cells. Nucleic acids that encode the anti-CD64 antibodies described herein are also provided.

[0013] Even further aspects of the present disclosure provide methods of using the anti-CD64 antibody conjugates described herein, e.g., for therapeutic purposes. In certain embodiments, provided are methods that comprise administering an anti-CD64 antibody conjugate described in the present disclosure to an individual having a disease, such as a cancer, an inflammatory disease, or an autoimmune disease. In certain such cases, the disease is a cancer and the individual comprises cancer cells that express CD64. In some cases, the disease is an inflammatory or an autoimmune disease and the individual comprises inflammatory cells or autoimmune cells that express CD64.

[0014] BRIEF DESCRIPTION OF THE FIGURES FIGS. 1A-1C show the sequence alignment of CDRs of the anti-CD64 antibodies described herein. A shows the alignment of the heavy chain CDRs and B shows the alignment of the light chain CDRs. C shows the sequence homology comparisons of the anti-CD64 antibodies described herein.FIGs. 2A-2B depict the expression profile of CD64 in AML patients. A shows the CD64 expression in monocytic precursors and mature monocytes. B shows the CD64 expression in M2, M4 and M5 type AML.

[0015] FIGs. 3A-3B depict ADC-like approach to evaluate optimal payloads to target monocytic cells using anti-CD64 antibodies. A shows the secondary antibody drug conjugates that recognize the Fc region of the primary antibody and are conjugated to various payloads. B shows the comparisons of the activity of the unconjugated CD64 primary antibody to the primary + secondary ADCs coupled to the different payloads.

[0016] FIGs. 4A-4C depict different linkers and payloads. A shows a cleavable valine-citrulline linker couple to PNU-159682. B shows a linker based on a triple glycine peptide coupled to PNU-159682 modified by an EDA group. C shows a protease cleavable linker based on the GGFG motif bound to Exatecan as payload.

[0017] FIGs. 5A-5B show that ADCs conjugated to PNU-159682 (but not Exatecan) display selective targeting of monocytic cells from AML patients. A shows dose response activity of anti-CD64 antibodies conjugated to PNU-159682. B shows dose response activity of anti-CD64 antibodies conjugated to Exatecan.

[0018] FIGs. 6A-6B show differential release of PNU-159682 conjugated to anti-CD64 antibody via different linkers. A shows the release of PNU-159682 conjugated to an anti-CD64 antibody via a cleavable linker. B shows the release of PNU-159682 conjugated to an anti-CD64 antibody via a non-cleavable linker.

[0019] FIGs. 7A-7C show the effects of a CD64 ADCs on disseminated leukemia in Nod SCID Gamma (NSG) Mice using cleavable and non-cleavable linkers. A schematically represents the experimental protocol. B shows the flow cytometry analysis to track the human leukemia cells in the mouse bone marrow (p = 0.01). C shows the different tolerability profiles of constructs with cleavable and non-cleavable linkers.

[0020] FIGs. 8A-8B show the effects of a CD64 ADC on circulating monocytes and TAMs in a humanized mouse model. A schematically presents the experimental protocol. B shows the flow cytometry analysis of circulating monocytes in the blood and of TAMs in the tumor microenvironment (p = 0.038).

[0021] FIGs. 9A-9B show the activity and specificity of ADCs generated using twelve of the anti-CD64 antibodies described herein conjugated to PNU-159682 via a non-cleavable linker. A demonstrates specificity and B demonstrates dose response activity of the anti-CD64 antibody PNU-159682 conjugates.FIGs. 10A-10B show the effects of a naked CD64 mAb vs. its derived ADC on disseminated leukemia in Nod SCID Gamma (NSG) Mice. A shows the flow cytometry analysis to track the human leukemia cells in the mouse bone marrow (p = 0.05). B shows the tolerability profiles of both ADC constructs.

[0022] FIGs. 11A-11C show the effects of a CD64 ADC on a kinetic CDX model of human monocytic leukemia in Mice. A schematically represents the experimental protocol. B shows the tri-weekly measurements tracking tumor growth and durability of remission. C shows the tolerability profiles.

[0023] DETAILED DESCRIPTION

[0024] Before the antibodies, antibody conjugates, compositions, and methods of the present disclosure are described in greater detail, it is to be understood that the antibodies, antibody conjugates, compositions, and methods are 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.

[0025] 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 antibodies, compositions and methods. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, 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 antibodies, antibody conjugates, compositions, and methods.

[0026] Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

[0027] 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 the antibodies, compositions and methods belong. Although any antibodies, compositions and methods similaror equivalent to those described herein can also be used in the practice or testing of the antibodies, antibody conjugates, compositions, and methods, representative illustrative antibodies, antibody conjugates, compositions, and methods are described below.

[0028] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the materials and / or methods in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present antibodies, compositions and methods are not entitled to antedate such publication, as the date of publication provided may be different from the actual publication date which may need to be independently confirmed.

[0029] It is 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. 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.

[0030] It is appreciated that certain features of the antibodies, antibody conjugates, compositions, and methods, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the antibodies, antibody conjugates, compositions, and methods, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace operable processes and / or compositions. In addition, all sub-combinations listed in the embodiments describing such variables are also specifically embraced by the present antibodies, compositions and methods and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.

[0031] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present methods. Any recitedmethod can be carried out in the order of events recited or in any other order that is logically possible.

[0032] ANTIBODIES

[0033] The present disclosure provides antibodies that specifically bind CD64 protein.

[0034] GD64 protein is expressed on the surface of certain immune cells, such as monocytes (including early monocyte precursors to mature monocytes), macrophages, dendritic cells and neutrophils. CD64 is also known in the art as: high affinity immunoglobulin gamma Fc receptor I, IgG Fc Receptor I, Fc gamma Ria, Fc-Gamma Receptor I A1 , or FcyRI.

[0035] GD64 is a high-affinity receptor for immunoglobulin G (IgG). CD64 plays a role in the immune response by binding to IgG-coated pathogens and immune complexes thereby facilitating their phagocytosis by immune cells.

[0036] An example of human CD64 is provided in the Gen Bank accession no. AAI52384.1 , which provides GD64 having the following amino acid sequence:

[0037] MWFLTTLLLWVPVDGQVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFL NGTATQTSTPSYRITSASVNDSGEYRCQRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLAL RCHAWKDKLVYNVLYYRNGKAFKFFHWNSNLTILKTNISHNGTYHCSGMGKHRYTSAGISVTV KELFPAPVLNASVTSPLLEGNLVTLSCETKLLLQRPGLQLYFSFYMGSKTLRGRNTSSEYQILTA RREDSGLYWCEAATEDGNVLKRSPELELQVLGLQLPTPVWFHVLFYLAVGIMFLVNTVLWVTIR KELKRKKKWDLEISLDSGHEKKVISSLQEDRHLEEELKCQEQKEEQLQEGVHRKEPQGAT (SEQ ID NO: 353).

[0038] Examples of CD64 in other animals, such as mouse, rat, bovine, porcine, canine, feline, and equine CD64 are known in the art and implementation of the antibodies, conjugates, compositions, and methods described herein in such animals is within the purview of the disclosure.

[0039] The term “antibody” (also used interchangeably with “immunoglobulin”) encompasses polyclonal (e.g., rabbit polyclonal) and monoclonal antibody preparations where the antibody may be an antibody or immunoglobulin of any isotype (e.g., IgG (e.g., IgG 1 , lgG2, lgG3, or lgG4), IgE, IgD, IgA, IgM, etc.), whole antibodies (e.g., antibodies composed of a tetramer which in turn is composed of two dimers of a heavy and light chain polypeptide); single chain antibodies (e.g., scFv); fragments of antibodies (e.g., fragments of whole or single chain antibodies) which retain specific binding to the compound, including, but not limited to single chain Fv (scFv), Fab, (Fab’ , (SCFV’)2, and diabodies; chimeric antibodies; monoclonal antibodies, humanized antibodies,human antibodies; comprising an antigen-binding portion of an antibody and a non-antibody protein. In some embodiments, the antibody is selected from an IgG, Fv, single chain antibody, scFv, a Fab, a F(ab’)2, and a F(ab’). The antibodies may be further conjugated to other moieties, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), and the like.

[0040] Immunoglobulin polypeptides include the kappa and lambda light chains and the alpha, gamma (IgGi, lgG2, IgGa, lgG4), delta, epsilon and mu heavy chains or equivalents in other species. Full-length immunoglobulin “light chains” (usually of about 25 kDa or about 214 amino acids) comprise a variable region of about 110 amino acids at the NHs-terminus and a kappa or lambda constant region at the COOH-terminus. Full-length immunoglobulin “heavy chains” (of about 150 kDa or about 446 amino acids), similarly comprise a variable region (of about 116 amino acids) and one of the aforementioned heavy chain constant regions, e.g., gamma (of about 330 amino acids).

[0041] An immunoglobulin light or heavy chain variable region (VLand VH, respectively) is composed of a “framework” region (FR) interrupted by three hypervariable regions, also called “complementarity determining regions” or “CDRs”. The extent of the framework region and CDRs have been defined (see, E. Kabat et al., Sequences of proteins of immunological interest, 4th ed. U.S. Dept. Health and Human Services, Public Health Services, Bethesda, MD (1987); and Lefranc et al. IMGT, the international ImMunoGeneTics information system®. Nucl. Acids Res., 2005, 33, D593-D597)). The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs. The CDRs are primarily responsible for binding to an epitope of an antigen. All CDRs and framework provided by the present disclosure are defined according to Kabat, supra, unless otherwise indicated.

[0042] An “antibody” thus encompasses a protein having one or more polypeptides that can be genetically encodable, e.g., by immunoglobulin genes or fragments of immunoglobulin genes. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. In some embodiments, an antibody of the present disclosure is an IgG antibody, e.g., an lgG1 antibody, such as a human lgG1 antibody. In some embodiments, an antibody of the present disclosure comprises a human Fc domain.A typical immunoglobulin (antibody) structural unit is known to comprise a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kD) and one "heavy" chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively.

[0043] Antibodies encompass intact immunoglobulins as well as a number of well characterized fragments which may be genetically encoded or produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CHI by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region thereby converting the (Fab')2 dimer into an Fab' monomer. The Fab' monomer is essentially a Fab with part of the hinge region (see, Fundamental Immunology, W.E. Paul, ed., Raven Press, N.Y. (1993), for a more detailed description of other antibody fragments). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of ordinary skill in the art will appreciate that such Fab' fragments may be synthesized de novo either chemically or by utilizing recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies or synthesized de novo using recombinant DNA methodologies, including, but are not limited to, Fab'2, IgG, IgM, IgA, scFv, dAb, nanobodies, unibodies, and diabodies. In certain embodiments, an antibody of the present disclosure is selected from an IgG, Fv, single chain antibody, scFv, Fab, F(ab')2, and Fab'.

[0044] According to some embodiments, an antibody of the present disclosure is a monoclonal antibody. "Monoclonal antibody" refers to a composition comprising one or more antibodies obtained from a population of substantially homogeneous antibodies, i.e., a population the individual antibodies of which are identical except for any naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site and generally to a single epitope on an antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and does not require that the antibody be produced by any particular method or be the only antibody in the composition.

[0045] In certain embodiments, an antibody of the present disclosure is a humanized antibody. As used herein, a humanized antibody is a recombinant polypeptide that is derived from a nonhuman (e.g., rabbit, rodent, or the like) antibody and has been modified to contain at least aportion of the framework and / or constant regions of a human antibody. Humanized antibodies also encompass chimeric antibodies and CDR-grafted antibodies in which various regions may be derived from different species. Chimeric antibodies may be antibodies that include a variable region from any source linked to a human constant region (e.g., a human Fc domain). Thus, in chimeric antibodies, the variable region can be non-human, and the constant region is human. CDR-grafted antibodies are antibodies that include the CDRs from a non-human “donor” antibody linked to the framework region from a human “recipient” antibody. For example, an antibody of the present disclosure in a form of an scFV may be linked to a human constant region (e.g., Fc domain) to be made into a human immunoglobulin.

[0046] In general, humanized antibodies produce a reduced immune response in a human host, as compared to a non-humanized version of the same antibody. Antibodies can be humanized using a variety of techniques including, for example, CDR-grafting, veneering or resurfacing, chain shuffling, and the like. In certain embodiments, framework substitutions are identified by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions.

[0047] Accordingly, any of the antibodies described herein may be humanized using available methods. The substitution of rabbit or mouse CDRs into a human variable domain framework can result in retention of their correct spatial orientation where, e.g., the human variable domain framework adopts the same or similar conformation to the rabbit or mouse variable framework from which the CDRs originated. This can be achieved by obtaining the human variable domains from human antibodies whose framework sequences exhibit a high degree of sequence identity with the rabbit or mouse variable framework domains from which the CDRs were derived. The heavy and light chain variable framework regions can be derived from the same or different human antibody sequences. The human antibody sequences can be the sequences of naturally occurring human antibodies or can be consensus sequences of several human antibodies.

[0048] Having identified the complementarity determining regions of the rabbit or mouse donor immunoglobulin and appropriate human acceptor immunoglobulins, the next step is to determine which, if any, residues from these components should be substituted to optimize the properties of the resulting humanized antibody. In general, substitution of human amino acid residues with rabbit or mouse should be minimized, because introduction of rabbit or mouse residues increases the risk of the antibody eliciting a human-anti-rabbit-antibody (HARA) or human-anti-mouse-antibody (HAMA) response in humans. Art-recognized methods of determining immune response can be performed to monitor a HARA or HAMA response in a particular patient or during clinicaltrials. Patients administered humanized antibodies can be given an immunogenicity assessment at the beginning and throughout the administration of said therapy. The HARA or HAMA response is measured, for example, by detecting antibodies to the humanized therapeutic reagent, in serum samples from the patient using a method known to one in the art, including surface plasmon resonance technology (BIAGORE) and / or solid-phase ELISA analysis. In many embodiments, a subject humanized antibody does not substantially elicit a HARA response in a human subject.

[0049] Certain amino acids from the human variable region framework residues are selected for substitution based on their possible influence on CDR conformation and / or binding to antigen. The unnatural juxtaposition of rabbit or murine CDR regions with human variable framework region can result in unnatural conformational restraints, which, unless corrected by substitution of certain amino acid residues, lead to loss of binding affinity. The selection of amino acid residues for substitution can be determined, in part, by computer modeling. Computer hardware and software for producing three-dimensional images of immunoglobulin molecules are known in the art. In general, molecular models are produced starting from solved structures for immunoglobulin chains or domains thereof. The chains to be modeled are compared for amino acid sequence similarity with chains or domains of solved three-dimensional structures, and the chains or domains showing the greatest sequence similarity is / are selected as starting points for construction of the molecular model. Chains or domains sharing at least 50% sequence identity are selected for modeling, and preferably those sharing at least 60%, 70%, 80%, 90% sequence identity or more are selected for modeling. The solved starting structures are modified to allow for differences between the actual amino acids in the immunoglobulin chains or domains being modeled, and those in the starting structure. The modified structures are then assembled into a composite immunoglobulin. Finally, the model is refined by energy minimization and by verifying that all atoms are within appropriate distances from one another and that bond lengths and angles are within chemically acceptable limits.

[0050] When framework residues, as defined by, e.g., Kabat, constitute structural loop residues as defined by, e.g., Chothia, the amino acids present in the rabbit or mouse antibody may be selected for substitution into the humanized antibody. Residues which are “adjacent to a CDR region” include amino acid residues in positions immediately adjacent to one or more of the CDRs in the primary sequence of the humanized immunoglobulin chain, for example, in positions immediately adjacent to a CDR as defined by Kabat, or a CDR as defined by Chothia (See e.g., Chothia and Lesk JMB 196:901 (1987)). These amino acids are particularly likely to interact with the amino acids in the CDRs and, if chosen from the acceptor, to distort the donor CDRs and reduce affinity. Moreover, the adjacent amino acids may interact directly with the antigen (Amit etal., Science, 233:747 (1986)) and selecting these amino acids from the donor may be desirable to keep all the antigen contacts that provide affinity in the original antibody. Approaches that may be employed to humanize any of the antibodies described herein include, but are not limited to, those described in Williams, D., Matthews, D. & Jones, T. Humanising Antibodies by CDR Grafting. Antibody Engineering 319-339 (2010) doi:10.1007 / 978-3-642-01144-3_21 ; Kuramochi, T., Igawa, T., Tsunoda, H. & Hattori, K. Humanization and simultaneous optimization of monoclonal antibody. Methods Mol. Biol. 1060, 123-37 (2014); Hwang, W. Y., Almagro, J. C., Buss, T. N., Tan, P. & Foote, J. Use of human germline genes in a CDR homology-based approach to antibody humanization. Methods 36, 35-42 (2005); Lo, B. K. Antibody humanization by CDR grafting. Methods Mol. Biol. 248, 135-59 (2004); and Lefranc, M.-P. P., Ehrenmann, F., Ginestoux, C., Giudicelli, V. & Duroux, P. Use of IMGT(®) databases and tools for antibody engineering and humanization. Methods Mol. Biol. 907, 3-37 (2012); the disclosures of which are incorporated herein by reference in their entireties for all purposes.

[0051] An antibody of the present disclosure specifically binds to CD64. An antibody “specifically binds” or “preferentially binds” to a target if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances, e.g., in a sample. In certain embodiments, an antibody “specifically binds” an antigen if it binds to or associates with the antigen with an affinity or Ka (that is, an association rate constant of a particular binding interaction with units of 1 / M) of, for example, greater than or equal to about 104M’1. Alternatively, affinity may be defined as an equilibrium dissociation constant (KD) of a particular binding interaction with units of M (e.g., 105M to 1013M, or less). In certain aspects, specific binding means the antibody binds to the antigen with a KD of less than or equal to about 10-5M, less than or equal to about 10'6M, less than or equal to about 10-7M, less than or equal to about 10-8M, or less than or equal to about 10-9M, 10-1° M, 10-11M, or 10-12M or less. The binding affinity of the antibody for the antigen can be readily determined using conventional techniques, e.g., by competitive ELISA (enzyme-linked immunosorbent assay), equilibrium dialysis, by using surface plasmon resonance (SPR) technology (e.g., the BIAcore 2000 or BIAcore T200 instrument, using general procedures outlined by the manufacturer); by radioimmunoassay; or the like.

[0052] Whether an antibody of the present disclosure “competes with” a second antibody for binding to the antigen may be readily determined using competitive binding assays known in the art. Competing antibodies may be identified, for example, via an antibody competition assay. For example, a sample of a first antibody can be bound to a solid support. Then, a sample of a second antibody suspected of being able to compete with such first antibody is added. One of the two antibodies is labeled. If the labeled antibody and the unlabeled antibody bind to separate anddiscrete sites on the antigen, the labeled antibody will bind to the same level whether or not the suspected competing antibody is present. However, if the sites of interaction are identical or overlapping, the unlabeled antibody will compete, and the amount of labeled antibody bound to the antigen will be lowered. If the unlabeled antibody is present in excess, very little, if any, labeled antibody will bind.

[0053] For purposes of the present disclosure, competing antibodies are those that decrease the binding of an antibody to the antigen by about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 99% or more. Details of procedures for carrying out such competition assays are known and can be found, for example, in Harlow and Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1988, 567-569, 1988, ISBN 0-87969-314-2. Such assays can be made quantitative by using purified antibodies. A standard curve may be established by titrating one antibody against itself, i.e., the same antibody is used for both the label and the competitor. The capacity of an unlabeled competing antibody to inhibit the binding of the labeled antibody to the plate may be titrated. The results may be plotted, and the concentrations necessary to achieve the desired degree of binding inhibition may be compared.

[0054] Anti-CD64 Antibodies having specific sequences

[0055] According to some embodiments, provided are antibodies that specifically bind CD64. In certain embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and competes for binding to CD64 with an antibody having one, two, three, four, five, or all six complementarity determining regions (CDRs) of one or more of the anti-CD64 antibodies designated herein by the clone IDs identified in Table 1 below. According to some embodiments, an antibody of the present disclosure specifically binds CD64 and comprises one, two, three, four, five, or all six CDRs of the anti-CD64 antibodies designated herein by the clone IDs identified in Table 1 below. The amino acid sequences of the variable heavy chain (VH) polypeptides and the variable light chain (VL) polypeptides of the various anti-CD64 antibodies described herein are provided in Table 1 below.Table 1 - Amino Acid Sequences of Example Anti-CD64 Antibodies

[0056] ID # in

[0057] Chain SEQ ID FIG. 1 / Sequence

[0058] type NO: Clone ID

[0059] EVQLQQSGPELVKPGALVKISCKASGYTFTSYDISWVMQRPGQ

[0060] 1

[0061] Heavy GLEWIGWIYPGDGSTKYNEKFKGKATLTADKSSSTAYMQLSSLT 1 12B02

[0062] SENSAVYFCVREVRREWYFDVWGAGTTVTVSS DIQMTQSPSSLSASLGGKVTITCKASQDINKYIAWYQHKPGKGP

[0063] 1

[0064] Light RLLIHYTSILQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYYCLQ 2 12B02

[0065] FDNLLRTFGGGTKLEIN EVQLQQSAAELARPGASVKMSCKASGYTFTTYTMHWVKQRPG

[0066] 2

[0067] Heavy QGLEWIGTINPGSGYIENNQKFKDKTTLTADKSSTTAYMHLSSLT 3 26E10

[0068] SE DS AVYYC ARSGTG I FYAM DYWGQGTTVTVSS DVVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQS

[0069] 2

[0070] Light PKLLIYSASNLYTGVPARFTGSGYGTDFTFTISTVQAEDLAVYFC 4 26E10

[0071] QQDYRSPYTFGGGTKLELK EVKLVESGGGLVKPGGSLKLSCAASGFTFSSYVMSWVRQTPEK

[0072] 3

[0073] Heavy RLEWVATISNGGSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLR 5 32E09

[0074] SEDTAMYYCSRHWGISGYDAMEYWGQGTSVTVSS DIQMTQSPASLSASVGETVTITCGASENIYGALNWYQRKQGKSP

[0075] 3

[0076] Light QLLIYGTTNLAEGMSSRFSGSGSGRQYSLKIRSLHPDDVATYYC 6 32E09

[0077] QSVLSFPYTFGGGTKLELK EVQLQQSGPELVTPGTLVKISCKASGYIFTSYDISWVKQSPGQG

[0078] 4

[0079] Heavy LEWIGWIYPGDGSAKYNEKFKGKATLTADKSSSTAYMQLSSLTS 7 3D03

[0080] ENS AVYFC AR EVR R E WF F D VWG AGTTVTVSS DIQMTQSPSSLSASLGDKVTITCRASQDINKYIAWYQHKPGRGP

[0081] 4

[0082] Light RLLIHYTSILQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYYCLQ 8 3D03

[0083] FDNLLRTFGGGTKLEIN EVQLHQSGAELLKPGASAKISCKATGYTFNTYWIEWVKQRPGH

[0084] 5

[0085] Heavy GLEWIGEILPGSGNTNYNEKFRGKATFTADSSSSTAYIQLSSLTS 9 3H09

[0086] EDSAVYFCARNYKYDVGKFDVWGAGTTVTVSS DIQMTQSPASLSVSVGETVTITCRASENIHTNLAWYQQKQGKSP

[0087] 5

[0088] Light QLLIYAASDLADGVPSRFSGRGSGSQYSLKINSLQSEDFGNYYC 10 3H09

[0089] QHFWGTPWTFGGGTKLEIN

[0090]

[0091] ID # in

[0092] Chain SEQ ID FIG. 1 / Sequence

[0093] type NO: Clone ID

[0094] EVQLKESGPGLVAPSQSLSITCTVSGFSLTSYGVHWIRQSPGKG

[0095] 6

[0096] Heavy LEWLGIIWAGGNTNYNSALMSRLSISKDNSKSQVFLKMNSLQTD 11 10B04

[0097] DTAMYYCAREFFVYWGQGTLVTVSA DIVMTQSPSSMNASLRTRVTITCKASQDINPYLSWFQQKPGKSP

[0098] 6

[0099] Light KTLIYRAYRLGDGVPSRFSGSGSGQEYSLTISSLEYEDMGIYYCL 12 10B04

[0100] QYDEFPYTFGGGTKLELK EVKLVESGGGLVQPGESLKLSCESNEYAFPSHDMSWVRKTPEK

[0101] 7

[0102] Heavy RLELVAAINSDGGTTYYPDTMERRFIISRDNTKKTLYLQMSSLRS 13 20A07

[0103] DDTALYYCARRGYEGGMDYWGQGTTVTVSS DIVMTQSPASLAVSLGQRATISCRASKSVSTSDYSYMHWYQQK

[0104] 7

[0105] Light PGQPPKLLIYLASNLESGVPARFSGSGSGTDFTLNIHPVEEEDAA 14 20A07

[0106] TYYCQHSRELPWTFGGGTKLEIN EVQLQQSGAELVKPGASVKLSCTASGFNIKDTYMHWVKQRPEQ

[0107] 8

[0108] Heavy GLEWIGRIDPANGNTKYDPKFQGKATITADTSSNTAYLQLSSLTS 15 22C06

[0109] EDTAVYYCARKGPDYWGQGTTVTVSS DIVMTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQK

[0110] 8

[0111] Light PGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAA 16 22C06

[0112] TYYCQQSNEDPYTFGGGTKLELK EVQLQQSGPELVKPGASVKISCKASGYTFTDYNMHWVKQSHGK

[0113] 9

[0114] Heavy SLEWIGYIYPYNGGTGYNQKFKSKATLTVDNSSSTAYMELRSLT 17 22E06

[0115] SEDSAVYYCARWTYDGYYWYFDVWGAGTTVTVSS DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTV

[0116] 9

[0117] Light KLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQ 18 22E06

[0118] QGNTLPWTFGGGTKLEIN EVKLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQSPEK

[0119] 10

[0120] Heavy RLEWVAEISSGGSYTYYPDTVTGRFTISRDNAKNTLYLEMSSLR 19 26E12

[0121] SEDTAMYYCARKSFDYWGQGTTVTVSS DIVMTQSPSSLSASLGERVSLTCRASQDIGSSLNWLQQEPDGTI

[0122] 10

[0123] Light KRLIYATSSLDSGVPKRFSGSRSGSDYSLTISSLESEDFVDYYCL 20 26E12

[0124] QYASSPPTFGAGTKLELK

[0125]

[0126] ID # in

[0127] Chain SEQ ID FIG. 1 / Sequence

[0128] type NO: Clone ID

[0129] EVQLVESGGGLVKPGGSLKLSCAASGFTFSDYYMYWVRQTPEK

[0130] 11

[0131] Heavy RLEWVATISDGGSYTYYPDSVKGRFTISRDNAKNNLYLQMSSLK 21 26F04

[0132] SEDTAMYYCARGGSSYERVWFAYWGQGTLVTVSA DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQ

[0133] 11

[0134] Light SPKALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYF 22 26F04

[0135] CQQYNSYPYTFGGGTKLELK EVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQPPGK

[0136] 12

[0137] Heavy GLEWLGVIWSGGSTDYNAAFISRLSISKDNSKSQVFFKMNSLQA 23 28C12

[0138] DDTAIYYCARKDGNYAMDYWGQGTTVTVSS DIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSP

[0139] 12

[0140] Light KRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYC 24 28012

[0141] QQWSSNPLTFGAGTKLELK EVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKLRPG

[0142] 13

[0143] Heavy QGFEWIGEINPSNGGTNYNEKFKRKATLTVDKSSSTAYMQLSSL 25 2D02

[0144] TS EDSAVYYCTI H D D AM DYWGQGTTVTVSS DIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSSTSP

[0145] 13

[0146] Light KLWIYDTSKLASGVPGRFSGSGSGNSYSLTISSMEAEDVATYYC 26 2D02

[0147] FQGSGYPLTFGSGTKLEIK EVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPG

[0148] 14

[0149] Heavy NKLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTT 27 30B11

[0150] EDTATYYCARSVDGYYWFAYWGQGTLVTVSA DIVLTQSPAIMSASPGEKVTLTCSASSNVNSSYLYWYQQKPGSS

[0151] 14

[0152] Light PKLWIYSTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAASYF 28 30B11

[0153] CHQWSSYPLTFGAGTKLELK EVKLQQSGPELVKPGASVKISCKASGYSFTGYYMHWVKQSHVK

[0154] 15

[0155] Heavy SLEWIGRINPYNGATSYNQNFKDKASLTVDKSSSTAYMELHSLT 29 34F04

[0156] SE DS AVYYC AR KE I DYDY DLYAM DYWGQGTTVTVSS DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTV

[0157] 15

[0158] Light KLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQ 30 34F04

[0159] QGNTLTFGAGTKLELK

[0160]

[0161] ID # in

[0162] Chain SEQ ID FIG. 1 / Sequence

[0163] type NO: Clone ID

[0164] EVQLQQPGAELVRPGASVKLSCKASGYSFTSYWMNWVKQRPG

[0165] 16

[0166] Heavy QGLEWIGMIHPSDSETRLNQKFKDKATLTVDKSSSTAYMQLSSP 31 10C08

[0167] TSEDSAVYYCARDGGSRFAYWGQGTLVTVSA DIQMTQS P ASLS VSVG ETVTITC R AS EN I HTN LAWYQQKQG KS P

[0168] 16

[0169] Light QLLIYAASDLADGVPSRFSGRGSGSQYSLKINSLQSEDFGNYYC 32 10C08

[0170] QHFWGTPWTFGGGTKLEIN EVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPG

[0171] 17

[0172] Heavy NKLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTT 33 37G09

[0173] EDTATYYCARFDVRYAMDYWGQGTTVTVSS DIVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSP

[0174] 17

[0175] Light KRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYC 34 37G09

[0176] QQWSSNPYTFGGGTKLELK EVQLQESGPDLVKPSQSLSLTCTVTGYSITSGYSWHWIRQFPG

[0177] 18

[0178] Heavy NKLEWMGYIHYSGSTNYNPSLKSRISITRDTSKNQFFLQLNSVTT 35 40A02

[0179] EDTATYYC AR I NYQ FAYWGQGTLVTVSA DIVMTQSPAIMSASLGEKVTMSCRASSSVNYMYWYQQKSDASP

[0180] 18

[0181] Light KLWIYYTSNLAPGVPARFSGSGSGNSYSLTISSMEGEDAATYYC 36 40A02

[0182] QQFTSSPYTFGGGTKLELK EVKLVESGGGLVKPGGSLKLSCAASGFAFSSYDMSWVRQTPEK

[0183] 19

[0184] Heavy RLEWVAFISSGGGSTYYPDTVKGRFTISRDNAKNTLYLQMSSLK 37 40C08

[0185] SEDTALYYCVRQLLGAYWGQGTLVTVSA DIVLTQSPAIMSASPGEKVTMTCSASSSISYMHWYQQKPGTSPK

[0186] 19

[0187] Light RWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCH 38 40C08

[0188] QRSSYPLTFGAGTKLELK EVQLQQPGSVLVRPGASVKLSCKASGYTFTSSWMHWAKQRPG

[0189] 20

[0190] Heavy QGLEWIGEIHPNSGNTNYNEKFKGKATLTVDTSSSTAYVDLSSL 39 7B07

[0191] TSEDSAVYYCARLGERGFAYWGQGTLVTVSA DIVMTQSPSSLSVSAGEKVTMSCKSSQSLLNSGNQKNYLAWYQ

[0192] 20

[0193] Light QKPGQPPKLLIYGASTRESGVPDRFTGSGSGTDFTLTISSVQAE 40 7B07

[0194] DLAVYYCQNDHSYPYTFGGGTKLELK

[0195]

[0196] ID # in

[0197] Chain SEQ ID FIG. 1 / Sequence

[0198] type NO: Clone ID

[0199] EVQLQESGPSLVKPSQTLSLTCSVTGDSIISGYWNWIRKFPGKK

[0200] 21

[0201] Heavy FEHMGYISYSGTTYYNPSLKSRISISRDTSKNHYYLQLSSVTTED 41 10C11

[0202] TATYYCAKSYNYDVHYWGQGTTVTVSS DIVMTQSQKFMSTLVGDRVSVTCKASQNVGTNVAWYQQKLGQ

[0203] 21

[0204] Light SPKALIYSASYRYSGVPDRFTGSGSGTDFTLNIRNVQSEDLAEY 42 10C11

[0205] FCQQYNSYPWTFGGGTKLEIN EVQLNQSGPGLVQPSQSLSITCTVSGFSLTNYGIHWVRQSPGK

[0206] 22

[0207] Heavy GLEWLGVIWSGGSTDYNAPFISRLSISKDNIKGQVFFKMNSLQV 43 11G08

[0208] NDTAIYYCAKMTDDYYWYFDVWGAGTTVTVSS DIQMTQSPASLSTSVGETVTITCRASGNIRNYLAWYQQKQGKSP

[0209] 22

[0210] Light QLLVYNAKTLADGVPSRFSGSGSETQYSLKINGLQPEDFGSYYC 44 11G08

[0211] QHFWTTPYTFGGGTKLELK EVQLQQSGAELAKPGASVKMSCKASGYTFTSYWMHWVKQRP

[0212] 23

[0213] Heavy GQGLEWIGYINPSTGYTEYNQKFKDKATLTADKSSSTAYMQLSS 45 12E01

[0214] LTSEDSAVYYCARSDYYGSSYGWYFDVWGAGTTVTVSS DIVMTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPK

[0215] 23

[0216] Light LLISEGNTLRPGVPSRFSSSGYGTDFVFTIENMLSEDVADYYCLQ 46 12E01

[0217] SDNLPYTFGGGTKLELK EVQLKQSGPGLVQPSQSLSITCTVSGFSLTDYGIHWVRQSPGK

[0218] 24

[0219] Heavy GLEWLGVIWSGGSTDYNAPFISRLTISKDNSKSQVFFKMNSLQA 47 1A07

[0220] NDTAIYYCAKMTDNYYWYFDVWGAGTTVTVSS DIQMTQSPASLSASVGETVTITCRASGNIRNYLAWYQQKQGKSP

[0221] 24

[0222] Light QLLVYNAETLADAVPSRFSGSGSGSQYSLKITSLQPEDFGSYYC 48 1A07

[0223] QHFWTTPYTFGGGTKLELK EVQLKESGPGLVAPSQSLSITCTVSGFSLTSYGVHWVRLPPGKG

[0224] 25

[0225] Heavy LEWLGVVWAGGSTNYNSALMSRLNIYKDNSKSQIFLKMNSLQS 49 20D11

[0226] DDTAMYYCAREKPITLSMDYWGQGTTVTVSS DVVMTQSPSSMYASLGERVTITCKASQDINSYLSWFQQKPGKS

[0227] 25

[0228] Light PKTLIYRADRLVDGVPSRFSGSGSGQDYSLTITSLEYEDLGIYYC 50 20D11

[0229] LQYDELPLTFGAGTKLELK

[0230]

[0231] ID # in

[0232] Chain SEQ ID FIG. 1 / Sequence

[0233] type NO: Clone ID

[0234] EVKLVESGGGLVKPGGSLKVSCAASGFTFSSYAMSWVRQTPER

[0235] 26

[0236] Heavy RLEWVATISSGGGYTYYLDSVKGRFTISRDNANNTLYLHMSSLR 51 10E02

[0237] SE DTAM YYC P RRG M APTG F AY WGQGTLVTVSA DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNVGNQKNYLTWYQ

[0238] 26

[0239] Light QKPGQPPKLLIYWSSTRESGVPDRFTGSVSGTDFTLTISSVQAE 52 10E02

[0240] DLAVYYCQNDYSYPYTFGGGTKLELK QVQMKESGPGILQPSQTLSLTCSFSGFSLSTSGMGVSWIRQPS

[0241] 27

[0242] Heavy GKGLEWLAHIYWDDDKRYNPSLKSRLTISKDTSRNQVFLKITSV 53 11A09

[0243] DTADTATYYCARRAWDYDGAWFAYWGQGTLVTVSA DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTV

[0244] 27

[0245] Light KLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQ 54 11A09

[0246] QGNTLPFTFGSGTKLEIK EVKLKQSGPGLVQPSQNLSITCTVSGFSLTDYGVHWVRQSPGK

[0247] 28

[0248] Heavy GLEWLGVIWSGGSTDYNAPFISRLIISKDNLKSQVFFKLHSLQPD 55 12A09

[0249] DTAIYYCAKMTDNYYWYFDVWGAGTTVTVSS DIQMTQSPASLSASVGETVTITCRTSGNIRDYLSWYQQKQGKSP

[0250] 28

[0251] Light QLLVYNAKTLADGVSSRFSGSGSGTQYSLKISSLQPEDFGSYYC 56 12A09

[0252] QHFWTTPYTFGGGTKLELK EVQLQQSGAELVKPGASVKLSCTASGFNIKDTYMHWVKQRPEQ

[0253] 29

[0254] Heavy GLEWIGRIDPANGNTKYDPKFQGKATITADTSSNTAYLQLSSLTS 57 21 D01

[0255] EDTAVYYC ARSG LTAPG F DYWGQGTTVTVSS DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTV

[0256] 29

[0257] Light KLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQ 58 21 D01

[0258] QGNTLPYTFGGGTKLELK EVQLQQPGAELVRPGISVKLSCKASGYTFTGYWIHWIKQRPEQ

[0259] 30

[0260] Heavy GLERIGEINPSVGATAYNAKFKTKATLTVDKSSSTAYMQLSSLTS 59 21H09

[0261] EDSAVYYCARVGDYFDFWGQGTTLTVSS DIVMTQSPVSLAISLGQRATISCRASQSVSSSNYNYMHWYQQKP

[0262] 30

[0263] Light RQPPKLLIKYASNLESGVPARFSGSGSGTDFTLNIHPVEEEDTAT 60 21H09

[0264] YYCQHSWEIPWTFGGGTKLEIN

[0265]

[0266] ID # in

[0267] Chain SEQ ID FIG. 1 / Sequence

[0268] type NO: Clone ID

[0269] EVKLVESGGGLVKPGGSLKLSCAASGFTFSTYAMSWIRQTPEK

[0270] 31

[0271] Heavy RLEWVATISHGGSYTYYPDSIKGRFTISRDNAKKILYLQMSSLRS 61 22B08

[0272] EDTAMYYCARHWGSSGYDALDFWGQGTTVTVSS DIQMTQSPASLSASVGETVTITCGASENIYGALNWYQRKQGKSP

[0273] 31

[0274] Light QLLIYGTTNLADGMSSRFSGSGSGRQYSLKISSLHPDDVATYYC 62 22B08

[0275] QNALSISYTFGGGTKLELK EVKLVESGGGLVQPGGSLKLSCAASGFTFSSYGMSWVRQTPD

[0276] 32

[0277] Heavy KRLELVATINSNGGSTYYPDSVKGRFTISRDNAKNTLYLQMSSLK 63 22E02

[0278] SEDTAMYYCARDDYYGSRGNWWYFDVWGAGTTVTVSS DIVMTQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQ

[0279] 32

[0280] Light QKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAE 64 22E02

[0281] DLAVYYCQQYYSYPLTFGAGTKLELK EVQLNQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGK

[0282] 33

[0283] Heavy GLEWLGVIWSGGTTDYNAPFISRLSISKDNIKGQVFFKMNSLQA 65 27B01

[0284] NDTAIYYCAKMTDDYYWYFDVWGAGTTVTVSS DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKPGQS

[0285] 33

[0286] Light PKLLIYSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYC 66 27B01

[0287] QQHYSTPPTFGGGTKLEIN EVKLHQSGTELMKPGASVKISCKATGYTFNNYWIEWVKQRPGH

[0288] 34

[0289] Heavy GLEWIGEILPGSGNTNYDEKFKGKATFTADSSSNTAYMQLSSLT 67 2B08

[0290] SEDSAVYFCARNYKYDVGKFDVWGAGTTVTVSS DIQMTQS P ASLS VSVG ETVTITC R AS EN I YTN LAWYQQKQG KS P

[0291] 34

[0292] Light QLLIYAASDLADGVPSRFSGRGSGSQYSLKINSLQSEDFGTYYC 68 2B08

[0293] QHFWGTPWTFGGGTKLEIN QVQLKESGAEVVMPGASVKMSCKASGYTITDYWMHWVKQRPG

[0294] 35

[0295] Heavy QGLEWIGGIDTSDSYTRYNQKFKGKATLTVDESSNTAYMQLSSL 69 2G08

[0296] TSEDSAVYYCARGRFITDYWGQGTTVTVSS DIVMTQSPSSMYASLGERVTITCKASQDINSYLGWFQQKPGKSP

[0297] 35

[0298] Light KTLIYRANRLVDGVPSRFSGSGSGQDYSLTINSLEYEDMGIYYCL 70 2G08

[0299] QYDEFPFTFGAGTKLELK

[0300]

[0301] ID # in

[0302] Chain SEQ ID FIG. 1 / Sequence

[0303] type NO: Clone ID

[0304] EVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPG

[0305] 36

[0306] Heavy NKLEWMGYISYSGSTDYNPSLKSRISITRDTSKNQFFLQLNSVTT 71 32B08

[0307] EDTATYYC AR EG DYYGTS PF DYWGQGTTVTVSS DIQMNQSPSSLSASLGDTITITCHASQNINFWLNWYQQKPGNIPK

[0308] 36

[0309] Light LLIYRASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQ 72 32B08

[0310] GQSYPLTFGAGTKLELK EVKLQQSAAELARPGASVKMSCKASGHTSTTYTMHWLKQRPG

[0311] 37

[0312] Heavy QGLEWIGCSNPSSGYTDYNQDFKDKTTLTADRSSNTAYMQMSS 73 33C03

[0313] LTS E DS ALYYC ASSSYYY AM D YWGQGTS VTVSS DIVMTQAPKFLLVSAGDRVTITCKASQSVGNDVAWYQQKPGQS

[0314] 37

[0315] Light PKLLIYYASNRYTGVPDRFTGSGYGTDFSFTISTVQAEDLAVYFC 74 33C03

[0316] QQDYSSPLTFGAGTKLELK EVQMKESGPGQVAPSQSLSIACTVSGFSLTSYGVHWVRQPPGK

[0317] 38

[0318] Heavy GLEWLGVIWAGGSTNYISALMSRLSISKDNSKSQVFLKMSSLQT 75 34G03

[0319] DDTAIYYCAREKRITLSM DYWGQGTTVTVSS DIVMTQSPSSMYASLGERVTITCKASQDINSYLSWFQQKPGKSP

[0320] 38

[0321] Light KTLIYRANRLVDGVPSRFSGSGSGQDYSLTISSLEYEDMGMYYC 76 34G03

[0322] LQYDELPLTFGAGTKLELK EVKLVESGGGLVKPGGSLKLSCAASGFTFSDYYMYWVRQTPEK

[0323] 39

[0324] Heavy RLEWVATISDGGSYTYYPDSVKGRFTISRDNAKNNLYLQMSSLK 77 3E11

[0325] SE DTAM YYC ARD EGTM P AVYY AM DYWGQGTTVTVSS DIVLTQSPAIMSASPGEKVTISCSASSSVSYMYWYQQKPGSSPK

[0326] 39

[0327] Light PWIYRTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQ 78 3E11

[0328] QYHSYPPTFGAGTKLELK EVQLQESGAELARPGASVKMSCKASGYTFTSYTMHWVKQRPG

[0329] 40

[0330] Heavy QGLEWIGVINLSSGYISYNQKFKDKATLTADKSSSTAYIQLSSLTS 79 3G09

[0331] EDS A VYYC ARSG LG I YYAM DYWGQGTTVTVSS DIVMTPTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSP

[0332] 40

[0333] Light KLLIYSASNRYTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQ 80 3G09

[0334] QDYSSPLTFGAGTKLELK

[0335]

[0336] ID # in

[0337] Chain SEQ ID FIG. 1 / Sequence

[0338] type NO: Clone ID

[0339] EVKLVESGGGLVQPGGSLKLSCATSGFTFSDYYMYWVRQTPEK

[0340] 41

[0341] Heavy RLEWVAYISNGGGSTYYPDTVKGRFTISRDNAKNTLYLQMSRLK 81 3H01

[0342] SEDTAMYYCARDDYDGYWYFDVWGAGTTVTVSS DIVMTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQK

[0343] 41

[0344] Light PGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAA 82 3H01

[0345] TYYCQQNNEDPYTFGGGTKLELK EVQLQESGAELVRPGASVTLSCKASGYTFTDYEMHWVKQTPVH

[0346] 42

[0347] Heavy GLEWIGAIDPETGGTAYNQKFKGKATLTADKSSSTAYMELRSLT 83 40A04

[0348] SEDSAVYYCTTNYFDYWGQGTTVTVSS DIVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWLLQRP

[0349] 42

[0350] Light GQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLG 84 40A04

[0351] VYYCWQGTHFPRTFGGGTKLEIN EVQLQQSGAELVKPGASVKLSCKASGYTFTSYDINWVRQRPEQ

[0352] 43

[0353] Heavy GLEWIGWIFPGDGSTKYNEKFKGKATLTTDKSSSTAYMQLSRLT 85 40D09

[0354] SEDSAVYFCARNLYGWFAYWGQGTLVTVSA DIVMTQSPSSLAMSVGQKVTMSCKSSQSLLNSSNQKNYLAWYQ

[0355] 43

[0356] Light QKPGQSPKLLVYFASTRESGVPDRFIGSGSGTDFTLTISSVQAE 86 40D09

[0357] DLADYFCQQHYSTPPTFGGGTKLEIN EVKLVQSGPELKKPGETVKISCKASGYSFTDYGMNWVKQTPGK

[0358] 44

[0359] Heavy DLKWMGWINTYNGEPTYVDDFKGRFAFSLETSANTAYLQINNLK 87 7G03

[0360] SEDTATYFCANRYDGKYFFALDYWGQGTTVTVSS DIVMTQNPLSLPVSLGDQASISCRSSQNIVHSNGNTYLEWYLQK

[0361] 44

[0362] Light PGQSPKLLIYKVSDRFFGVPDRFSGSGSGTDFTLKISRVEAEDL 88 7G03

[0363] GVYYCFQGSHVPYTFGGGTKLELK

[0364]

[0365] The amino acid sequences of the CDRs of the various anti-CD64 antibodies designated herein by the clone IDs identified in Table 1 above are provided in Table 2 below. All CDRs and framework regions described throughout the present disclosure are defined according to Kabat unless otherwise indicated.

[0366] Table 2. CDRs of various anti-CD64 antibodies described in Table 1.CDR1 SEQ CDR2 SEQ CDR3 SEQ Clone Chain

[0367] ID NO: ID NO: ID ID type

[0368] NO: 12B02 Heavy GYTFTSYD 89 IYPGDGST 90 VREVRREWYFDV 91 12B02 Light □ DINKY 92 YTS 93 LQFDNLLRT 94 26E10 Heavy GYTFTTYT 95 INPGSGYI 96 ARSGTGIFYAMDY 97 26E10 Light QSVSND 98 SAS 99 QQDYRSPYT 100

[0369] 101 102 SRHWGISGYDAME 103 32E09 Heavy

[0370] GFTFSSYV ISNGGSYT Y

[0371] 32E09 Light ENIYGA 104 GTT 105 QSVLSFPYT 106 3D03 Heavy GYIFTSYD 107 IYPGDGSA 108 AREVRREWFFDV 109 3D03 Light QDINKY 110 YTS 111 LQFDNLLRT 112 3H09 Heavy GYTFNTYW 113 ILPGSGNT 114 ARNYKYDVGKFDV 115 3H09 Light ENIHTN 116 AAS 117 QHFWGTPWT 118 10B04 Heavy GFSLTSYG 119 IWAGGNT 120 AREFFVY 121 10B04 Light QDINPY 122 RAY 123 LQYDEFPYT 124 20A07 Heavy EYAFPSHD 125 INSDGGTT 126 ARRGYEGGMDY 127 20A07 Light KSVSTSDYSY 128 LAS 129 QHSRELPWT 130 22006 Heavy GFNIKDTY 131 IDPANGNT 132 ARKGPDY 133 22C06 Light QSVDYDGDSY 134 AAS 135 QQSNEDPYT 136

[0372] 137 138 ARWTYDGYYWYFD 139 22E06 Heavy

[0373] GYTFTDYN IYPYNGGT V

[0374] 22E06 Light QDISNY 140 YTS 141 QQGNTLPWT 142 26E12 Heavy GFTFSSYA 143 ISSGGSYT 144 ARKSFDY 145 26E12 Light QDIGSS 146 ATS 147 LQYASSPPT 148

[0375] 149 150 ARGGSSYERVWFA 151 26F04 Heavy

[0376] GFTFSDYY ISDGGSYT Y

[0377] 26F04 Light QNVGTN 152 SAS 153 QQYNSYPYT 154 28C12 Heavy GFSLTSYG 155 IWSGGST 156 ARKDGNYAMDY 157 28012 Light SSVSY 158 DTS 159 QQWSSNPLT 160 2D02 Heavy GYTFTSYW 161 INPSNGGT 162 TIHDDAMDY 163

[0378]

[0379] CDR1 SEQ CDR2 SEQ CDR3 SEQ Clone Chain

[0380] ID NO: ID NO: ID ID type

[0381] NO: 2D02 Light SSVSY 164 DTS 165 FQGSGYPLT 166 30B11 Heavy GYSITSDYA 167 ISYSGST 168 ARSVDGYYWFAY 169 30B11 Light SNVNSSY 170 STS 171 HQWSSYPLT 172

[0382] 173 174 ARKEIDYDYDLYAM 175 34F04 Heavy

[0383] GYSFTGYY INPYNGAT DY

[0384] 34F04 Light QDISNY 176 YTS 177 QQGNTLT 178 10C08 Heavy GYSFTSYW 179 IHPSDSET 180 ARDGGSRFAY 181 10C08 Light ENIHTN 182 AAS 183 QHFWGTPWT 184 37G09 Heavy GYSITSDYA 185 ISYSGST 186 ARFDVRYAMDY 187 37G09 Light SSVSY 188 DTS 189 QQWSSNPYT 190 40A02 Heavy GYSITSGYS 191 IHYSGST 192 ARINYQFAY 193 40A02 Light SSVNY 194 YTS 195 QQFTSSPYT 196 40C08 Heavy GFAFSSYD 197 ISSGGGST 198 VRQLLGAY 199 40C08 Light SSISY 200 DTS 201 HQRSSYPLT 202 7B07 Heavy GYTFTSSW 203 IHPNSGNT 204 ARLGERGFAY 205

[0385] QSLLNSGNQKN 206 207 208 7B07 Light

[0386] Y GAS QNDHSYPYT

[0387] 10C11 Heavy GDSIISGY 209 ISYSGTT 210 AKSYNYDVHY 211 10011 Light QNVGTN 212 SAS 213 QQYNSYPWT 214 11G08 Heavy GFSLTNYG 215 IWSGGST 216 AKMTDDYYWYFDV 217 11G08 Light GNIRNY 218 NAK 219 QHFWTTPYT 220

[0388] 221 222 ARSDYYGSSYGWY 223 12E01 Heavy

[0389] GYTFTSYW INPSTGYT FDV

[0390] 12E01 Light TDIDDD 224 EGN 225 LQSDNLPYT 226 1A07 Heavy GFSLTDYG 227 IWSGGST 228 AKMTDNYYWYFDV 229 1A07 Light GNIRNY 230 NAE 231 QHFWTTPYT 232 20D11 Heavy GFSLTSYG 233 VWAGGST 234 AREKPITLSMDY 235 20D11 Light QDINSY 236 RAD 237 LQYDELPLT 238

[0391]

[0392] CDR1 SEQ CDR2 SEQ CDR3 SEQ Clone Chain

[0393] ID NO: ID NO: ID ID type

[0394] NO: 10E02 Heavy GFTFSSYA 239 ISSGGGYT 240 PRRGMAPTGFAY 241

[0395] QSLLNVGNQKN 242 243 244 10E02 Light

[0396] Y WSS QNDYSYPYT

[0397] 245 246 ARRAWDYDGAWFA 247 11A09 Heavy

[0398] GFSLSTSGMG IYWDDDK Y

[0399] 11A09 Light QDISNY 248 YTS 249 QQGNTLPFT 250 12A09 Heavy GFSLTDYG 251 IWSGGST 252 AKMTDNYYWYFDV 253 12A09 Light GNIRDY 254 NAK 255 QHFWTTPYT 256 21 D01 Heavy GFNIKDTY 257 IDPANGNT 258 ARSGLTAPGFDY 259 21 D01 Light QDISNY 260 YTS 261 QQGNTLPYT 262 21H09 Heavy GYTFTGYW 263 INPSVGAT 264 ARVGDYFDF 265 21H09 Light QSVSSSNYNY 266 YAS 267 QHSWEIPWT 268

[0400] 269 270 ARHWGSSGYDALD 271 22B08 Heavy

[0401] GFTFSTYA ISHGGSYT F

[0402] 22B08 Light ENIYGA 272 GTT 273 QNALSISYT 274

[0403] 275 276 ARDDYYGSRGNW 277 22E02 Heavy

[0404] GFTFSSYG INSNGGST WYFDV QSLLYSSNQKN 278 279 280 22E02 Light

[0405] Y WAS QQYYSYPLT

[0406] 27B01 Heavy GFSLTNYG 281 IWSGGTT 282 AKMTDDYYWYFDV 283 27B01 Light QDVSTA 284 SAS 285 QQHYSTPPT 286 2B08 Heavy GYTFNNYW 287 ILPGSGNT 288 ARNYKYDVGKFDV 289 2B08 Light ENIYTN 290 AAS 291 QHFWGTPWT 292 2G08 Heavy GYTITDYW 293 IDTSDSYT 294 ARGRFITDY 295 2G08 Light QDINSY 296 RAN 297 LQYDEFPFT 298 32B08 Heavy GYSITSDYA 299 ISYSGST 300 AREGDYYGTSPFDY 301 32B08 Light QNINFW 302 RAS 303 QQGQSYPLT 304 33C03 Heavy GHTSTTYT 305 SNPSSGYT 306 ASSSYYYAMDY 307 33C03 Light QSVGND 308 YAS 309 QQDYSSPLT 310

[0407]

[0408] CDR1 SEQ CDR2 SEQ CDR3 SEQ Clone Chain

[0409] ID NO: ID NO: ID ID type

[0410] NO: 34G03 Heavy GFSLTSYG 311 IWAGGST 312 AREKRITLSMDY 313 34G03 Light QDINSY 314 RAN 315 LQYDELPLT 316

[0411] 317 318 ARDEGTMPAVYYA 319 3E11 Heavy

[0412] GFTFSDYY ISDGGSYT MDY

[0413] 3E11 Light SSVSY 320 RTS 321 QQYHSYPPT 322 3G09 Heavy GYTFTSYT 323 INLSSGYI 324 ARSGLGIYYAMDY 325 3G09 Light QSVSND 326 SAS 327 QQDYSSPLT 328 3H01 Heavy GFTFSDYY 329 ISNGGGST 330 ARDDYDGYWYFDV 331 3H01 Light ESVDSYGNSF 332 LAS 333 QQNNEDPYT 334 40A04 Heavy GYTFTDYE 335 IDPETGGT 336 TTNYFDY 337 40A04 Light QSLLDSDGKTY 338 LVS 339 WQGTHFPRT 340 40D09 Heavy GYTFTSYD 341 IFPGDGST 342 ARNLYGWFAY 343

[0414] QSLLNSSNQKN 344 345 346 40D09 Light

[0415] Y FAS QQHYSTPPT

[0416] 7G03 Heavy GYSFTDYG 347 INTYNGEP 348 ANRYDGKYFFALDY 349 7G03 Light QNIVHSNGNTY 350 KVS 351 FQGSHVPYT 352

[0417]

[0418] In certain embodiments, an antibody of the present disclosure specifically binds CD64 and comprises, or competes for binding to CD64 with an antibody comprising:

[0419] a variable heavy chain (VH) polypeptide comprising

[0420] the V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 1 , and a variable light chain (VL) polypeptide comprising

[0421] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 2; a variable heavy chain (VH) polypeptide comprising

[0422] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 3, and a variable light chain (VL) polypeptide comprising

[0423] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 4; a variable heavy chain (VH) polypeptide comprising

[0424] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 5, anda variable light chain (VL) polypeptide comprising

[0425] the V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 6; a variable heavy chain (VH) polypeptide comprising

[0426] the V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 7, and a variable light chain (VL) polypeptide comprising

[0427] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 8; a variable heavy chain (VH) polypeptide comprising

[0428] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 9, and a variable light chain (VL) polypeptide comprising

[0429] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 10; a variable heavy chain (VH) polypeptide comprising

[0430] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 11 , and a variable light chain (VL) polypeptide comprising

[0431] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 12; a variable heavy chain (VH) polypeptide comprising

[0432] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 13, and a variable light chain (VL) polypeptide comprising

[0433] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 14; a variable heavy chain (VH) polypeptide comprising

[0434] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 15, and a variable light chain (VL) polypeptide comprising

[0435] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 16; a variable heavy chain (VH) polypeptide comprising

[0436] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 17, and a variable light chain (VL) polypeptide comprising

[0437] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 18; a variable heavy chain (VH) polypeptide comprising

[0438] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 19, and a variable light chain (VL) polypeptide comprising

[0439] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 20; a variable heavy chain (VH) polypeptide comprising

[0440] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 21 , and a variable light chain (VL) polypeptide comprising

[0441] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 22;a variable heavy chain (VH) polypeptide comprising

[0442] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 23, and a variable light chain (VL) polypeptide comprising

[0443] the V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 24; a variable heavy chain (VH) polypeptide comprising

[0444] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 25, and a variable light chain (VL) polypeptide comprising

[0445] the V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 26; a variable heavy chain (VH) polypeptide comprising

[0446] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 27, and a variable light chain (VL) polypeptide comprising

[0447] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 28; a variable heavy chain (VH) polypeptide comprising

[0448] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 29, and a variable light chain (VL) polypeptide comprising

[0449] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 30; a variable heavy chain (VH) polypeptide comprising

[0450] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 31 , and a variable light chain (VL) polypeptide comprising

[0451] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 32; a variable heavy chain (VH) polypeptide comprising

[0452] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 33, and a variable light chain (VL) polypeptide comprising

[0453] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 34; a variable heavy chain (VH) polypeptide comprising

[0454] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 35, and a variable light chain (VL) polypeptide comprising

[0455] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 36. a variable heavy chain (VH) polypeptide comprising

[0456] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 37, and a variable light chain (VL) polypeptide comprising

[0457] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 38; a variable heavy chain (VH) polypeptide comprising

[0458] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 39, anda variable light chain (VL) polypeptide comprising

[0459] the V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 40; a variable heavy chain (VH) polypeptide comprising

[0460] the V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 41 , and a variable light chain (VL) polypeptide comprising

[0461] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 42; a variable heavy chain (VH) polypeptide comprising

[0462] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 43, and a variable light chain (VL) polypeptide comprising

[0463] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 44; a variable heavy chain (VH) polypeptide comprising

[0464] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 45, and a variable light chain (VL) polypeptide comprising

[0465] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 46; a variable heavy chain (VH) polypeptide comprising

[0466] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 47, and a variable light chain (VL) polypeptide comprising

[0467] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 48; a variable heavy chain (VH) polypeptide comprising

[0468] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 49, and a variable light chain (VL) polypeptide comprising

[0469] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 50; a variable heavy chain (VH) polypeptide comprising

[0470] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 51 , and a variable light chain (VL) polypeptide comprising

[0471] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 52; or a variable heavy chain (VH) polypeptide comprising

[0472] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 53, and a variable light chain (VL) polypeptide comprising

[0473] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 54. a variable heavy chain (VH) polypeptide comprising

[0474] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 55, and a variable light chain (VL) polypeptide comprising

[0475] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 56;a variable heavy chain (VH) polypeptide comprising

[0476] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 57, and a variable light chain (VL) polypeptide comprising

[0477] the V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 58; a variable heavy chain (VH) polypeptide comprising

[0478] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 59, and a variable light chain (VL) polypeptide comprising

[0479] the V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 60; a variable heavy chain (VH) polypeptide comprising

[0480] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 61 , and a variable light chain (VL) polypeptide comprising

[0481] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 62; a variable heavy chain (VH) polypeptide comprising

[0482] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 63, and a variable light chain (VL) polypeptide comprising

[0483] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 64; a variable heavy chain (VH) polypeptide comprising

[0484] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 65, and a variable light chain (VL) polypeptide comprising

[0485] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 66; a variable heavy chain (VH) polypeptide comprising

[0486] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 67, and a variable light chain (VL) polypeptide comprising

[0487] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 68; a variable heavy chain (VH) polypeptide comprising

[0488] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 69, and a variable light chain (VL) polypeptide comprising

[0489] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 70; or a variable heavy chain (VH) polypeptide comprising

[0490] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 71 , and a variable light chain (VL) polypeptide comprising

[0491] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 72. a variable heavy chain (VH) polypeptide comprising

[0492] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 73, anda variable light chain (VL) polypeptide comprising

[0493] the V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 74; a variable heavy chain (VH) polypeptide comprising

[0494] the V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 75, and a variable light chain (VL) polypeptide comprising

[0495] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 76; a variable heavy chain (VH) polypeptide comprising

[0496] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 77, and a variable light chain (VL) polypeptide comprising

[0497] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 78; a variable heavy chain (VH) polypeptide comprising

[0498] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 79, and a variable light chain (VL) polypeptide comprising

[0499] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 80; a variable heavy chain (VH) polypeptide comprising

[0500] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 81 , and a variable light chain (VL) polypeptide comprising

[0501] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 82; a variable heavy chain (VH) polypeptide comprising

[0502] the VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 83, and a variable light chain (VL) polypeptide comprising

[0503] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 84; a variable heavy chain (VH) polypeptide comprising

[0504] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 85, and a variable light chain (VL) polypeptide comprising

[0505] the VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 86; or a variable heavy chain (VH) polypeptide comprising

[0506] the VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 87, and a variable light chain (VL) polypeptide comprising

[0507] the VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 88. According to some embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 1; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% orgreater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 2; or both.

[0508] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0509] a VH polypeptide comprising

[0510] a VH CDR1 comprising the amino acid sequence GYTFTSYD (SEQ ID NO: 89), a VHCDR2 comprising the amino acid sequence IYPGDGST (SEQ ID NO: 90), and a VH CDR3 comprising the amino acid sequence VREVRREWYFDV (SEQ ID NO: 91); and

[0511] a VLpolypeptide comprising

[0512] a VL CDR1 comprising the amino acid sequence QDINKY (SEQ ID NO: 92),

[0513] a VL CDR2 comprising the amino acid sequence YTS (SEQ ID NO: 93), and

[0514] a VLCDR3 comprising the amino acid sequence LQFDNLLRT (SEQ ID NO: 94).

[0515] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 3; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 4; or both.

[0516] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0517] a VH polypeptide comprising

[0518] a VHCDR1 comprising the amino acid sequence GYTFTTYT (SEQ ID NO: 95), a VHCDR2 comprising the amino acid sequence INPGSGYI (SEQ ID NO: 96), and a VHCDR3 comprising the amino acid sequence ARSGTGIFYAMDY (SEQ ID NO: 97); and

[0519] a VLpolypeptide comprising

[0520] a VL CDR1 comprising the amino acid sequence QSVSND (SEQ ID NO: 98),

[0521] a VLCDR2 comprising the amino acid sequence SAS (SEQ ID NO: 99), and

[0522] a VLCDR3 comprising the amino acid sequence QQDYRSPYT (SEQ ID NO: 100).In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 5; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 6; or both.

[0523] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0524] a V polypeptide comprising

[0525] a VH CDR1 comprising the amino acid sequence GFTFSSYV (SEQ ID NO: 101), a VHCDR2 comprising the amino acid sequence ISNGGSYT (SEQ ID NO: 102), and a VH CDR3 comprising the amino acid sequence SRHWGISGYDAMEY (SEQ ID NO: 103); and

[0526] a VLpolypeptide comprising

[0527] a VL CDR1 comprising the amino acid sequence ENIYGA (SEQ ID NO: 104), a VL CDR2 comprising the amino acid sequence GTT (SEQ ID NO: 105), and

[0528] a V CDR3 comprising the amino acid sequence QSVLSFPYT (SEQ ID NO: 106).

[0529] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 7; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 8; or both.

[0530] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0531] a VH polypeptide comprising

[0532] a VH CDR1 comprising the amino acid sequence GYIFTSYD (SEQ ID NO: 107), a VHCDR2 comprising the amino acid sequence IYPGDGSA (SEQ ID NO: 108), and a VHCDR3 comprising the amino acid sequence AREVRREWFFDV (SEQ ID NO: 109); and

[0533] a VLpolypeptide comprising

[0534] a VL CDR1 comprising the amino acid sequence QDINKY (SEQ ID NO: 110),a VLCDR2 comprising the amino acid sequence YTS (SEQ ID NO: 111), and a V CDR3 comprising the amino acid sequence LQFDNLLRT (SEQ ID NO: 112).

[0535] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 9; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 10; or both.

[0536] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0537] a VHpolypeptide comprising

[0538] a VH CDR1 comprising the amino acid sequence GYTFNTYW (SEQ ID NO: 113), a V CDR2 comprising the amino acid sequence ILPGSGNT (SEQ ID NO: 114), and a VHCDR3 comprising the amino acid sequence ARNYKYDVGKFDV (SEQ ID NO: 115); and

[0539] a VL polypeptide comprising

[0540] a VL CDR1 comprising the amino acid sequence ENIHTN (SEQ ID NO: 116), a VLCDR2 comprising the amino acid sequence AAS (SEQ ID NO: 117), and

[0541] a VLCDR3 comprising the amino acid sequence QHFWGTPWT (SEQ ID NO: 118). In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 11 ; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 12; or both.

[0542] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0543] a VHpolypeptide comprising

[0544] a VHCDR1 comprising the amino acid sequence GFSLTSYG (SEQ ID NO: 119), a VHCDR2 comprising the amino acid sequence IWAGGNT (SEQ ID NO: 120), and a VHCDR3 comprising the amino acid sequence AREFFVY (SEQ ID NO: 121); anda VLpolypeptide comprising

[0545] a V CDR1 comprising the amino acid sequence QDINPY (SEQ ID NO: 122), a VLCDR2 comprising the amino acid sequence RAY (SEQ ID NO: 123), and a V CDR3 comprising the amino acid sequence LQYDEFPYT (SEQ ID NO: 124).

[0546] In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 13; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 14; or both.

[0547] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0548] a V polypeptide comprising

[0549] a V CDR1 comprising the amino acid sequence EYAFPSHD (SEQ ID NO: 125), a VH CDR2 comprising the amino acid sequence INSDGGTT (SEQ ID NO: 126), and a VH GDR3 comprising the amino acid sequence ARRGYEGGMDY (SEQ ID NO: 127); and

[0550] a VLpolypeptide comprising

[0551] a V CDR1 comprising the amino acid sequence KSVSTSDYSY (SEQ ID NO: 128), a VLCDR2 comprising the amino acid sequence LAS (SEQ ID NO: 129), and

[0552] a VL CDR3 comprising the amino acid sequence QHSRELPWT (SEQ ID NO: 130). In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 15; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 16; or both.

[0553] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0554] a V polypeptide comprising

[0555] a VHCDR1 comprising the amino acid sequence GFNIKDTY (SEQ ID NO: 131),a VH CDR2 comprising the amino acid sequence IDPANGNT (SEQ ID NO: 132), and a V CDR3 comprising the amino acid sequence ARKGPDY (SEQ ID NO: 133); and a VLpolypeptide comprising

[0556] a V CDR1 comprising the amino acid sequence QSVDYDGDSY (SEQ ID NO: 134), a VL CDR2 comprising the amino acid sequence AAS (SEQ ID NO: 135), and

[0557] a V CDR3 comprising the amino acid sequence QQSNEDPYT (SEQ ID NO: 136).

[0558] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 17; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 18; or both.

[0559] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0560] a VH polypeptide comprising

[0561] a VH CDR1 comprising the amino acid sequence GYTFTDYN (SEQ ID NO: 137), a VHCDR2 comprising the amino acid sequence IYPYNGGT (SEQ ID NO: 138), and a VHCDR3 comprising the amino acid sequence ARWTYDGYYWYFDV (SEQ ID NO: 139); and

[0562] a VLpolypeptide comprising

[0563] a VL CDR1 comprising the amino acid sequence QDISNY (SEQ ID NO: 140), a VLCDR2 comprising the amino acid sequence YTS (SEQ ID NO: 141), and

[0564] a VL CDR3 comprising the amino acid sequence QQGNTLPWT (SEQ ID NO: 142). In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 19; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 20; or both.

[0565] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:a VHpolypeptide comprising

[0566] a V CDR1 comprising the amino acid sequence GFTFSSYA (SEQ ID NO: 143), a V CDR2 comprising the amino acid sequence ISSGGSYT (SEQ ID NO: 144), and a V CDR3 comprising the amino acid sequence ARKSFDY (SEQ ID NO: 145); and a VL polypeptide comprising

[0567] a V CDR1 comprising the amino acid sequence QDIGSS (SEQ ID NO: 146), a VLCDR2 comprising the amino acid sequence ATS (SEQ ID NO: 147), and

[0568] a VLCDR3 comprising the amino acid sequence LQYASSPPT (SEQ ID NO: 148).

[0569] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 21 ; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 22; or both.

[0570] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0571] a VHpolypeptide comprising

[0572] a VHCDR1 comprising the amino acid sequence GFTFSDYY (SEQ ID NO: 149), a V CDR2 comprising the amino acid sequence ISDGGSYT (SEQ ID NO: 150), and a VHCDR3 comprising the amino acid sequence ARGGSSYERVWFAY (SEQ ID NO: 151); and

[0573] a VLpolypeptide comprising

[0574] a VL CDR1 comprising the amino acid sequence QNVGTN (SEQ ID NO: 152), a VLCDR2 comprising the amino acid sequence SAS (SEQ ID NO: 153), and

[0575] a VLCDR3 comprising the amino acid sequence QQYNSYPYT (SEQ ID NO: 154).

[0576] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 23; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 24; or both.Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0577] a V polypeptide comprising

[0578] a VH CDR1 comprising the amino acid sequence GFSLTSYG (SEQ ID NO: 155), a VHCDR2 comprising the amino acid sequence IWSGGST (SEQ ID NO: 156), and a VH GDR3 comprising the amino acid sequence ARKDGNYAMDY (SEQ ID NO: 157); and

[0579] a VLpolypeptide comprising

[0580] a VLCDR1 comprising the amino acid sequence SSVSY (SEQ ID NO: 158),

[0581] a VL CDR2 comprising the amino acid sequence DTS (SEQ ID NO: 159), and

[0582] a V CDR3 comprising the amino acid sequence QQWSSNPLT (SEQ ID NO: 160). In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 25; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 26; or both.

[0583] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0584] a VH polypeptide comprising

[0585] a VH CDR1 comprising the amino acid sequence GYTFTSYW (SEQ ID NO: 161), a VHCDR2 comprising the amino acid sequence INPSNGGT (SEQ ID NO: 162), and a VHCDR3 comprising the amino acid sequence TIHDDAMDY (SEQ ID NO: 163); and a VLpolypeptide comprising

[0586] a VLCDR1 comprising the amino acid sequence SSVSY (SEQ ID NO: 164),

[0587] a VL CDR2 comprising the amino acid sequence DTS (SEQ ID NO: 165), and

[0588] a VLCDR3 comprising the amino acid sequence FQGSGYPLT (SEQ ID NO: 166).

[0589] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 27; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80%or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 28; or both.

[0590] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0591] a V polypeptide comprising

[0592] a V CDR1 comprising the amino acid sequence GYSITSDYA (SEQ ID NO: 167), a V CDR2 comprising the amino acid sequence ISYSGST (SEQ ID NO: 168), and a VH CDR3 comprising the amino acid sequence ARSVDGYYWFAY (SEQ ID NO: 169); and

[0593] a VLpolypeptide comprising

[0594] a VLCDR1 comprising the amino acid sequence SNVNSSY (SEQ ID NO: 170), a VLCDR2 comprising the amino acid sequence STS (SEQ ID NO: 171), and

[0595] a V CDR3 comprising the amino acid sequence HQWSSYPLT (SEQ ID NO: 172).

[0596] In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 29; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 30; or both.

[0597] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0598] a V polypeptide comprising

[0599] a V CDR1 comprising the amino acid sequence GYSFTGYY (SEQ ID NO: 173), a VH CDR2 comprising the amino acid sequence INPYNGAT (SEQ ID NO: 174), and a VH CDR3 comprising the amino acid sequence ARKEIDYDYDLYAMDY (SEQ ID NO: 175); and

[0600] a VLpolypeptide comprising

[0601] a V CDR1 comprising the amino acid sequence QDISNY (SEQ ID NO: 176), a VLCDR2 comprising the amino acid sequence YTS (SEQ ID NO: 177), and

[0602] a VL CDR3 comprising the amino acid sequence QQGNTLT (SEQ ID NO: 178).In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 31 ; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 32; or both.

[0603] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0604] a VHpolypeptide comprising

[0605] a VHCDR1 comprising the amino acid sequence GYSFTSYW (SEQ ID NO: 179), a V CDR2 comprising the amino acid sequence IHPSDSET (SEQ ID NO: 180), and a V CDR3 comprising the amino acid sequence ARDGGSRFAY (SEQ ID NO: 181); and a VLpolypeptide comprising

[0606] a VL CDR1 comprising the amino acid sequence ENIHTN (SEQ ID NO: 182), a V CDR2 comprising the amino acid sequence AAS (SEQ ID NO: 183), and

[0607] a VL CDR3 comprising the amino acid sequence QHFWGTPWT (SEQ ID NO: 184). In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 33; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 34; or both.

[0608] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0609] a VHpolypeptide comprising

[0610] a VHCDR1 comprising the amino acid sequence GYSITSDYA (SEQ ID NO: 185), a V CDR2 comprising the amino acid sequence ISYSGST (SEQ ID NO: 186), and a VHCDR3 comprising the amino acid sequence ARFDVRYAMDY (SEQ ID NO: 187); and

[0611] a VL polypeptide comprising

[0612] a VLCDR1 comprising the amino acid sequence SSVSY (SEQ ID NO: 188),a VLCDR2 comprising the amino acid sequence DTS (SEQ ID NO: 189), and

[0613] a VLCDR3 comprising the amino acid sequence QQWSSNPYT (SEQ ID NO: 190). In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 35; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 36; or both.

[0614] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0615] a VHpolypeptide comprising

[0616] a VH CDR1 comprising the amino acid sequence GYSITSGYS (SEQ ID NO: 191), a V CDR2 comprising the amino acid sequence IHYSGST (SEQ ID NO: 192), and a V CDR3 comprising the amino acid sequence ARINYQFAY (SEQ ID NO: 193); and a VL polypeptide comprising

[0617] a VL CDR1 comprising the amino acid sequence SSVNY (SEQ ID NO: 194),

[0618] a V CDR2 comprising the amino acid sequence YTS (SEQ ID NO: 195), and

[0619] a VLCDR3 comprising the amino acid sequence QQFTSSPYT (SEQ ID NO: 196).

[0620] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 37; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 38; or both.

[0621] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0622] a VHpolypeptide comprising

[0623] a VHCDR1 comprising the amino acid sequence GFAFSSYD (SEQ ID NO: 197), a VHCDR2 comprising the amino acid sequence ISSGGGST (SEQ ID NO: 198), and a V CDR3 comprising the amino acid sequence VRQLLGAY (SEQ ID NO: 199); and a VLpolypeptide comprisinga VLCDR1 comprising the amino acid sequence SSISY (SEQ ID NO: 200), a VLCDR2 comprising the amino acid sequence DTS (SEQ ID NO: 201), and

[0624] a VLCDR3 comprising the amino acid sequence HQRSSYPLT (SEQ ID NO: 202).

[0625] In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 39; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 40; or both.

[0626] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0627] a VH polypeptide comprising

[0628] a V CDR1 comprising the amino acid sequence GYTFTSSW (SEQ ID NO: 203), a VHCDR2 comprising the amino acid sequence IHPNSGNT (SEQ ID NO: 204), and a VH CDR3 comprising the amino acid sequence ARLGERGFAY (SEQ ID NO: 205); and a VL polypeptide comprising

[0629] a VL CDR1 comprising the amino acid sequence QSLLNSGNQKNY (SEQ ID NO: 206), a VLCDR2 comprising the amino acid sequence GAS (SEQ ID NO: 207), and a VLCDR3 comprising the amino acid sequence QNDHSYPYT (SEQ ID NO: 208).

[0630] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 41 ; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 42; or both.

[0631] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0632] a VHpolypeptide comprising

[0633] a VHCDR1 comprising the amino acid sequence GDSIISGY (SEQ ID NO: 209), a V CDR2 comprising the amino acid sequence ISYSGTT (SEQ ID NO: 210), and a VHCDR3 comprising the amino acid sequence AKSYNYDVHY (SEQ ID NO: 211 ); anda VLpolypeptide comprising

[0634] a V CDR1 comprising the amino acid sequence QNVGTN (SEQ ID NO: 212), a VLCDR2 comprising the amino acid sequence SAS (SEQ ID NO: 213), and

[0635] a V CDR3 comprising the amino acid sequence QQYNSYPWT (SEQ ID NO: 214). In certain embodiments, the antibody comprises: V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 43; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 44; or both.

[0636] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0637] a V polypeptide comprising

[0638] a V CDR1 comprising the amino acid sequence GFSLTNYG (SEQ ID NO: 215), a VH CDR2 comprising the amino acid sequence IWSGGST (SEQ ID NO: 216), and a VH CDR3 comprising the amino acid sequence AKMTDDYYWYFDV (SEQ ID NO: 217); and

[0639] a VLpolypeptide comprising

[0640] a VLCDR1 comprising the amino acid sequence GNIRNY (SEQ ID NO: 218), a VLCDR2 comprising the amino acid sequence NAK (SEQ ID NO: 219), and a VL CDR3 comprising the amino acid sequence QHFWTTPYT (SEQ ID NO: 220).

[0641] In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 45; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 46; or both.

[0642] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0643] a V polypeptide comprising

[0644] a VHCDR1 comprising the amino acid sequence GYTFTSYW (SEQ ID NO: 221),a VH CDR2 comprising the amino acid sequence INPSTGYT (SEQ ID NO: 222), and a VHCDR3 comprising the amino acid sequence ARSDYYGSSYGWYFDV (SEQ ID NO: 223); and

[0645] a VLpolypeptide comprising

[0646] a VL CDR1 comprising the amino acid sequence TDIDDD (SEQ ID NO: 224), a V CDR2 comprising the amino acid sequence EGN (SEQ ID NO: 225), and a VL CDR3 comprising the amino acid sequence LQSDNLPYT (SEQ ID NO: 226).

[0647] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 47; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 48; or both.

[0648] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0649] a VH polypeptide comprising

[0650] a VH CDR1 comprising the amino acid sequence GFSLTDYG (SEQ ID NO: 227), a VHCDR2 comprising the amino acid sequence IWSGGST (SEQ ID NO: 228), and a VHCDR3 comprising the amino acid sequence AKMTDNYYWYFDV (SEQ ID NO: 229); and

[0651] a VL polypeptide comprising

[0652] a VL CDR1 comprising the amino acid sequence GNIRNY (SEQ ID NO: 230), a VL CDR2 comprising the amino acid sequence NAE (SEQ ID NO: 231), and a VLCDR3 comprising the amino acid sequence QHFWTTPYT (SEQ ID NO: 232).

[0653] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 49; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 50; or both.Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0654] a V polypeptide comprising

[0655] a VH CDR1 comprising the amino acid sequence GFSLTSYG (SEQ ID NO: 233), a VHCDR2 comprising the amino acid sequence VWAGGST (SEQ ID NO: 234), and a VH GDR3 comprising the amino acid sequence AREKPITLSMDY (SEQ ID NO: 235); and

[0656] a VLpolypeptide comprising

[0657] a VLCDR1 comprising the amino acid sequence QDINSY (SEQ ID NO: 236), a VL CDR2 comprising the amino acid sequence RAD (SEQ ID NO: 237), and a VL CDR3 comprising the amino acid sequence LQYDELPLT (SEQ ID NO: 238).

[0658] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 51 ; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 52; or both.

[0659] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0660] a VH polypeptide comprising

[0661] a VHCDR1 comprising the amino acid sequence GFTFSSYA (SEQ ID NO: 239), a VHCDR2 comprising the amino acid sequence ISSGGGYT (SEQ ID NO: 240), and a VHCDR3 comprising the amino acid sequence PRRGMAPTGFAY (SEQ ID NO: 241); and

[0662] a VLpolypeptide comprising

[0663] a VL CDR1 comprising the amino acid sequence QSLLNVGNQKNY (SEQ ID NO: 242), a VLCDR2 comprising the amino acid sequence WSS (SEQ ID NO: 243), and a VL CDR3 comprising the amino acid sequence QNDYSYPYT (SEQ ID NO: 244).

[0664] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 53;a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 54; or both.

[0665] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0666] a V polypeptide comprising

[0667] a V CDR1 comprising the amino acid sequence GFSLSTSGMG (SEQ ID NO: 245), a VH CDR2 comprising the amino acid sequence IYWDDDK (SEQ ID NO: 246), and a VH CDR3 comprising the amino acid sequence ARRAWDYDGAWFAY (SEQ ID NO: 247); and

[0668] a VLpolypeptide comprising

[0669] a V CDR1 comprising the amino acid sequence QDISNY (SEQ ID NO: 248), a VLCDR2 comprising the amino acid sequence YTS (SEQ ID NO: 249), and

[0670] a VL CDR3 comprising the amino acid sequence QQGNTLPFT (SEQ ID NO: 250).

[0671] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 55; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 56; or both.

[0672] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0673] a V polypeptide comprising

[0674] a VH CDR1 comprising the amino acid sequence GFSLTDYG (SEQ ID NO: 251), a VHCDR2 comprising the amino acid sequence IWSGGST (SEQ ID NO: 252), and a VH CDR3 comprising the amino acid sequence AKMTDNYYWYFDV (SEQ ID NO: 253); and

[0675] a VLpolypeptide comprising

[0676] a VLCDR1 comprising the amino acid sequence GNIRDY (SEQ ID NO: 254), a VL CDR2 comprising the amino acid sequence NAK (SEQ ID NO: 255), and a VL CDR3 comprising the amino acid sequence QHFWTTPYT (SEQ ID NO: 256).In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 57; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 58; or both.

[0677] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0678] a VHpolypeptide comprising

[0679] a VH CDR1 comprising the amino acid sequence GFNIKDTY (SEQ ID NO: 257), a VHCDR2 comprising the amino acid sequence IDPANGNT (SEQ ID NO: 258), and a VHCDR3 comprising the amino acid sequence ARSGLTAPGFDY (SEQ ID NO: 259); and

[0680] a VL polypeptide comprising

[0681] a V CDR1 comprising the amino acid sequence QDISNY (SEQ ID NO: 260), a VL CDR2 comprising the amino acid sequence YTS (SEQ ID NO: 261), and

[0682] a VLCDR3 comprising the amino acid sequence QQGNTLPYT (SEQ ID NO: 262).

[0683] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 59; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 60; or both.

[0684] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0685] a VHpolypeptide comprising

[0686] a VHCDR1 comprising the amino acid sequence GYTFTGYW (SEQ ID NO: 263), a VHCDR2 comprising the amino acid sequence INPSVGAT (SEQ ID NO: 264), and a VHCDR3 comprising the amino acid sequence ARVGDYFDF (SEQ ID NO: 265); and a VL polypeptide comprising

[0687] a VLCDR1 comprising the amino acid sequence QSVSSSNYNY (SEQ ID NO: 266),a VLCDR2 comprising the amino acid sequence YAS (SEQ ID NO: 267), and a VLCDR3 comprising the amino acid sequence QHSWEIPWT (SEQ ID NO: 268).

[0688] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 61 ; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 62; or both.

[0689] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0690] a VHpolypeptide comprising

[0691] a VH CDR1 comprising the amino acid sequence GFTFSTYA (SEQ ID NO: 269), a V CDR2 comprising the amino acid sequence ISHGGSYT (SEQ ID NO: 270), and a VHCDR3 comprising the amino acid sequence ARHWGSSGYDALDF (SEQ ID NO: 271); and

[0692] a VL polypeptide comprising

[0693] a VL CDR1 comprising the amino acid sequence ENIYGA (SEQ ID NO: 272), a VLCDR2 comprising the amino acid sequence GTT (SEQ ID NO: 273), and

[0694] a VLCDR3 comprising the amino acid sequence QNALSISYT (SEQ ID NO: 274).

[0695] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 63; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 64; or both.

[0696] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0697] a VHpolypeptide comprising

[0698] a VHCDR1 comprising the amino acid sequence GFTFSSYG (SEQ ID NO: 275), a V CDR2 comprising the amino acid sequence INSNGGST (SEQ ID NO: 276), anda VH CDR3 comprising the amino acid sequence ARDDYYGSRGNWWYFDV (SEQ ID NO: 277); and

[0699] a VLpolypeptide comprising

[0700] a V CDR1 comprising the amino acid sequence QSLLYSSNQKNY (SEQ ID NO: 278), a VL CDR2 comprising the amino acid sequence WAS (SEQ ID NO: 279), and a V CDR3 comprising the amino acid sequence QQYYSYPLT (SEQ ID NO: 280).

[0701] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 65; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 66; or both.

[0702] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0703] a VH polypeptide comprising

[0704] a VH CDR1 comprising the amino acid sequence GFSLTNYG (SEQ ID NO: 281), a VHCDR2 comprising the amino acid sequence IWSGGTT (SEQ ID NO: 282), and a VHCDR3 comprising the amino acid sequence AKMTDDYYWYFDV (SEQ ID NO: 283); and

[0705] a VLpolypeptide comprising

[0706] a VL CDR1 comprising the amino acid sequence QDVSTA (SEQ ID NO: 284), a VLCDR2 comprising the amino acid sequence SAS (SEQ ID NO: 285), and

[0707] a VLCDR3 comprising the amino acid sequence QQHYSTPPT (SEQ ID NO: 286).

[0708] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 67; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 68; or both.

[0709] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:a VHpolypeptide comprising

[0710] a VHCDR1 comprising the amino acid sequence GYTFNNYW (SEQ ID NO: 287), a V CDR2 comprising the amino acid sequence ILPGSGNT (SEQ ID NO: 288), and a V CDR3 comprising the amino acid sequence ARNYKYDVGKFDV (SEQ ID NO: 289); and

[0711] a V polypeptide comprising

[0712] a VL CDR1 comprising the amino acid sequence ENIYTN (SEQ ID NO: 290),

[0713] a VLCDR2 comprising the amino acid sequence AAS (SEQ ID NO: 291 ), and

[0714] a VLCDR3 comprising the amino acid sequence QHFWGTPWT (SEQ ID NO: 292). In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 69; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 70; or both.

[0715] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0716] a V polypeptide comprising

[0717] a V CDR1 comprising the amino acid sequence GYTITDYW (SEQ ID NO: 293), a V CDR2 comprising the amino acid sequence IDTSDSYT (SEQ ID NO: 294), and a VH CDR3 comprising the amino acid sequence ARGRFITDY (SEQ ID NO: 295); and a VLpolypeptide comprising

[0718] a V CDR1 comprising the amino acid sequence QDINSY (SEQ ID NO: 296), a VLCDR2 comprising the amino acid sequence RAN (SEQ ID NO: 297), and a VLCDR3 comprising the amino acid sequence LQYDEFPFT (SEQ ID NO: 298).

[0719] In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 71 ; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 72; or both.Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0720] a V polypeptide comprising

[0721] a VH CDR1 comprising the amino acid sequence GYSITSDYA (SEQ ID NO: 299), a VHCDR2 comprising the amino acid sequence ISYSGST (SEQ ID NO: 300), and a VH CDR3 comprising the amino acid sequence AREGDYYGTSPFDY (SEQ ID NO: 301 ); and

[0722] a VLpolypeptide comprising

[0723] a V CDR1 comprising the amino acid sequence QNINFW (SEQ ID NO: 302), a VL CDR2 comprising the amino acid sequence RAS (SEQ ID NO: 303), and a V CDR3 comprising the amino acid sequence QQGQSYPLT (SEQ ID NO: 304).

[0724] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 73; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 74; or both.

[0725] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0726] a VH polypeptide comprising

[0727] a VH CDR1 comprising the amino acid GHTSTTYT (SEQ ID NO: 305),

[0728] a VHCDR2 comprising the amino acid sequence SNPSSGYT (SEQ ID NO: 306), and a VHCDR3 comprising the amino acid sequence ASSSYYYAMDY (SEQ ID NO: 307); and a VLpolypeptide comprising

[0729] a VLCDR1 comprising the amino acid sequence QSVGND (SEQ ID NO: 308), a VL CDR2 comprising the amino acid sequence YAS (SEQ ID NO: 309), and

[0730] a VLCDR3 comprising the amino acid sequence QQDYSSPLT (SEQ ID NO: 310).

[0731] In certain embodiments, the antibody comprises: a VH polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 75; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80%or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 76; or both.

[0732] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0733] a V polypeptide comprising

[0734] a V CDR1 comprising the amino acid GFSLTSYG (SEQ ID NO: 311),

[0735] a V CDR2 comprising the amino acid sequence IWAGGST (SEQ ID NO: 312), and a VH CDR3 comprising the amino acid sequence AREKRITLSMDY (SEQ ID NO: 313); and

[0736] a VLpolypeptide comprising

[0737] a VLCDR1 comprising the amino acid sequence QDINSY (SEQ ID NO: 314), a V CDR2 comprising the amino acid sequence RAN (SEQ ID NO: 315), and a V CDR3 comprising the amino acid sequence LQYDELPLT (SEQ ID NO: 316).

[0738] In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 77; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 78; or both.

[0739] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0740] a V polypeptide comprising

[0741] a VHCDR1 comprising the amino acid GFTFSDYY (SEQ ID NO: 317),

[0742] a VH CDR2 comprising the amino acid sequence ISDGGSYT (SEQ ID NO: 318), and a VH CDR3 comprising the amino acid sequence ARDEGTMPAVYYAMDY (SEQ ID NO: 319); and

[0743] a VLpolypeptide comprising

[0744] a VLCDR1 comprising the amino acid sequence SSVSY (SEQ ID NO: 320),

[0745] a VLCDR2 comprising the amino acid sequence RTS (SEQ ID NO: 321), and

[0746] a VL CDR3 comprising the amino acid sequence QQYHSYPPT (SEQ ID NO: 322).In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 79; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 80; or both.

[0747] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0748] a VHpolypeptide comprising

[0749] a VH CDR1 comprising the amino acid GYTFTSYT (SEQ ID NO: 323),

[0750] a V CDR2 comprising the amino acid sequence INLSSGYI (SEQ ID NO: 324), and a VHCDR3 comprising the amino acid sequence ARSGLGIYYAMDY (SEQ ID NO: 325); and

[0751] a VL polypeptide comprising

[0752] a V CDR1 comprising the amino acid sequence QSVSND (SEQ ID NO: 326), a VL CDR2 comprising the amino acid sequence SAS (SEQ ID NO: 327), and

[0753] a VLCDR3 comprising the amino acid sequence QQDYSSPLT (SEQ ID NO: 328).

[0754] In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 81 ; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 82; or both.

[0755] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0756] a VHpolypeptide comprising

[0757] a VHCDR1 comprising the amino acid GFTFSDYY (SEQ ID NO: 329),

[0758] a V CDR2 comprising the amino acid sequence ISNGGGST (SEQ ID NO: 330), and a VHCDR3 comprising the amino acid sequence ARDDYDGYWYFDV (SEQ ID NO: 331 ); and

[0759] a VLpolypeptide comprisinga VL CDR1 comprising the amino acid sequence ESVDSYGNSF (SEQ ID NO: 332), a VLCDR2 comprising the amino acid sequence LAS (SEQ ID NO: 333), and

[0760] a VLCDR3 comprising the amino acid sequence QQNNEDPYT (SEQ ID NO: 334). In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 83; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 84; or both.

[0761] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0762] a VH polypeptide comprising

[0763] a VHCDR1 comprising the amino acid GYTFTDYE (SEQ ID NO: 335),

[0764] a V CDR2 comprising the amino acid sequence IDPETGGT (SEQ ID NO: 336), and a VH CDR3 comprising the amino acid sequence TTNYFDY (SEQ ID NO: 337); and a VL polypeptide comprising

[0765] a VL CDR1 comprising the amino acid sequence QSLLDSDGKTY (SEQ ID NO: 338), a VLCDR2 comprising the amino acid sequence LVS (SEQ ID NO: 339), and

[0766] a VLCDR3 comprising the amino acid sequence WQGTHFPRT (SEQ ID NO: 340). In certain embodiments, the antibody comprises: a VHpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 85; a VL polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 86; or both.

[0767] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0768] a VHpolypeptide comprising

[0769] a VHCDR1 comprising the amino acid GYTFTSYD (SEQ ID NO: 341),

[0770] a V CDR2 comprising the amino acid sequence IFPGDGST (SEQ ID NO: 342), and a VHCDR3 comprising the amino acid sequence ARNLYGWFAY (SEQ ID NO: 343); anda VLpolypeptide comprising

[0771] a V CDR1 comprising the amino acid sequence QSLLNSSNQKNY (SEQ ID NO: 344), a VLCDR2 comprising the amino acid sequence FAS (SEQ ID NO: 345), and

[0772] a VLCDR3 comprising the amino acid sequence QQHYSTPPT (SEQ ID NO: 346).

[0773] In certain embodiments, the antibody comprises: a V polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 87; a VLpolypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 88; or both.

[0774] Accordingly, in some embodiments, an anti-CD64 antibody of the present disclosure specifically binds CD64 and either has the following CDRs or competes for binding with an antibody having the following CDRs:

[0775] a V polypeptide comprising

[0776] a V CDR1 comprising the amino acid GYSFTDYG (SEQ ID NO: 347),

[0777] a VH CDR2 comprising the amino acid sequence INTYNGEP (SEQ ID NO: 348), and a VH CDR3 comprising the amino acid sequence ANRYDGKYFFALDY (SEQ ID NO: 349); and

[0778] a VLpolypeptide comprising

[0779] a V CDR1 comprising the amino acid sequence QNIVHSNGNTY (SEQ ID NO: 350), a VLCDR2 comprising the amino acid sequence KVS (SEQ ID NO: 351 ), and

[0780] a VL CDR3 comprising the amino acid sequence FQGSHVPYT (SEQ ID NO: 352).

[0781] In some cases, an anti-GD64 antibody described herein is a fully human antibody, a humanized antibody, or a chimeric antibody. An anti-CD64 antibody can be an IgG, such as igGi.

[0782] In certain embodiments, an anti-CD64 antibody described herein comprises an Fc region, and the Fc region is heterologous to the VHof the antibody. In certain such cases, the Fc region is a variant Fc region, for example, a variant Fc region comprising one or more amino acid substitutions, one or more amino acid insertions, one or more amino acid deletions, or any combination thereof, relative to a wild-type Fc region.

[0783] In some cases, an anti-CD64 antibody described is a fragment of a full antibody, for example, the antibody is a Fab.

[0784] In even further embodiments, an anti-CD64 antibody described herein is a single chain antibody, such as scFv.Bispecific Antibodies

[0785] As noted above, bispecific antibodies having one anti-CD64 binding domain and the other binding domain specific for a different antigen are useful in the art, for example, to recruit CD64 expressing immune cells to other cells expressing the different antigen.

[0786] Accordingly, certain aspects of the disclosure provide bispecific antibodies. In certain embodiments, a bispecific antibody of the present disclosure comprises a first antigen-binding domain comprising a VH polypeptide-Vi. polypeptide pair of any of the anti-CD64, including any of such antibodies described hereinabove, for example, the antibodies described in Tables 1 and 2. The bispecific antibody may include a second antigen-binding domain that specifically binds the CD64 epitope bound by the first antigen-binding domain. In certain embodiments, the bispecific antibody includes a second antigen-binding domain that specifically binds a CD64 epitope other than the CD64 epitope bound by the first antigen-binding domain.

[0787] According to some embodiments, a bispecific antibody of the present disclosure includes a second antigen-binding domain that specifically binds an antigen other than CD64. In certain embodiments, the antigen other than CD64 is a tumor antigen. Non-limiting examples of tumor antigens are CD3, major histocompatibility class II (MHC II), 5T4, AXL receptor tyrosine kinase (AXL), B-cell maturation antigen (BCMA), c-MET, C4.4a, carbonic anhydrase 6 (GA6), carbonic anhydrase 9 (CA9), Cadherin-6, CD19, CD20, CD22, CD25, CD27L, CD30, CD33, CD37, CD44v6, CD56, CD70, CD74, CD79b, CD123, CD138, carcinoembryonic antigen (CEA), cKit, Cripto protein, CS1, delta-like canonical Notch ligand 3 (DLL3), endothelin receptor type B (EDNRB), EpCAM, ephrin A4 (EFNA4), epidermal growth factor receptor (EGFR), EGFRvlll, ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3), EPH receptor A2 (EPHA2), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), FMS-like tyrosine kinase 3 (FLT3), folate receptor 1 (FOLR1), GLUT3, glycoprotein non-metastatic B (GPNMB), guanylate cyclase 2C (GUCY2C), HCAM, human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), Integrin alpha, lysosomal-associated membrane protein 1 (LAMP-1), Lewis Y, LIV-1, leucine rich repeat containing 15 (LRRC15), mesothelin (MSLN), sodium-dependent phosphate transport protein 2B (NaPi2b), Nectin-4, NMB, NOTCH3, p-cadherin (p-GAD), prostate-specific membrane antigen (PSMA), protein tyrosine kinase 7 (PTK7), solute carrier family 44 member 4 (SLC44A4), SLIT like family member 6 (SLITRK6), STEAP family member 1 (STEAP1), tissue factor (TF), T cell immunoglobulin and mucin protein-1 (TIM-1), trophoblast cell-surface antigen (TROP-2), or VEGF-A..Bispecific antibodies of the present disclosure include antibodies having a full-length antibody structure, and bispecific antibody fragments. “Full-length” as used herein refers to an antibody having two full-length antibody heavy chains and two full length antibody light chains. A full-length antibody heavy chain (HC) consists of well-known heavy chain variable and constant domains VH, CH1, CH2, and CH3. A full-length antibody light chain (LC) consists of well-known light chain variable and constant domains VL and CL. The full-length antibody may be lacking the C-terminal lysine in either one or both heavy chains. The term “Fab arm” refers to one heavy chain :light chain pair that specifically binds an antigen.

[0788] Full-length bispecific antibodies may be generated for example using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in a cell-free environment or using co-expression. The Fab arm exchange reaction is the result of a disulfide-bond isomerization reaction and dissociation-association of CH3 domains. The heavy chain disulfide bonds in the hinge regions of the parent monospecific antibodies are reduced. The resulting free cysteines of one of the parent monospecific antibodies form an inter heavy-chain disulfide bond with cysteine residues of a second parent monospecific antibody molecule and simultaneously CH3 domains of the parent antibodies release and reform by dissociationassociation. The CH3 domains of the Fab arms may be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody having two Fab arms or half molecules which each bind a distinct epitope.

[0789] The “knob-in-hole” strategy (see, e.g., WO 2006 / 028936) may be used to generate full length bispecific antibodies. Briefly, selected amino acids forming the interface of the CHS domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of the preferential interaction of the heavy chain with a “hole” with the heavy chain with a “knob”. Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): T366Y7F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T3945 / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V.Other strategies such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues at one CH3 surface and negatively charged residues at a second CH3 surface may be used, as described in US2010 / 0015133; US2009 / 0182127; US2010 / 028637 or US2011 / 0123532. In other strategies, heterodimerization may be promoted by the following substitutions (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): L351 Y_F405A_Y407V T394W, T366l_K392M_T394W / F405A_Y407V, T366L K392M T394W / F405A Y407V, L351 Y_Y407A'T366A_K409F, L351 Y Y407A / T366V K409F, Y407A / T366A_K409F, or T350V L351 Y_F405A_Y407V / T350V_T366L_K392L_T394W as described in US2012 / 0149876 or US2013 / 0195849.

[0790] Also provided are single chain bispecific antibodies. In some embodiments, a single chain bispecific antibody of the present disclosure is a bispecific scFv. Details regarding bispecific scFvs may be found, e.g., in Zhou et al. (2017) J Cancer 8(18):3689-3696.

[0791] Approaches that may be employed to produce multispecific (e.g., bispecific) antibodies from the antibodies described herein include, but are not limited to, Ellerman, D. (2019). "Bispecific T-cell engagers: Towards understanding variables influencing the in vitro potency and tumor selectivity and their modulation to enhance their efficacy and safety." Methods 154: 102-117; Brinkmann, U. and R. E. Kontermann (2017). "The making of bispecific antibodies." mAbs 9(2): 182-212; and Suurs, F. V., et al. (2019). "A review of bispecific antibodies and antibody constructs in oncology and clinical challenges." Pharmacol Ther 201 : 103-119; the disclosures of which are incorporated herein by reference in their entireties for all purposes.

[0792] Conjugates

[0793] The present disclosure also provides anti-CD64 antibody conjugates. According to some embodiments, a conjugate of the present disclosure comprises any of the antibodies of the present disclosure, for example, antibodies described above in Tables 1 and 2 and related disclosures, and an agent conjugated to the antibody. 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 certain embodiments, the agent conjugated to the antibody is selected from a chemotherapeutic agent, a toxin, a radiationsensitizing agent, a radioactive isotope (e.g., a therapeutic radioactive isotope), a detectable label, and a half-life extending moiety.According to some embodiments, the agent is a therapeutic agent, e.g., a chemotherapeutic agent. Therapeutic agents of interest include agents capable of affecting the function of a cell / tissue to which the conjugate binds via specific binding of the antibody portion of the conjugate to CD64. When the function of the cell / tissue is pathological, an agent that reduces the function of the cell / tissue may be employed. In certain aspects, a conjugate of the present disclosure includes an agent that reduces the function of a target cell / tissue by inhibiting cell proliferation and / or killing the cell / tissue. Such agents may vary and include cytostatic agents and cytotoxic agents, e.g., an agent capable of killing a target cell tissue with or without being internalized into a target cell.

[0794] In certain embodiments, the therapeutic agent is a cytotoxic agent selected from an enediyne, a lexitropsin, a duocarmycin, a taxane, a puromycin, a dolastatin, a maytansinoid, and a vinca alkaloid. In some embodiments, the cytotoxic agent is paclitaxel, docetaxel, CC-1065, CPT-11 (SN-38), topotecan, doxorubicin, morpholino-doxorubicin, rhizoxin, cyanomorpholinodoxorubicin, dolastatin-10, echinomycin, combretastatin, calicheamicin, maytansine, maytansine DM1 , maytansine DM4, DM-1 , an auristatin or other dolastatin derivatives, such as auristatin E or auristatin F, AEB (AEB-071), AEVB (5-benzoylvaleric acid-AE ester), AEFP (antibody-endostatin fusion protein), MMAE (monomethylauristatin E), MMAF (monomethylauristatin F), pyrrolobenzodiazepines (PBDs), eleutherobin, netropsin, or any combination thereof.

[0795] In a specific embodiment, the therapeutic agent is a chemotherapeutic agent. In some cases, a chemotherapeutic agent is an anthracycline or an anthracycline derivative. In certain such embodiments, the anthracycline derivative is PNU-159682. Additional anthracyclines or anthracycline derivatives are known in the art and are described, for example, in PCT Publication No. WO 2022 / 251850, which is herein incorporated by reference in its entirety.

[0796] According to some embodiments, the agent is a toxin, such as a protein toxin selected from hemiasterlin and hemiasterlin analogs such as HTI-286 (e.g., see USPN 7,579,323; WO 2004 / 026293; and USPN 8,129,407, the full disclosures of which are incorporated herein by reference), abrin, brucine, cicutoxin, diphtheria toxin, batrachotoxin, botulism toxin, shiga toxin, endotoxin, Pseudomonas exotoxin, Pseudomonas endotoxin, tetanus toxin, pertussis toxin, anthrax toxin, cholera toxin, falcarinol, fumonisin Bl, fumonisin B2, aflatoxin, maurotoxin, agitoxin, charybdotoxin, margatoxin, slotoxin, scyllatoxin, hefutoxin, calciseptine, taicatoxin, calcicludine, geldanamycin, gelonin, lotaustralin, ocratoxin A, patulin, ricin, strychnine, trichothecene, zearlenone, and tetradotoxin. Enzymatically active toxins and fragments thereof which may be employed include diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin and the tricothecenes.

[0797] In certain embodiments, the agent is a radiation-sensitizing agent. As used herein, a “radiation-sensitizing agent” is an agent that enhances the ability of radiation to kill tumor cells. Non-limiting examples of radiation-sensitizing agents that may be conjugated to the antibody include cisplatin, 5-fluorouracil (5-FU), AZD7762, selumetinib, and the like.

[0798] In certain embodiments, the agent is a radioisotope, e.g., useful for therapy and / or detection (e.g., imaging). Non-limiting examples of radioisotopes that may be conjugated to the antibody include but are not limited to225Ac,111Ag,114Ag,71As,72As,77As,211At,198Au,199Au,212Bi,213Bi,75Br,76Br,11C,13C,55Co,62Cu,64Cu,67Cu,165Dy,166Dy,169Er,18F,19F,52Fe,59Fe,66Ga,67Ga,68Ga72Ga154-158Gd157Gd159Gd166Ho120l121l123l124l125l131l110ln111ln113m|n194lr81mKr177Lu,51Mn,52Mn,99Mo,13N,15N,15O,170,32P,33P,211Pb,212Pb,1"Pd,149Pm,151Pm,142Pr,143Pr, 191 p-|- 193mp-|" 195mpt223Ra,142Rb,186Re,188Re,189Re,105Rh,47Sc,75Se,153Sm,117mSn,121Sn,83Sr,89Sr,161Tb,94Tc, "Tc,99mTc,227Th,201TI,172Tm,127Te, "Y,169Yb,175Yb,133X, and89Zr.

[0799] In certain embodiments, a radioisotope is conjugated to the antibody via a chelator, for example, a bifunctional chelator. A bifunctional chelator may contain a metal chelating moiety that binds the radioisotope in a stable coordination complex and a reactive functional group that is covalently linked to a targeting moiety, such as any of the antibodies of the present disclosure, so that the radioisotope may be properly directed to the desirable molecular target in vivo. Nonlimiting examples of bifunctional chelators that may be employed to conjugate an antibody of the present disclosure to a radioisotope include p-SCN-Bn-DOTA and p-SCN-Bn-deferoxamine. Additional examples of bifunctional chelators that may be employed to conjugate an antibody of the present disclosure to a radioisotope include those described in Price & Orvig (2014) Chem. Soc. Rev. 43:260; and Brechbiel (2008) Q J Nucl Med Mol Imaging 52(2) : 166-173.

[0800] According to some embodiments, the radioisotope is a therapeutic radioisotope. In certain embodiments, the radioisotope is an alpha emitting radioisotope, e.g.,225Ac,211At,212Bi / 212Pb,213Bi,223Ra, or227Th. In other embodiments, the radioisotope is a beta minus emitting radioisotope, e.g.,32P,33P,67Cu,90Y,1311 or177Lu.

[0801] According to some embodiments, the agent is a labeling agent. By “labeling agent” (or “detectable label”) is meant the agent detectably labels the antibody, such that the antibody may be detected in an application of interest (e.g., in vitro and / or in vivo research and / or clinical applications). Detectable labels of interest include radioisotopes (e.g., gamma or positronemitters), enzymes that generate a detectable product (e.g., horseradish peroxidase, alkaline phosphatase, luciferase, etc.), fluorescent proteins, paramagnetic atoms, and the like. In certain aspects, the antibody is conjugated to a specific binding partner of detectable label, e.g., conjugated to biotin such that detection may occur via a detectable label that includes avidin / streptavidin.

[0802] In certain embodiments, the agent is a labeling agent that finds use in in vivo imaging, such as near-infrared (NIR) optical imaging, single-photon emission computed tomography (SPECT) ± CT imaging, positron emission tomography (PET) ± CT imaging, nuclear magnetic resonance (NMR) spectroscopy, or the like. Labeling agents that find use in such applications include, but are not limited to, fluorescent labels, radioisotopes, and the like. In certain aspects, the labeling agent is a multi-modal in vivo imaging agent that permits in vivo imaging using two or more imaging approaches (e.g., see Thorp-Greenwood and Coogan (2011) Dalton Trans.

[0803] 40:6129-6143).

[0804] In certain embodiments, the labeling agent is an in vivo imaging agent that finds use in near-infrared (NIR) imaging applications. Such agents include, but are not limited to, a Kodak X-SIGHT dye, Pz 247, DyLight 750 and 800 Fluors, Cy 5.5 and 7 Fluors, Alexa Fluor 680 and 750 Dyes, IRDye 680 and 800CW Fluors. According to some embodiments, the labeling agent is an in vivo imaging agent that finds use in SPECT imaging applications, non-limiting examples of which include99mTc,111In,123l,201TI, and133Xe. In certain embodiments, the labeling agent is an in vivo imaging agent that finds use in PET imaging applications, e.g.,11C,13N,15O,18F,64Cu,62Cu,124l,76Br,82Rb,68Ga, or the like.

[0805] For half-life extension, the antibodies of the present disclosure may be conjugated to an agent that provides for an improved pharmacokinetic profile (e.g., by PEGylation, hyperglycosylation, and the like). Modifications that can enhance serum half-life are of interest. A subject antibody may be “PEGylated”, as containing one or more polyethylene glycol (PEG) moieties. Methods and reagents suitable for PEGylation of a protein are well known in the art and may be found, e.g., in US Pat. No. 5,849,860. PEG suitable for conjugation to a protein is generally soluble in water at room temperature and has the general formula R(O-CH2-CH2)nO-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons. The PEG conjugated to the subject antibody can be linear. The PEG conjugated to the subject antibody may also be branched. Branched PEG derivatives can be those described in U.S. Pat. No. 5,643,575, “star-PEGs” and multi-armed PEGs. Star PEGs are described in the art including, e.g., in U.S. Patent No. 6,046,305.Where the subject antibody is to be isolated from a source, the antibody may be conjugated to one or more moieties that facilitate purification, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), a lectin, and the like. The antibody can also be bound to (e.g., immobilized onto) a solid support, including, but not limited to, polystyrene plates or beads, magnetic beads, test strips, membranes, and the like.

[0806] Where the antibodies are to be detected in an assay, the antibodies may contain a detectable label, e.g., a radioisotope (e.g.,89Zr;111In, and the like), an enzyme which generates a detectable product (e.g., luciferase, p-galactosidase, horse radish peroxidase, alkaline phosphatase, and the like), a fluorescent protein, a chromogenic protein, dye (e.g., fluorescein isothiocyanate, rhodamine, phycoerythrin, and the like); fluorescence emitting metals, e.g.,152Eu, or others of the lanthanide series, attached to the protein through metal chelating groups such as EDTA; chemiluminescent compounds, e.g., luminol, isoluminol, acridinium salts, and the like; bioluminescent compounds, e.g., luciferin; fluorescent proteins; and the like. Indirect labels include antibodies specific for a subject protein, wherein the antibody may be detected via a secondary antibody; and members of specific binding pairs, e.g., biotin-avidin, and the like.

[0807] Any of the above agents may be conjugated to the antibody via a linker. If present, the linker molecule(s) may be of sufficient length to permit the antibody and the linked agent to allow some flexible movement between the antibody and the linked agent. Linker molecules may be, e.g., about 6-50 atoms long. Linker molecules may also be, e.g., aryl acetylene, ethylene glycol oligomers containing 2-10 monomer units, diamines, diacids, amino acids, or combinations thereof.

[0808] Where the linkers are peptides, the linkers can be of any suitable length, such as from 1 amino acid (e.g., Gly) to 20 or more amino acids, from 2 amino acids to 15 amino acids, from 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and may be 1, 2, 3, 4, 5, 6, or 7 amino acids in length.

[0809] Flexible linkers include glycine polymers (G)n, glycine-serine polymers, glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Glycine and glycine-serine polymers may be used where relatively unstructured amino acids are of interest, and may serve as a neutral tether between components. The ordinarily skilled artisan will recognize that design of an antibody conjugated to any agents described above can include linkers that are all or partially flexible, such that the linker can include a flexible linker as well as one or more portions that confer a less flexible structure.According to some embodiments, the antibody is conjugated to the agent via a non-cleavable linker. Non-cleavable linkers of interest include, but are not limited to, thioether linkers. An example of a thioether linker that may be employed includes a succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 -carboxylate (SMCC) linker.

[0810] Another example of al inker that may be employed in the antibody conjugates described herein is Mal-C2-Gly3-EDA.

[0811] In certain embodiments, the antibody is conjugated to the agent via a cleavable linker. According to some embodiments, the linker is a chemically-labile linker, such as an acid-cleavable linker that is stable at neutral pH (bloodstream pH 7.3-7.5) but undergoes hydrolysis upon internalization into the mildly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0) of a target cell (e.g., a cancer cell). Chemically-labile linkers include, but are not limited to, hydrazonebased linkers, oxime-based linkers, carbonate-based linkers, ester-based linkers, etc. In certain embodiments, the linker is an enzyme-labile linker, such as an enzyme-labile linker that is stable in the bloodstream but undergoes enzymatic cleavage upon internalization into a target cell, e.g., by a lysosomal protease (such as cathepsin or plasmin) in a lysosome of the target cell (e.g., a cancer cell). Enzyme-labile linkers include, but are not limited to, linkers that include peptidic bonds, e.g., dipeptide-based linkers such as valine-citrulline (VC) linkers, such as a maleimidocaproyl-valine-citruline-p-aminobenzyl (MC-vc-PAB) linker, a valyl-alanyl-para-aminobenzyloxy (Val-Ala-PAB) linker, and the like. Chemically-labile linkers, enzyme-labile, and non-cleavable linkers are known and described in detail, e.g., in Ducry & Stump (2010) Bioconjugate Chem. 21 :5-13; Nolting, B. (2013) Methods Mol Biol. 1045:71-100; Tsuchikamaand An (2018) Protein & Ce / / 9(1):33-46; and elsewhere.

[0812] Numerous strategies are available for linking agents to an antibody directly, or indirectly via a linker. For example, the agent may be derivatized by covalently attaching a linker to the agent, where the linker has a functional group capable of reacting with a “chemical handle” on the antibody. The functional group on the linker may vary and may be selected based on compatibility with the chemical handle on the antibody. According to one embodiment, the chemical handle on the antibody is provided by incorporation of an unnatural amino acid having the chemical handle into the antibody. Unnatural amino acids which find use for preparing the conjugates of the present disclosure include those having a functional group selected from an azide, alkyne, alkene, amino-oxy, hydrazine, aldehyde (e.g., formylglycine, e.g., SMARTag™ technology from Catalent Pharma Solutions), nitrone, nitrile oxide, cyclopropene, norbornene, iso-cyanide, aryl halide, and boronic acid functional group. Unnatural amino acids which may be incorporated into an antibody of a conjugate of the present disclosure, which unnatural amino acid may be selected to providea functional group of interest, are known and described in, e.g., Maza et al. (2015) Bioconjug. Chem. 26(9):1884-9; Patterson et al. (2014) ACS Chem. Biol. 9:592-605; Adumeau et al. (2016) Mol. Imaging Biol. (2) :153-65; and elsewhere. An unnatural amino acid may be incorporated into an antibody via chemical synthesis or recombinant approaches, e.g., using a suitable orthogonal amino acyl tRNA synthetase-tRNA pair for incorporation of the unnatural amino acid during translation of the antibody in a host cell.

[0813] The functional group of an unnatural amino acid present in the antibody may be an azide, alkyne, alkene, amino-oxy, hydrazine, aldehyde, nitrone, nitrile oxide, cyclopropene, norbornene, iso-cyanide, aryl halide, boronic acid, diazo, tetrazine, tetrazole, quadrocyclane, iodobenzene, or other suitable functional group, and the functional group on the linker is selected to react with the functional group of the unnatural amino acid (or vice versa). As just one example, an azide-bearing unnatural amino acid (e.g., 5-azido-L-norvaline, or the like) may be incorporated into the antibody and the linker portion of a linker-agent moiety may include an alkyne functional group, such that the antibody and linker-agent moiety are covalently conjugated via azide-alkyne cycloaddition. Conjugation may be carried out using, e.g., a copper-catalyzed azide-alkyne cycloaddition reaction.

[0814] In certain embodiments, the chemical handle on the antibody does not involve an unnatural amino acid. An antibody containing no unnatural amino acids may be conjugated to the agent by utilizing, e.g., nucleophilic functional groups of the antibody (such as the N-terminal amine or the primary amine of lysine, or any other nucleophilic amino acid residue) as a nucleophile in a substitution reaction with a moiety bearing a reactive leaving group or other electrophilic group. An example would be to prepare an agent-linker moiety bearing an N-hydroxysuccinimidyl (NHS) ester and allow it to react with the antibody under aqueous conditions at elevated pH (~10) or in polar organic solvents such as DMSO with an added non-nucleophilic base, such as N,N-diisopropylethylamine.

[0815] It will be appreciated that the particular approach for attaching a linker, agent and / or antibody to each other may vary depending upon the particular linker, agent and / or antibody and functional groups selected and employed for conjugating the various components to each other.

[0816] Conjugates of an anti-CD64 antibody and an anthracycline

[0817] As noted above, CD64 is expressed on the surface of certain immune cells, such as monocytes (including early monocyte precursors to mature monocytes), macrophages, dendriticcells and neutrophils. Therefore, anti-CD64 antibodies can be used to deliver an agent to these cells that express CD64 on their surfaces.

[0818] Certain CD64 expressing cells are involved in the development of certain diseases, such as certain cancers, inflammatory disease, or autoimmune diseases. Such disease can be treated by targeting the CD64 expressing cells, e.g., cancer cells or immune cells, using an anti-CD64 antibody.

[0819] An anti-CD64 antibody can be conjugated to an agent, such as a chemotherapeutic agent or a toxin, to specifically deliver such agents to the CD64 expressing cells involved in disease development, such as cancer, inflammatory diseases, or autoimmune diseases. To that end, certain embodiments of the disclosure provide anti-CD64 antibodies that are conjugated to an anthracycline or an anthracycline derivative.

[0820] In some cases, a conjugate comprising an anthracycline or an anthracycline derivative can comprise an anti-CD64 antibody from the anti-CD64 antibodies described in Tables 1 and 2. In some cases, a conjugate comprising an anthracycline or an anthracycline derivative can comprise an anti-CD64 antibody different from the anti-CD64 antibodies described in Tables 1 and 2.

[0821] Anthracyclines are intercalating toxins and are used as chemotherapeutic agents, for example, in cancer therapy. An anthracycline derivative, called PNU-159682, is a metabolite of nemorubicin, which exhibits high potency for cancer cell killing.

[0822] Certain aspects of this disclosure provide that anti-CD64 antibodies conjugated to an anthracycline or an anthracycline derivative, such as PNU-159682, exhibit superior cytotoxic effects on cells expressing CD64 compared to anti-CD64 antibodies conjugated to other cytotoxic agents. For example, FIG. 3B shows that an anti-CD64 antibody conjugated to PNU-159682 exhibited cytotoxic effects in CD64 expressing cancer cells in M4 type - AML patients and M5 type - AML patients. Importantly, FIG. 3B shows that the cytotoxic effects of an anti-CD64 antibody conjugated to PNU-159682 were higher than the cytotoxic effects of an anti-CD64 antibody conjugated to pyrrolobenzodiazepine (PBD), ducarmycin (DMDM), exatecan mesylate (DX8951), or monomethyl auristatin F (MMAF).

[0823] Accordingly, certain embodiments of the disclosure provide an anti-CD64 antibody conjugated to an anthracycline or an anthracycline derivative. In some cases, the anthracycline derivative is PNU-159682. Additional anthracyclines or anthracycline derivatives are known in the art and are described, for example, in PCT Publication No. WO 2022 / 251850, which is hereinincorporated by reference in its entirety.

[0824] An anti-CD64 antibody can be conjugated to PNU-159682 via a cleavable or a non-cleavable linker.

[0825] Any one of the cleavable and non-cleavable linkers described above can be used in conjugating an anti-CD64 antibody to PNU-159682.

[0826] In certain cases, the linker is a maleimide based linker. In certain such cases, a conjugate comprising an anti-CD64 antibody conjugated to an anthracycline or an anthracycline derivative through a maleimide based linker has the following formula:

[0827]

[0828] wherein:

[0829] Ab is an anti-CD64 antibody;

[0830] AN is an anthracycline or an anthracycline derivative;

[0831] each Rxxis independently hydrogen or C1-3 alkyl;

[0832] n1 is an integer from 0 to 4;

[0833] each AA is independently selected from the group consisting of alanine, glycine, lysine, serine, aspartic acid, aspartate methyl ester, N,N-dimethyl-lysine, phenylalanine, citrulline, valine, asparagine, homoserine methyl ether, isoleucine, leucine, glutamic acid, histidine, arginine, threonine, O-methylserine, O-methylaspartic acid, O-methylglutamic acid, N-methyllysine, O-methyltyrosine, O-methylhistidine, and O-methylthreonine; and

[0834] n2 is an integer from 1 to 4.

[0835] In certain embodiments, each Rxxis hydrogen, n1 is 3, AA is glycine, and n2 is 1. In certain such embodiments, AN is PNU-159682.

[0836] In a further embodiment, the maleimide based linker is Mal-G2-Gly3-EDA, which has the following structure.

[0837]

[0838] When Mal-C2-Gly3-EDA is used as a linker between an anti-CD64 antibody an anthracycline or an anthracycline derivative, such as PNU-159682, the maleimide group of the linker is conjugated to a thiol reactive group on an anti-CD64 antibody. An anthracycline or an anthracycline derivative, such as PNU-159682 is conjugated to the amine group at the other end of the linker.

[0839] For example, when the anthracycline derivative is PNU-159682 conjugated to the amine group of Mal-C2-Gly3-EDA at one end and an anti-CD64 antibody is conjugated to the maleimide group of Mal-C2-Gly3-EDA at the other end, the conjugate has the following formula.

[0840]

[0841] wherein Ab is an anti-CD64 antibody.

[0842] In some cases, one or more molecules of anthracycline or anthracycline derivatives, for example, two to ten, such as one, two, three, four, five, and six molecules are conjugated to one molecule of an anti-CD64 antibody. Thus, in some cases, the anti-CD64 antibody - anthracycline conjugates described herein have a drug to antibody ratio (DAR) of between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0843] Methods of Producing Antibodies

[0844] Using the information provided herein, the anti-CD64 antibodies of the present disclosure may be prepared using standard techniques well known to those of skill in the art. For example, a nucleic acid sequence(s) encoding the amino acid sequence of an antibody of the present disclosure can be used to express the antibodies. The polypeptide sequences provided herein(see, e.g., Tables 1-2) can be used to determine appropriate nucleic acid sequences encoding the antibodies and the nucleic acids sequences then used to express one or more antibodies specific for CD64. The nucleic acid sequence(s) can be optimized to reflect particular codon “preferences” for various expression systems according to standard methods well known to those of skill in the art. Using the sequence information provided, the nucleic acids may be synthesized according to a number of standard methods known to those of skill in the art.

[0845] Once a nucleic acid(s) encoding a subject antibody is synthesized, it can be amplified and / or cloned according to standard methods. Molecular cloning techniques to achieve these ends are known in the art. A wide variety of cloning and in vitro amplification methods suitable for the construction of recombinant nucleic acids are known to persons of skill in the art and are the subjects of numerous textbooks and laboratory manuals.

[0846] Expression of natural or synthetic nucleic acids encoding the antibodies of the present disclosure can be achieved by operably linking a nucleic acid encoding the antibody to a promoter (which is either constitutive or inducible), and incorporating the construct into an expression vector to generate a recombinant expression vector. The vectors can be suitable for replication and integration in prokaryotes, eukaryotes, or both. Typical cloning vectors contain functionally appropriately oriented transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the nucleic acid encoding the antibody. The vectors optionally contain generic expression cassettes containing at least one independent terminator sequence, sequences permitting replication of the cassette in both eukaryotes and prokaryotes, e.g., as found in shuttle vectors, and selection markers for both prokaryotic and eukaryotic systems.

[0847] To obtain high levels of expression of a cloned nucleic acid it is common to construct expression plasmids which typically contain a strong promoter to direct transcription, a ribosome binding site for translational initiation, and a transcription / translation terminator, each in functional orientation to each other and to the protein-encoding sequence. Examples of regulatory regions suitable for this purpose in E. coli are the promoter and operator region of the E. coli tryptophan biosynthetic pathway, the leftward promoter of phage lambda (PL), and the L-arabinose (araBAD) operon. The inclusion of selection markers in DNA vectors transformed in E. coli is also useful. Examples of such markers include genes specifying resistance to ampicillin, tetracycline, or chloramphenicol. Expression systems for expressing antibodies are available using, for example, E. coli, Bacillus sp. and Salmonella. E. co / / systems may also be used.The antibody gene(s) may also be subcloned into an expression vector that allows for the addition of a tag (e.g., FLAG, hexahistidine, and the like) at the C-terminal end or the N-terminal end of the antibody (e.g., IgG, Fab, scFv, etc.) to facilitate purification. Methods of transfecting and expressing genes in mammalian cells are known in the art. Transfecting cells with nucleic acids can involve, for example, incubating lipidic microparticles containing nucleic acids with cells or incubating viral vectors containing nucleic acids with cells within the host range of the vector. The culture of cells used in the present disclosure, including cell lines and cultured cells from tissue (e.g., tumor) or blood samples is well known in the art.

[0848] Once the nucleic acid encoding a subject antibody is isolated and cloned, one can express the nucleic acid in a variety of recombinantly engineered cells known to those of skill in the art. Examples of such cells include bacteria, yeast, filamentous fungi, insect (e.g. those employing baculoviral vectors), and mammalian cells.

[0849] Isolation and purification of a subject antibody can be accomplished according to methods known in the art. For example, a protein can be isolated from a lysate of cells genetically modified to express the protein constitutively and / or upon induction, or from a synthetic reaction mixture, by immunoaffinity purification (or precipitation using Protein L or A), washing to remove non-specifically bound material, and eluting the specifically bound antibody. The isolated antibody can be further purified by dialysis and other methods normally employed in protein purification methods. In one embodiment, the antibody may be isolated using metal chelate chromatography methods. Antibodies of the present disclosure may contain modifications to facilitate isolation, as discussed above.

[0850] The antibodies may be prepared in substantially pure or isolated form (e.g., free from other polypeptides). The protein can be present in a composition that is enriched for the polypeptide relative to other components that may be present (e.g., other polypeptides or other host cell components). Purified antibodies may be provided such that the antibody is present in a composition that is substantially free of other expressed proteins, e.g., less than 90%, usually less than 60% and more usually less than 50% of the composition is made up of other expressed proteins.

[0851] The antibodies produced by prokaryotic cells may require exposure to chaotropic agents for proper folding. During purification from E. coli, for example, the expressed protein can be optionally denatured and then renatured. This can be accomplished, e.g., by solubilizing the bacterially produced antibodies in a chaotropic agent such as guanidine HOL The antibody is then renatured, either by slow dialysis or by gel filtration. Alternatively, nucleic acid encoding theantibodies may be operably linked to a secretion signal sequence such as pelB so that the antibodies are secreted into the periplasm in correctly-folded form.

[0852] The present disclosure also provides cells that produce the antibodies of the present disclosure, where suitable cells include eukaryotic cells, e.g., mammalian cells. The cells can be a hybrid cell or “hybridoma” that is capable of reproducing antibodies in vitro (e.g. monoclonal antibodies, such as IgG). For example, the present disclosure provides a recombinant host cell (also referred to herein as a “genetically modified host cell”) that is genetically modified with one or more nucleic acids comprising a nucleotide sequence encoding a heavy and / or light chain of an antibody of the present disclosure.

[0853] Techniques for creating recombinant DNA versions of the antigen-binding regions of antibody molecules which bypass the generation of hybridomas are also contemplated herein. DNA is cloned into a bacterial (e.g., bacteriophage), yeast (e.g. Saccharomyces or Pichia), insect or mammalian expression system, for example. One example of a suitable technique uses a bacteriophage lambda vector system having a leader sequence that causes the expressed antibody (e.g. Fab or scFv) to migrate to the periplasmic space (between the bacterial cell membrane and the cell wall) or to be secreted. One can rapidly generate great numbers of functional fragments (e.g. Fab or scFv) for those which bind the antigen of interest.

[0854] Antibodies that specifically bind CD64 can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, phage display technologies, Selected Lymphocyte Antibody Method (SLAM), or a combination thereof. For example, an antibody may be made and isolated using methods of phage display. Phage display is used for the high-throughput screening of protein interactions. Phages may be utilized to display antigenbinding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine). Phage expressing an antigen binding domain that binds CD64 can be selected or identified with CD64, e.g., using labeled CD64 bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 binding domains expressed from phage with Fab, Fv (individual Fv region from light or heavy chains) or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. The production of high affinity human antibodies by chain shuffling is known, as are combinatorial infection and in vivo recombination as a strategy for constructing large phage libraries. In another embodiment, ribosomal display can be used to replace bacteriophage as the display platform. Cell surface libraries may be screened for antibodies. Such procedures provide alternatives to traditional hybridoma techniques for the isolation and subsequent cloning of monoclonal antibodies.After phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria. For example, techniques to recombinantly produce Fv, scFv, Fab, F(ab')2, and Fab' fragments may be employed using methods known in the art.

[0855] Nucleic Acids, Expression Vectors and Cells

[0856] In view of the section above regarding methods of producing the antibodies of the present disclosure, it will be appreciated that the present disclosure also provides nucleic acids, expression vectors and cells.

[0857] In certain embodiments, provided is a nucleic acid encoding a variable heavy chain (VH) polypeptide, a variable light chain (VL) polypeptide, or both, of an antibody of the present disclosure, including any of the anti-CD64 antibodies of the present disclosure, e.g., any of such antibodies described herein. According to some embodiments, the antibody is a single chain antibody (e.g., an scFv), and the nucleic acid encodes the single chain antibody.

[0858] According to some embodiments, provided are nucleic acids that encode the variable heavy chain (VH) polypeptide, the variable light chain (VL) polypeptide, or both, of the anti-CD64 antibodies identified in Tables 1 and 2.

[0859] Also provided are expression vectors comprising any of the nucleic acids of the present disclosure. Expression of natural or synthetic nucleic acids encoding the antibodies of the present disclosure can be achieved by operably linking a nucleic acid encoding the antibody to a promoter (which is either constitutive or inducible) and incorporating the construct into an expression vector to generate a recombinant expression vector. The vectors can be suitable for replication and integration in prokaryotes, eukaryotes, or both. Typical cloning vectors contain functionally appropriately oriented transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the nucleic acid encoding the antibody. The vectors optionally contain generic expression cassettes containing at least one independent terminator sequence, sequences permitting replication of the cassette in both eukaryotes and prokaryotes, e.g., as found in shuttle vectors, and selection markers for both prokaryotic and eukaryotic systems.

[0860] Cells that comprise any of the nucleic acids and / or expression vectors of the present disclosure are also provided. According to some embodiments, a cell of the present disclosure includes a nucleic acid that encodes the VHpolypeptide of the antibody and the VLpolypeptide ofthe antibody. In certain such embodiments, the antibody is a single chain antibody (e.g., an scFv), and the nucleic acid encodes the single chain antibody. According to some embodiments, provided is a cell comprising a first nucleic acid encoding a variable heavy chain (VH) polypeptide of an antibody of the present disclosure, and a second nucleic acid encoding a variable light chain (VL) polypeptide of the antibody. In certain embodiments, such as cell comprises a first expression vector comprising the first nucleic acid, and a second expression vector comprising the second nucleic acid.

[0861] Also provided are methods of making an antibody of the present disclosure, the methods including culturing a cell of the present disclosure under conditions suitable for the cell to express the antibody, wherein the antibody is produced. The conditions for culturing the cell such that the antibody is expressed may vary. Such conditions may include culturing the cell in a suitable container (e.g., a cell culture plate or well thereof), in suitable medium (e.g., cell culture medium, such as DMEM, RPMI, MEM, IMDM, DMEM / F-12, or the like) at a suitable temperature (e.g., 32°C - 42°C, such as 37°C) and pH (e.g., pH 7.0 - 7.7, such as pH 7.4) in an environment having a suitable percentage of CO2, e.g., 3% to 10%, such as 5%).

[0862] COMPOSITIONS

[0863] As summarized above, the present disclosure also provides compositions comprising anti-CD64 antibodies or conjugates thereof. According to some embodiments, a composition of the present disclosure includes an antibody or conjugate of the present disclosure. For example, the antibody or conjugate may be any of the antibodies or conjugates described in the “Anti-CD64 Antibodies,” “Conjugates,” and “Conjugates of an anti-CD64 antibody and an anthracycline” sections hereinabove, which descriptions are incorporated but not reiterated herein for purposes of brevity.

[0864] In certain aspects, a composition of the present disclosure includes the antibody or conjugate present in a liquid medium. The liquid medium may be an aqueous liquid medium, such as water, a buffered solution, or the like. One or more additives such as a salt (e.g., NaCI, MgCh, KCI, MgSO4), a buffering agent (a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS), etc.), a solubilizing agent, a detergent (e.g., a non-ionic detergent such as Tween-20, etc.), a nuclease inhibitor, a protease inhibitor, glycerol, a chelating agent, and the like may be present in such compositions.Aspects of the present disclosure further include pharmaceutical compositions. In some embodiments, a pharmaceutical composition of the present disclosure includes an anti-CD64 antibody of the present disclosure (or a conjugate comprising same), and a pharmaceutically acceptable carrier.

[0865] The antibodies or conjugates can be incorporated into a variety of formulations for therapeutic administration. More particularly, the antibodies or conjugates can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable excipients or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, inhalants and aerosols.

[0866] Formulations of the antibodies or conjugates for administration to an individual (e.g., suitable for human administration) are generally sterile and may further be free of detectable pyrogens or other contaminants contraindicated for administration to a patient according to a selected route of administration.

[0867] In pharmaceutical dosage forms, the antibodies or conjugates can be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and carriers / excipients are merely examples and are in no way limiting.

[0868] For oral preparations, the antibodies or conjugates can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[0869] The antibodies or conjugates can be formulated for parenteral (e.g., intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrathecal, subcutaneous, etc.) administration. In certain aspects, the antibodies or conjugates are formulated for injection by dissolving, suspending or emulsifying the antibodies or conjugates in an aqueous or non-aqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.Pharmaceutical compositions that include the antibodies or conjugates may be prepared by mixing the antibodies or conjugates having the desired degree of purity with optional physiologically acceptable carriers, excipients, stabilizers, surfactants, buffers and / or tonicity agents. Acceptable carriers, excipients and / or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid, glutathione, cysteine, methionine and citric acid; preservatives (such as ethanol, benzyl alcohol, phenol, m-cresol, p-chlor-m-cresol, methyl or propyl parabens, benzalkonium chloride, or combinations thereof); amino acids such as arginine, glycine, ornithine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, proline and combinations thereof; monosaccharides, disaccharides and other carbohydrates; low molecular weight (less than about 10 residues) polypeptides; proteins, such as gelatin or serum albumin; chelating agents such as EDTA; sugars such as trehalose, sucrose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, raffinose, glucosamine, N-methylglucosamine, galactosamine, and neuraminic acid; and / or non-ionic surfactants such as Tween, Brij Pluronics, Triton-X, or polyethylene glycol (PEG).

[0870] The pharmaceutical composition may be in a liquid form, a lyophilized form or a liquid form reconstituted from a lyophilized form, wherein the lyophilized preparation is to be reconstituted with a sterile solution prior to administration. The standard procedure for reconstituting a lyophilized composition is to add back a volume of pure water (typically equivalent to the volume removed during lyophilization); however, solutions comprising antibacterial agents may be used for the production of pharmaceutical compositions for parenteral administration.

[0871] An aqueous formulation of the antibodies or conjugates may be prepared in a pH-buffered solution, e.g., at pH ranging from about 4.0 to about 7.0, or from about 5.0 to about 6.0, or alternatively about 5.5. Examples of buffers that are suitable for a pH within this range include phosphate-, histidine-, citrate-, succinate-, acetate-buffers and other organic acid buffers. The buffer concentration can be from about 1 mM to about 100 mM, or from about 5 mM to about 50 mM, depending, e.g., on the buffer and the desired tonicity of the formulation.

[0872] A tonicity agent may be included to modulate the tonicity of the formulation. Example tonicity agents include sodium chloride, potassium chloride, glycerin and any component from the group of amino acids, sugars as well as combinations thereof. In some embodiments, the aqueous formulation is isotonic, although hypertonic or hypotonic solutions may be suitable. The term "isotonic" denotes a solution having the same tonicity as some other solution with which it iscompared, such as physiological salt solution or serum. Tonicity agents may be used in an amount of about 5 mM to about 350 mM, e.g., in an amount of 100 mM to 350 mM.

[0873] A surfactant may also be added to the formulation to reduce aggregation and / or minimize the formation of particulates in the formulation and / or reduce adsorption. Example surfactants include polyoxyethylensorbitan fatty acid esters (Tween), polyoxyethylene alkyl ethers (Brij), alkylphenylpolyoxyethylene ethers (Triton-X), polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic), and sodium dodecyl sulfate (SDS). Examples of suitable polyoxyethylenesorbitan-fatty acid esters are polysorbate 20, (sold under the trademark Tween 20™) and polysorbate 80 (sold under the trademark Tween 80™). Examples of suitable polyethylene-polypropylene copolymers are those sold under the names Pluronic® F68 or Poloxamer 188™. Examples of suitable Polyoxyethylene alkyl ethers are those sold under the trademark Brij™. Example concentrations of surfactant may range from about 0.001% to about 1 % w / v.

[0874] A lyoprotectant may also be added in order to protect the antibody and / or T cell activator against destabilizing conditions during a lyophilization process. For example, known lyoprotectants include sugars (including glucose and sucrose); polyols (including mannitol, sorbitol and glycerol); and amino acids (including alanine, glycine and glutamic acid). Lyoprotectants can be included, e.g., in an amount of about 10 mM to 500 nM.

[0875] In some embodiments, the pharmaceutical composition includes the antibody or conjugate, and one or more of the above-identified components (e.g., a surfactant, a buffer, a stabilizer, a tonicity agent) and is essentially free of one or more preservatives, such as ethanol, benzyl alcohol, phenol, m-cresol, p-chlor-m-cresol, methyl or propyl parabens, benzalkonium chloride, and combinations thereof. In other embodiments, a preservative is included in the formulation, e.g., at concentrations ranging from about 0.001 to about 2% (w / v).

[0876] KITS

[0877] Aspects of the present disclosure further include kits. In certain embodiments, the kits find use in practicing the methods of the present disclosure, e.g., methods comprising administering a pharmaceutical composition of the present disclosure to an individual to target the antibody or conjugates to CD64 expressing cells, such as CD64 expressing cancer cells, inflammatory cells, or autoimmune cells in the individual.

[0878] Accordingly, in certain embodiments, a kit of the present disclosure comprises any of the pharmaceutical compositions of the present disclosure, and instructions for administering the pharmaceutical composition to an individual in need thereof. The pharmaceutical compositionincluded in the kit may include any of the antibodies and / or conjugates of the present disclosure, e.g., any of the antibodies and / or conjugates described hereinabove. As will be appreciated, the kits of the present disclosure may include any of the agents and features described above in the sections relating to the subject antibodies’ conjugates and compositions, which are not reiterated herein for purposes of brevity.

[0879] The kits of the present disclosure may include a quantity of the compositions, present in unit dosages, e.g., ampoules, or a multi-dosage format. As such, in certain embodiments, the kits may include one or more (e.g., two or more) unit dosages (e.g., ampoules) of a composition that includes an antibody and / or conjugate of the present disclosure. The term “unit dosage”, as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of the composition calculated in an amount sufficient to produce the desired effect. The amount of the unit dosage depends on various factors, such as the particular antibody and / or conjugate employed, the effect to be achieved, and the pharmacodynamics associated with the antibody and / or conjugate, in the individual. In yet other embodiments, the kits may include a single multi dosage amount of the composition.

[0880] In certain embodiments, a kit of the present disclosure includes instructions for targeting the antibody or conjugate present in the pharmaceutical composition to CD64 expressing cells in an individual having cancer (e.g., to treat the cancer of the individual), e.g., by administering the pharmaceutical composition to the individual, wherein the individual comprises cancer cells expressing CD64, and wherein the antibody or conjugate is targeted to the cancer cells by CD64 expressed on the surface of the cancer cells.

[0881] In certain embodiments, a kit of the present disclosure includes instructions for targeting the antibody or conjugate present in the pharmaceutical composition to CD64 expressing cells in an individual having an inflammatory or an autoimmune disease (e.g., to treat the inflammatory or the autoimmune disease of the individual), e.g., by administering the pharmaceutical composition to the individual, wherein the individual comprises inflammatory cells or autoimmune cells expressing CD64, and wherein the antibody or conjugate is targeted to the inflammatory cells or autoimmune cells by GD64 expressed on the surface of these cells.

[0882] The instructions (e.g., instructions for use (IFU)) included in the kits may be recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packagingor sub-packaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g., portable flash drive, DVD, CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and / or from which the instructions can be downloaded. As with the instructions, the means for obtaining the instructions is recorded on a suitable substrate.

[0883] METHODS

[0884] Aspects of the present disclosure include methods of using the antibodies and conjugates of the present disclosure. The methods are useful in a variety of contexts, including in vitro and / or in vivo research and / or clinical applications.

[0885] Methods of treating a cancer

[0886] As discussed elsewhere in this disclosure, anti-CD64 antibodies conjugated to certain agents can be used for targeting cells that express CD64, for example, CD64 expressing cancer cells.

[0887] Accordingly, in certain aspects, provided herein are methods that comprise administering to an individual having a cancer an effective amount of a pharmaceutical composition comprising a conjugate comprising an anti-CD64 antibody conjugated to a cancer therapeutic, where the individual comprises cancer cells that express CD64, and wherein the anti-CD64 antibody conjugate is targeted to the cancer cells that express CD64. Such methods find use, e.g., in treating the cancer of the individual.

[0888] By treatment is meant at least an amelioration of one or more symptoms associated with the cancer of the individual, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom, associated with the cancer being treated. As such, treatment also includes situations where the cancer, or at least one or more symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the individual no longer suffers from the cancer, or at least the symptoms that characterize the cancer.

[0889] Various anti-CD64 antibody conjugated to a cancer therapeutic described above under “Conjugates” and “Conjugates of an anti-CD64 antibody and an anthracycline” sections can be used in the methods disclosed herein. In specific embodiments, an anti-CD64 antibody comprisesheavy chain and light chain CDRs as the antibodies described in Tables 1 and 2. In certain such cases, an anti-CD64 antibody comprises an amino acid sequence of the V polypeptides and the VLpolypeptides as described in Table 1 above.

[0890] In certain embodiments, an anti-CD64 antibody is conjugated to an anthracycline or an anthracycline derivative. In some cases, an anthracycline derivative is PNU-169682. In further embodiments, an anti-CD64 antibody is conjugated to PNU-169682 via a maleimide based linker, particularly, Mal-C2-Gly3-EDA linker.

[0891] A person of ordinary skill in the art can select an appropriate anti-CD64 antibody conjugated to a cancer therapeutic to be used in treating a specific type of cancer and / or a specific cancer in an individual and such embodiments are within the purview of the disclosure.

[0892] In certain such cases, the cancer is a hematologic cancer, such as a leukemia, a lymphoma, or a myeloma. A leukemia can be a monocytic leukemia, such as chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute monocytic leukemia, or acute myelomonocytic leukemia. A lymphoma can be a T-cell lymphoma or Hodgkin lymphoma.

[0893] Also, in certain aspects, provided herein are methods that comprise administering to an individual having a solid tumor an effective amount of a pharmaceutical composition comprising an anti-CD64 antibody conjugate comprising a cancer therapeutic, where the solid tumor in the individual comprises TAMs or TRMs that express CD64, and wherein the anti-CD64 antibody conjugate is targeted to the TAMs or TRMs that express CD64. Such methods find use, e.g., in treating the cancer of the individual.

[0894] Examples of solid tumors that may be treated using the subject methods include, but are not limited to, carcinoma, blastoma, and sarcoma. More particular examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bile duct cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, various types of head and neck cancer, and the like. In certain embodiments, the individual has a cancer selected from a solid tumor, recurrent glioblastoma multiforme (GBM), non-small cell lung cancer, metastatic melanoma, melanoma, peritoneal cancer, epithelial ovarian cancer, glioblastoma multiforme (GBM), metastatic colorectal cancer, colorectal cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma, esophageal cancer, gastric cancer, neuroblastoma, fallopian tubecancer, bladder cancer, metastatic breast cancer, pancreatic cancer, soft tissue sarcoma, recurrent head and neck cancer squamous cell carcinoma, head and neck cancer, anaplastic astrocytoma, malignant pleural mesothelioma, breast cancer, squamous non-small cell lung cancer, rhabdomyosarcoma, metastatic renal cell carcinoma, basal cell carcinoma (basal cell epithelioma), and gliosarcoma. In certain aspects, the individual has a cancer selected from melanoma, Hodgkin lymphoma, renal cell carcinoma (RCC), bladder cancer, non-small cell lung cancer (NSCLC), and head and neck squamous cell carcinoma (HNSCC).

[0895] As noted above, certain bispecific antibodies having one anti-CD64 binding domain and the other binding domain specific for a tumor antigen can be used to recruit CD64 expressing immune cells to tumor antigens on various tumor cells thereby mediating targeted killing of the cancer cells.

[0896] Accordingly, certain embodiments of the disclosure provide administering to an individual having a cancer an effective amount of a pharmaceutical composition comprising a bispecific antibody having a CD64-binding domain and another binding-domain that specifically binds to a cancer antigen.

[0897] Various bispecific antibodies described above under “bispecific antibody” section can be used in the methods disclosed herein. Particularly, a person of ordinary skill in the art can select an appropriate bispecific antibody to be used in treating a specific type of cancer and / or a specific cancer in an individual and such embodiments are within the purview of the disclosure.

[0898] In some cases, an anti-CD64 antibody conjugate or a bispecific antibody of the present disclosure may be administered to the individual alone or in combination with a second agent. Second agents of interest include, but are not limited to, agents approved by the United States Food and Drug Administration and / or the European Medicines Agency (EMA) for use in treating cancer.

[0899] When an antibody conjugate or a bispecific antibody of the present disclosure is administered with a second agent, the antibody conjugate or a bispecific antibody and the second agent may be administered to the individual according to any suitable administration regimen. According to certain embodiments, the antibody conjugate or a bispecific antibody and the second agent are administered according to a dosing regimen approved for individual use. In some embodiments, the administration of an antibody conjugate or a bispecific antibody permits the second agent to be administered according to a dosing regimen that involves one or more lower and / or less frequent doses, and / or a reduced number of cycles as compared with that utilized when the second agent is administered without administration of the antibody or conjugate. Incertain aspects, the administration of the second agent permits the antibody or conjugate to be administered according to a dosing regimen that involves one or more lower and / or less frequent doses, and / or a reduced number of cycles as compared with that utilized when an antibody conjugate or a bispecific antibody is administered without administration of the second agent.

[0900] In some embodiments, one or more doses of an antibody conjugate or a bispecific antibody and the second agent are administered concurrently to the individual. By “concurrently” is meant the antibody conjugate or the bispecific antibody and the second agent are either present in the same pharmaceutical composition, or the antibody conjugate or the bispecific antibody and the second agent are administered as separate pharmaceutical compositions within 1 hour or less, 30 minutes or less, or 15 minutes or less.

[0901] In some embodiments, one or more doses of the antibody conjugate or the bispecific antibody and the second agent are administered sequentially to the individual.

[0902] In some embodiments, the antibody conjugate or the bispecific antibody and the second agent are administered to the individual in different compositions and / or at different times. For example, the antibody conjugate or the bispecific antibody may be administered prior to administration of the second agent, e.g., in a particular cycle. Alternatively, the second agent may be administered prior to administration of the antibody or conjugate, e.g., in a particular cycle. The second agent to be administered may be administered a period of time that starts at least 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, or up to 5 days or more after the administration of the first agent to be administered.

[0903] In one example, the second agent is administered to the individual for a desirable period of time prior to administration of the antibody conjugate or the bispecific antibody. In certain aspects, such a regimen “primes” the cancer cells to potentiate the anti-cancer effect of an antibody conjugate or a bispecific antibody. Such a period of time separating a step of administering the second agent from a step of administering an antibody conjugate or a bispecific antibody is of sufficient length to permit priming of the cancer cells, desirably so that the anticancer effect of the antibody conjugate or the bispecific antibody.

[0904] In some embodiments, administration of one agent is specifically timed relative to administration of the other agent. For example, in some embodiments, the antibody conjugate or the bispecific antibody is administered so that a particular effect is observed (or expected to be observed, for example based on population studies showing a correlation between a given dosing regimen and the particular effect of interest).In certain aspects, desired relative dosing regimens for agents administered in combination may be assessed or determined empirically, for example using ex vivo, in vivo and / or in vitro models; in some embodiments, such assessment or empirical determination is made in vivo, in a patient population (e.g., so that a correlation is established), or alternatively in a particular individual of interest.

[0905] In some embodiments, an antibody conjugate or a bispecific antibody and the second agent are administered according to an intermittent dosing regimen including at least two cycles. Where two or more agents are administered in combination, and each by such an intermittent, cycling, regimen, individual doses of different agents may be interdigitated with one another. In certain aspects, one or more doses of a second agent is administered a period of time after a dose of the first agent. In some embodiments, each dose of the second agent is administered a period of time after a dose of the first agent. In certain aspects, each dose of the first agent is followed after a period of time by a dose of the second agent. In some embodiments, two or more doses of the first agent are administered between at least one pair of doses of the second agent; in certain aspects, two or more doses of the second agent are administered between at least one pair of doses of the first agent. In some embodiments, different doses of the same agent are separated by a common interval of time; in some embodiments, the interval of time between different doses of the same agent varies. In certain aspects, different doses of the antibody or conjugate and the second agent are separated from one another by a common interval of time; in some embodiments, different doses of the different agents are separated from one another by different intervals of time.

[0906] One exemplary protocol for interdigitating two intermittent, cycled dosing regimens may include: (a) a first dosing period during which a therapeutically effective amount an antibody conjugate or a bispecific antibody is administered to the individual; (b) a first resting period; (c) a second dosing period during which a therapeutically effective amount of the second agent is administered to the individual; and (d) a second resting period. A second exemplary protocol for interdigitating two intermittent, cycled dosing regimens may include: (a) a first dosing period during which a therapeutically effective amount the second agent is administered to the individual; (b) a first resting period; (c) a second dosing period during which a therapeutically effective amount of the antibody or conjugate is administered to the individual; and (d) a second resting period.

[0907] In some embodiments, the first resting period and second resting period may correspond to an identical number of hours or days. Alternatively, in some embodiments, the first resting period and second resting period are different, with either the first resting period being longer thanthe second one or, vice versa. In some embodiments, each of the resting periods corresponds to 120 hours, 96 hours, 72 hours, 48 hours, 24 hours, 12 hours, 6 hours, 30 hours, 1 hour, or less. In some embodiments, if the second resting period is longer than the first resting period, it can be defined as a number of days or weeks rather than hours (for instance 1 day, 3 days, 5 days, 1 week, 2, weeks, 4 weeks or more).

[0908] If the first resting period’s length is determined by existence or development of a particular biological or therapeutic event, then the second resting period’s length may be determined on the basis of different factors, separately or in combination. Exemplary such factors may include type and / or stage of a cancer against which the therapy is administered; properties (e.g., pharmacokinetic properties) of the antibody or conjugate, and / or one or more features of the patient’s response to therapy with the antibody conjugate or the bispecific antibody. In some embodiments, length of one or both resting periods may be adjusted in light of pharmacokinetic properties (e.g., as assessed via plasma concentration levels) of one or the other of the administered agents. For example, a relevant resting period might be deemed to be completed when plasma concentration of the relevant agent is below a pre-determined level, optionally upon evaluation or other consideration of one or more features of the individual’s response.

[0909] In certain aspects, the number of cycles for which a particular agent is administered may be determined empirically. Also, in some embodiments, the precise regimen followed (e.g., number of doses, spacing of doses (e.g., relative to each other or to another event such as administration of another therapy), amount of doses, etc.) may be different for one or more cycles as compared with one or more other cycles.

[0910] An antibody conjugate or a bispecific antibody and the second agent may be administered together or independently via any suitable route of administration. The antibody conjugate or the bispecific antibody and the second agent may be administered via a route of administration independently selected from oral, parenteral (e.g., by intravenous, intra-arterial, subcutaneous, intramuscular, or epidural injection), topical, or intra-nasal administration. According to certain embodiments, antibody or conjugate and the second agent are both administered orally (e.g., in tablet form, capsule form, liquid form, or the like) either concurrently (in the same pharmaceutical composition or separate pharmaceutical compositions) or sequentially. The antibody conjugate or the bispecific antibody of the present disclosure may be administered via a route of administration selected from oral (e.g., in tablet form, capsule form, liquid form, or the like), parenteral (e.g., by intravenous, intra-arterial, subcutaneous, intramuscular, or epidural injection), topical, intra-nasal, or intra-tumoral administration.In some embodiments, the second agent is an immune checkpoint inhibitor. In specific embodiments, an immune checkpoint inhibitor is administered as a second agent in a method of treating a solid tumor in an individual. Non-limiting examples of such immune checkpoints include PD-1 : programmed cell death protein 1 ; PD-L1 : programmed cell death-ligand 1 ; PD-L2: Programmed cell death-ligand 2; SIRP-cc signal regulatory protein a; VISTA: V-type immunoglobulin domain-containing suppressor of T cell activation; VSIG-3: V-set and Ig domaincontaining 3; and siglec-10: Sialic-acid-binding Ig-like lectin 10.

[0911] Additional immune checkpoint inhibitors are known in the art and use of such inhibitors is within the purview of the disclosure. Certain examples of such additional immune checkpoint inhibitors include but are not limited to: a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, a T-cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor, an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a B7-H3 inhibitor, and any combination thereof.

[0912] Accordingly, certain embodiments of the disclosure include methods of treating a solid tumor in an individual by administering to the individual:

[0913] 1) an effective amount of a pharmaceutical composition comprising an anti-CD64 antibody conjugate comprising a cancer therapeutic disclosed herein, and

[0914] 2) an immune checkpoint inhibitor.

[0915] Methods of treating inflammatory or autoimmune diseases

[0916] As discussed elsewhere in this disclosure, anti-CD64 antibodies conjugated to certain agents can be used for treating inflammatory or autoimmune diseases.

[0917] Accordingly, in certain aspects, provided herein are methods that comprise administering an effective amount of a pharmaceutical composition comprising an anti-CD64 antibody conjugate disclosed herein to an individual having an inflammatory or an autoimmune disease, where the individual comprises inflammatory or autoimmune cells that express CD64, and where the anti-CD64 antibody conjugate is targeted to the inflammatory or autoimmune cells that express CD64 on their surface. Such methods find use, e.g., in treating the inflammatory or autoimmune disease in the individual.

[0918] By treatment is meant at least an amelioration of one or more symptoms associated with the inflammatory or autoimmune disease of the individual, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom, associatedwith the inflammatory or autoimmune disease being treated. As such, treatment also includes situations where the inflammatory or autoimmune disease, or at least one or more symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the individual no longer suffers from the inflammatory or autoimmune disease, or at least the symptoms that characterize the inflammatory or autoimmune disease.

[0919] In certain cases, an inflammatory or autoimmune disease involves inflammation driven or promoted by dysregulated macrophages, such as M1-type dysregulated macrophages. Such inflammatory or autoimmune diseases can be treated by specifically targeting the dysregulated macrophages using an anti-CD64 antibody conjugated to a cytotoxic agent to specifically target and kill the inflammatory dysregulated macrophages.

[0920] In some cases, an anti-CD64 antibody is conjugated to a cytotoxic agent. Non-limiting examples of such cytotoxic agents appropriate for use in anti-CD64 antibody conjugates for treating an inflammatory or an autoimmune disease include Ricin-A, Pseudomonas exotoxin A, Granzyme B, angiogenin, and microtubule-associated protein tau. Additional cytotoxic agents suitable for use in the conjugates for treating an inflammatory and autoimmune diseases are known in the art and use of such embodiments is within the purview of the disclosure.

[0921] In certain embodiments, an inflammatory or an autoimmune disease treated according to the methods disclosed herein is graft versus host disease (GVHD), chronic cutaneous inflammation, atopic dermatitis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, systemic lupus erythematosus (SLE), chronic diabetic wound, or multiple sclerosis. Additional inflammatory or autoimmune diseases that could be treated using the anti-CD64 antibody conjugates described herein are known in the art and such embodiments are within the purview of the disclosure.

[0922] Methods of targeting CD64 expressing cells

[0923] In certain embodiments, the disclosure provides methods of administering to an individual a pharmaceutical composition comprising any of the anti-CD64 antibody conjugates of the present disclosure. For example, the pharmaceutical composition may comprise an anti-CD64 antibody conjugated to a detectable label or radioactive isotope which is an in vivo imaging agent. Such methods may further comprise imaging the cancer cells, inflammatory cells, or autoimmune cells that express CD64 in the individual using the in vivo imaging agent. The methods in which a conjugate comprising a detectable label or radioactive isotope is administered to the individualfind use in imaging the cancer cells, inflammatory cells, or autoimmune cells that express CD64 in the individual, e.g., for diagnostic, prognostic, and / or therapy monitoring purposes.

[0924] In certain embodiments, the pharmaceutical composition may comprise an anti-CD64 antibody conjugate, where the anti-CD64 antibody is conjugated to an agent selected from a chemotherapeutic agent, a toxin, a radiation sensitizing agent, a therapeutic radioactive isotope, and a radioisotope that permits in vivo imaging of the antibody. The agent may be any such agents described in the Conjugates section above.

[0925] The antibody may be provided in any desired format, e.g., tetrameric format, single chain (e.g., scFv) format, etc. as described in the preceding sections of the present disclosure. According to some embodiments, the pharmaceutical composition comprises the antibody conjugated to a detectable label or radioactive isotope. In certain embodiments, the detectable label or radioactive isotope is an in vivo imaging agent. The methods in which the antibody is conjugated to an in vivo imaging agent may further comprise detecting the in vivo imaging agent to image the cancer cells, inflammatory cells, or autoimmune cells that express CD64 in the individual in vivo, e.g., for diagnostic, prognostic, and / or therapy monitoring purposes.

[0926] The pharmaceutical compositions may be administered to any of a variety of individuals. In certain aspects, the individual is a “mammal” or “mammalian,” where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In some embodiments, the individual is a human. In certain aspects, the individual is an animal model (e.g., a mouse model, a primate model, or the like) of a cellular proliferative disorder, e.g., cancer. In certain aspects, the individual is an animal model (e.g., a mouse model, a primate model, or the like) of an inflammatory or an autoimmune disease.

[0927] The following examples are offered by way of illustration and not by way of limitation.

[0928] EXPERIMENTAL

[0929]

[0930] 1 -Anti-CD64 antibodies havinq if ic CDRs and Their

[0931]

[0932] Forty-four Monoclonal antibodies against human CD64 were generated and sequenced. These antibodies were also tested for their activity in targeting CD64 expressing cells.

[0933] Using the MUSCLE algorithm from EMBL-EBI, an initial alignment of the variable region of the heavy chain sequence (FIG. 1 A) and light chain sequence (FIG. 1 B) was obtained. Thesealignments highlight the homology between CDRs. The UPGMA method (Unweighted Pair-Group Method using Arithmetic Averages) was used for creating phylogenetic trees that reflect the homology and diversity between the variable regions sequences (FIG. 1C).

[0934] Activity and selectivity were tested for ADCs conjugated with twelve of the forty-four monoclonal antibodies against CD64 (Figure 1 C - clones highlighted in bold). Such selection was performed with the aim of selecting representative antibodies that cover the sequence diversity of the 44 clones. The ADCs contained the anti-CD64 antibodies conjugated via a non-cleavable linker to PNU-159682. While all the ADCs exhibited the ability to target CD64 expressing cells and to deliver the payload into the target cells, some of the ADCs performed better than others. The ADCs with the most desirable properties were used in further validation experiments and for identifying the top performing ADC.

[0935] K562 (CD64 negative) and TH P-1 (CD64 positive) cells were treated with the twelve selected ADCs. After 3 days of treatment, the treated cultures were analyzed by flow cytometry to track the cytotoxic activity of ADCs. The side-by-side comparison was performed in the same dose-response range (0.05 to 14,000 pM). Activity was normalized and referred to the activity of the isotype control ADC (same payload and DAR in a non-targeting antibody with the same backbone).

[0936] The activity and specificity of the tested batch of twelve ADCs generated is provided in FIG. 9A-9B. As shown in FIG. 9A, none of CD64 ADCs displayed any activity on a myeloid leukemia cell line that does not express CD64, thus demonstrating the lack of off-target biding of the antibodies to other protein of the surface proteome. FIG. 9B shows that seven of the twelve ADCs (dark grey lines) displayed a remarkable dose-response activity in the low picomolar range on a myeloid leukemia cell line positive for CD64 expression. The other 5 ADCs (light grey lines) displayed much less potency, closer to the nanomolar range, indicating that the affinity and / or internalization of those antibodies is relatively lower. However, all of the tested ADCs exhibited dose-response activity on the myeloid leukemia cell line positive for CD64 expression. The ID of the tags on FIG. 9B refers to the clones’ sequences depicted in FIG.1 .

[0937]

[0938] of CD64 in Monocytic Leukemia Cells

[0939] The expression profile of CD64 in monocytic leukemia cells from patients was examined across the maturation axis of cells of monocytic lineage, i.e., from monocytic precursors to mature monocytes.CD64 expression was screened in cohort of patients of monocytic AML (M4 & M5 subtypes from the French British American (FAB) classification) and patients with AML subtypes that could display monocytic maturation in subpopulations of cells (FAB M2).

[0940] Mononuclear cells (MNCs) were isolated by Ficoll gradient centrifugation from peripheral blood or bone marrow from AML patients with different FAB subtypes. Using multiparametric flow cytometry with viability markers, the living cells subpopulation was identified. The myeloid and lymphoid lineages were segmented by size and internal complexity parameters. Myeloid cells were then profiled with fluorescent antibodies against different Cluster Differentiation markers including CD45 and CD11b to define a maturation axis of monocytic cells, from precursors to mature monocytes. Post acquisition analysis was performed using FlowJo™ Software. The expression profile of CD64 in AML patients is shown in FIGs. 2A-2B.

[0941] FIG. 2A shows that by exploring expression biomarkers such as CD45 and CD11b, the expression of CD64 was tracked in monocytic precursors and mature monocytes in AML patient-derived samples with a tool antibody. The expression of CD64 was pervasive from early monocytic precursors to mature monocytes, and such expression profiled was remarkably similar to other targets for which antibody-based therapies are currently in clinical stages (e.g., Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4) and C-C Motif Chemokine Receptor 2 (CCR2)). FIG. 2B shows that the expression of CD64 is consistent across monocytic AML patients (M4 and M5 types) and is observed in minor subpopulations of cells within M2 types of AML, which are known to have blasts that depict some degree of maturation into monocytes.

[0942] Thus, CD64 was expressed across the maturation axis of cells of monocytic lineage. Such expression profile is similar to other targets for which antibody-based therapies are currently in clinical stages.

[0943] Example 3 - Druggabilitv of CD64 Using an Antibody Drua Conjugate

[0944] The druggability of CD64 with an antibody drug conjugate (ADC) approach was evaluated. Primary tool antibodies against CD64 were transformed into ADC-like molecules by using payload-coupled secondary antibodies that recognize the Fc portion of the CD64 antibody.

[0945] The optimal mechanism of action that leverage vulnerabilities in monocytic cells was determined by testing a battery of secondary antibodies coupled to multiple payloads. Top performing payloads were then selected to generate ADCs.

[0946] Patient-derived cells from monocytic leukemia patients (M4 / M5 FAB) were cultured ex-vivo with the triple co-culture system involving Patient Micro-Avatars (PMAs) technology as described in the PCT Application Publication WO2022251475. PMAs were treated with a toolantibody against CD64 (Cion S18012c) followed by IgGs anti-mouse IgG (Fc specific) ADCs coupled to multiple payloads (developed by Moradec). After 72 h of treatment, PMAs were processed and analyzed by flow cytometry to track the cytotoxic activity of ADCs over the monocytic cell population in a wide dose-response curve. The tool antibody and anti IgG ADCs were tested at different concentrations.

[0947] FIGs. 3A-3B show the results of the ADC-like approach to evaluate optimal payloads to target monocytic cells from patients with anti-CD64 antibodies converted into ADC-like particles with the sequential incubation with secondary antibodies conjugated to payloads. FIG. 3A schematically represents different secondary antibody drug conjugates that recognize the Fc region of the primary antibodies of interest. These ADCs were obtained by conjugation to payloads with different mechanisms of action (drug antibody ration (DAR) of about 4). Monocytic cells from M4 and M5-AML patients were treated with tool antibodies that detect human CD64. FIG. 3B shows side-by-side comparison of the activity of the unconjugated primary antibody to the combination of the primary + secondary ADCs coupled to different payloads. This approach simultaneously derisks the druggability of targets using an ADC-like approach and identifies the optimal payload to leverage key vulnerabilities of target cells. In monocytic cells from patients, the highest CD64-mediated cytotoxicity was observed with the payload PNU-169682, a derivative from the anthracycline nemorubicin.

[0948] 4 - Construction and Testing of Maleimide-based ADCs Against CD64 with Different Linker-Payloads (PNU-169682 and

[0949]

[0950] ADCs against CD64 using the three linker-payloads shown in FIGs. 4A-4C were generated.

[0951] Two linkers were used for PNU-169682: a cleavable linker (L1, FIG. 4A) and a non-cleavable linker (L2, FIG. 4B). FIG. 4A shows a cleavable valine-citrulline linker couple to PNU-159682. The PEG4 spacer aims to decrease the hydrophobicity of the derived ADCs, since PNU is a highly hydrophobic molecule. FIG. 4B shows a linker based on a triple glycine peptide coupled to a PNU-159682 molecule modified by an EDA group.

[0952] Although Exatecan did not show promising activity on the ADC-like experiments (FIG. 3B), given the optimal tolerability displayed by this payload in the clinic, an Exatecan-based ADC for CD64 was also generated. The linker used in this ADC is described as cleavable and is described in FIG. 4C, which shows a protease cleavable linker based on the GGFG motif, bound to the Topo I inhibitor Exatecan as the payload.Antibodies were buffer exchanged and concentrated in pH 7.4 PBS buffer using a 50 kDa membrane in preparation for the conjugation process. The concentrated antibodies were reduced by 1-25 eq. of tris-(2-carboxyethyl)-phosphine hydrochloride (TCEP-HCI). The reaction mixture was stirred at 1300 rpm for 1-10 h at 37°C. The resulting reaction was stopped by incubation on ice for 5 min. Excess of TCEP-HCI was removed by repeated diafiltration centrifugal filter. The reduced antibodies were then conjugated by adding 2-30 eq. of maleimide-functionalized linker-payload. The reaction mixture was stirred at 1300 rpm for 1-5 h at 25°C. The reaction was then terminated by the addition of 10-100 eq of N-acetyl-L-cysteine (NAC). This last step might also prevent the reversibility of maleimide-thiol conjugates by promoting their conversion into the non-reversible ring-opened form of maleimide, a stable moiety that significantly increases plasma half-life. Preparations of antibody-drug conjugates (ADCs) were purified using mini-trap columns and eluted with pH 7.4 PBS buffer. The purified ADCs were filtered using 0.22 pm Polyvinylidene difluoride (PVDF) syringe filters and stored at 4°C.

[0953] Example 5 - Superior Activity of PNU-159682 Apainst the Cells of the Monocytic Lineage Activity of ADCs containing PNU-159682 against the patient-derived cells of monocytic lineage was evaluated. Also evaluated was the efficacy and selectivity of ADCs containing different payloads.

[0954] Patient-derived cells from monocytic leukemia (M4 / M5 FAB) and primitive leukemia (M0 / M1 FAB) were cultured ex-vivo with PMAs and treated with ADCs coupled to either PNU or Exatecan. After 5 days of treatment, PMAs were processed and analyzed by flow cytometry to track the cytotoxic activity of ADCs over the entire population of myeloid cells in a wide doseresponse (2 - 500 pM for PNU and 0.5 to 14 nM for Exatecan). Activity was normalized and referred to the activity of the isotype control ADC (same payload and DAR in a non-targeting antibody with the same backbone). For Exatecan-coupled ADCs, an additional positive control (monocytic cell line) was included to show that the tested ADCs are active, yet not sufficiently potent to trigger activity in patient-derived cells.

[0955] FIG. 5A shows that the PNU-159682-coupled CD64-ADCs are highly potent, e.g., even at sub-nanomolar range, against patient-derived monocytic leukemia cells, yet inactive against primitive leukemia cells. FIG. 5A also shows that the PNU-159682-coupled CD64-ADCs were highly selective to CD64 expression. No effect of the ADCs was observed in primitive AML patients (CD64 negative). The PNU-159682-coupled CD64-ADCs were tested in a cohort of 15 AML patients, 10 of monocytic lineage and 5 of primitive lineage (without monocytic cells). After 6 days of treatment, the relative survival to the isotype ADC was evaluated, showing sub-nanomolar dose-response activity exclusively on monocytic AML patients, without any detectable activity in primitive AML patients.

[0956] FIG. 5B shows that the ADCs containing Exatecan as the payload have only vestigial activity in patient-derived cells, even when substantial activity is observed in monocytic cell lines. ADCs containing exatecan were tested in a cohort of 10 AML patients, 7 of monocytic lineage and 3 of primitive lineage (without monocytic cells). After 6 days of treatment, the relative survival to the isotype ADC was evaluated, showing negligible activity against AML cells derived from patients. A monocytic cell line was tested in parallel as positive control for ADC proficiency in the nanomolar range.

[0957] 6 - Efficacy and

[0958]

[0959] of ADCs containing PNU-159682 with Cleavable or Noncleavable Linkers

[0960] Efficacy and specificity of ADCs containing PNU-159682 and cleavable or non-cleavable linkers were evaluated. CD64-positive target cells (monocytic precursors and mature monocytes) as well as CD64-negative target cells were tracked to evaluate potential bystander effect.

[0961] Patient-derived cells from a M5 monocytic leukemia were cultured ex-vivo as PMAs and treated with ADCs containing PNU-159682 and having a cleavable or a non-cleavable linker. After 5 days of treatment, PMAs were processed and analyzed by flow cytometry to track the cytotoxic activity of ADCs over the different subpopulations of myeloid cells as well as in the internal control cells of PMAs, namely, System-Control cells (cells with known drug sensitivity) and Tox-Control cells (non-cancerous bone marrow stroma cells). Both the System-Control cells and the Tox-Control cells were CD64 negative. The side-by-side comparison was performed in the same dose-response range of 6 pM to 1.125 nM.

[0962] FIG. 6A-6B show that differential release of PNU-159682 by different linkers leads to differential specificity and bystander effect in co-cultures of CD64 positive patient cells with CD64 negative cell lines. For the data presented in FIG. 6A, the cells from a monocytic AML patient cocultured with reference cell lines negative for CD64 were treated with an ADC generated using a tool antibody against CD64 with a cleavable linker coupled to PNU-159682. While potent sub-nanomolar activity was observed against monocytic cells from the patient (CD64 positive), a strong bystander effect against the CD64 negative heterologous cell lines was also observed. For the data presented in FIG. 6B, a sample from the same patient treated in FIG. 6A was treated with an ADC generated using the same tool antibody against CD64 but with a non-cleavable linkercoupled to PNU-159682. In this case only selective targeting was observed, with no detectable activity against CD64 negative cell lines.

[0963] These data show that PNU-159682-coupled ADCs with a cleavable linker shows robust activity against the CD64 positive cells as well as strong bystander effect on the GD64 negative cells. The results are compatible with a passive release of free PNU from target cells to nontarget cells. In contrast, PNU-159682-coupled ADC with a non-cleavable linker shows robust against CD64 positive cells without triggering bystander effect. The non-cleavable linker triggers a more robust activity on mature monocytes, yet a milder activity on monocytic precursors (both CD64 positive). These results suggest that the enhanced activity of the cleavable linker on monocytic precursors can be due to a combination of specific activity + bystander effect.

[0964] Example 7 - Activity of ADCs containing PNU-159682 against CD64 expressing cells in a CDX model of disseminated leukemia in Nod SCID Gamma mice using cleavable and non-cleavable linkers

[0965] The activity of PNU-159682-coupled ADCs against CD64 expressing cells was evaluated in a CDX model of disseminated leukemia in Nod SCID Gamma (NSG) mice.

[0966] Data schematic protocol of the experiment is presented in FIG. 7A. Briefly, NSG mice were first treated with busulfan (40 mg / kg) to condition the bone marrow for efficient engraftment. Two days later, 1 million MV-4-11 human monocytic leukemia cells were engrafted through i.v. injection and 14 days after engraftment, mice were treated with a single i.v. dose of 1 mg / kg of an ADC generated using a tool antibody against CD64 and a cleavable or a non-cleavable linker coupled to PNU-159682. 7 days after the ADC injection, mice were sacrificed and the bone marrow from the mice femurs was collected for analysis. Body weight and temperature were monitored daily during the week of treatment. A comprehensive blood panel and clinical chemistry were performed to monitor tolerability of each ADC construct at study end. For the data presented in FIG. 7B, bone marrow samples from each animal (n = 7 for the control and non-cleavable linker group; n = 5 for the cleavable linker group) were analyzed by flow cytometry to track the human leukemic cells within the mouse compartment using fluorescent antibodies against human CD33 and CD45. The percentage of human vs mouse cells in the individual bone marrow of each mouse was quantified and T-test was performed. For the data presented in FIG. 7C, the major differences of tolerability between ADC constructs conjugated to PNU-159682 through cleavable and non-cleavable linkers are shown.

[0967] FIGs. 7A-7B show that CD64 ADC triggers complete remission in a disseminated leukemia model. A single injection of a PNU-159682-coupled ADC led to complete remission (p< 0.01) in the bone marrow of all mice engrafted with human monocytic leukemia cells. CD64 ADCs with cleavable and non-cleavable linkers showed similar efficacy profiles, without significant differences between them.

[0968] For the various steps depicted in FIG. 7A, certain details are provided below:

[0969] Bone Marrow Conditioning: Busulfan (40 mg / kg) was administered on Day -16 to deplete endogenous hematopoietic cells and facilitate efficient engraftment of transplanted cells.

[0970] Xenograft Tumor Generation: AML cells (1x106MV-4-11) were injected IV into the tail vein two days after Busulfan treatment at Day -14. Engraftment was performed within 14 days after injection.

[0971] Treatment: The animals were treated with a single IV injection of 1 mg / kg of CD64-ADC, administered into the tail vein on Day 0. Two different versions of ADC were used: an ADC with a cleavable linker and an ADC with a non-cleavable linker.

[0972] Monitoring: Overall animal condition was monitored throughout the study. Body temperature and weight were regularly measured to assess well-being, detect fever, and identify significant changes indicating toxicity or disease progression.

[0973] Quantitative Analysis of Engrafted Cells: Assessment of human leukemic cell engraftment in bone marrow by flow cytometry was performed using anti-hCD45 and anti-hCD33 fluorescent antibodies.

[0974] Comprehensive Blood Panel: Blood analyses were performed on Day 0 (ADC administration) and on Day 7 to evaluable the effects on hematological, renal, and hepatic function.

[0975] Final Necropsy: An inspection of organs and tissues was performed at the study’s end to assess damage and confirm therapeutic outcomes.

[0976] FIG. 7C shows that the CD64 ADC with a non-cleavable linker is far better tolerated than the one with a cleavable linker. Also, Table 3 shows the effect on various hematological parameters of ADC having either a cleavable or a non-cleavable linker.

[0977] Table 3. Effects on hematological parameters of tested ADCs.

[0978] Average values Control (Vehicle) CD64-ADC with a CD64-ADC with a N = 7 cleavable linker non-cleavable linker N = 5 N = 7 RBC (106 / mm3) 8.1 5.7 9.4

[0979]

[0980] Hematocrit (%) 37.8 24.5 42.8

[0981] Hb (g / dl) 12.6 8.9 14.5 MCV (fl) 46.5 43.7 45.5 MCH (pg) 15.6 15.5 15.5 MCHC (%) 33.6 35.8 34.0 WBC (1000 per pl) 0.9 12 0.9 Neutrophils (%) 44.7 53.3 56.6 Eosinophils (%) 0 0 0 Basophils (%) 0 0 0 Lymphocytes (%) 46.5 42.0 36.3 Monocytes (%) 8.8 4.8 7.1 AST / GOT (Ul / L) 191.3 651.5 213.6 ALT / GPT (Ul / L) 18.8 358.0 33.9 Creatinine (mg / dl) 0.3 0.25 0.2

[0982] Urea (mg / dl) 63.3 123.5 58.4

[0983]

[0984] Thus, FIGS. 7A-7C and Table 3 show that the non-cleavable version of the ADC did not significantly affect body weight, temperature, nor hematology and clinical chemistry parameters. However, the ADC construct with a cleavable linker had a substantial impact on several other parameters, leading to the death of two animals in the group at day 6 post-injection.

[0985] Example 8 - Effects of ADCs targeting CD64 on Healthy Human monocytes and TAMs in a Humanized Mouse Model

[0986] The ability of ADCs targeting CD64 to deplete healthy human monocytes and Tumor Associated Macrophages (TAMs) in a humanized mouse model was evaluated.

[0987] NOG mice were humanized by i.v. of PBMCs from human cord blood. Humanized mice were then engrafted subcutaneously with glioblastoma U87 cells. After tumors reached a size of ~ 250 mm3, randomization was performed, and animals were treated with a single i.v. injection of either vehicle (PBS) or an ADC generated using a tool antibody against CD64 and a cleavable linker coupled to PNU-159682 (0.75 mg / kg). After 4 days, mice were sacrificed, and blood andtumor biopsies were obtained for profiling by flow cytometry the abundance of human immune cells, such as B cells, T cells, and monocytes (FIG. 8A). For the case of peripheral blood, the ratio of each immune cell type before and after injection was plotted. For the case of the tumor infiltrate, tumors from each mouse were removed and disaggregated into monocellular suspensions. The absolute TAM count per gram of tumor material was plotted (FIG. 8B).

[0988] FIGS. 8A-8B show that CD64 ADC triggers in vivo depletion of circulating monocytes and TAMs in a humanized mouse model.

[0989] Example 9 - CD64 ADCs, but not their naked backbone, target human leukemic cells in a CDX model of disseminated leukemia in Nod SCID Gamma mice

[0990] The activity of PNU-159682-coupled ADCs vs the same backbone of naked mAb were evaluated side-by-side against human CD64-expressing cells in a CDX model.

[0991] Briefly, NSG mice were first treated with busulfan (40 mg / kg) to condition the bone marrow for efficient engraftment. Two days later, 1 million MV-4-11 human monocytic leukemia cells were engrafted through i.v. injection and 14 days after engraftment, mice were treated with a single i.v. dose of the naked mAb#01 or the derived ADC using a non-cleavable linker (mAb#01 -ADC). The naked mAb was tested at 20 mg / kg and the ADC at 1 mg / kg. 7 days after the ADC injection, mice were sacrificed and the bone marrow from the mice femurs was collected for analysis. During the week of treatment body weight and temperature were monitored daily. For the data presented in FIG. 10A, bone marrow samples from each animal were analyzed by flow cytometry to track the human leukemic cells within the mouse compartment using fluorescent antibodies against human CD33 and CD45. The percentage of human vs mouse cells in the individual bone marrow of each mouse was quantified and T-test was performed. For the data presented in FIG. 10B, the tolerability comparison between the naked and ADC constructs are shown.

[0992] 10 - CD64 ADCs trigger long-lasting remissions in a kinetic CDX model of human leukemia in Nude mice

[0993] The activity of PNU-159682-coupled ADCs in a double-injection schedule was evaluated for 7 weeks to explore the durability of the complete remissions achieved by leveraging a kinetic CDX model of human monocytic leukemia.

[0994] Data schematic protocol of the experiment is presented in FIG. 11 A. For the various steps depicted in FIG. 11 A, certain details are provided below:Animal strain: Immunodeficient nude mice (NLAE:NIH(S)Foxinu / nu), ideal for xenograft studies due to their impaired capacity to mount an immune response against foreign cells.

[0995] Tumor generation: Tumors were generated by subcutaneously implanting (5x106cells) human monocytic AML cells (THP-1) into the right flank of mice. Cells were suspended in 50% hydrogel (Geltrex™) to promote engraftment and tumor growth in vivo.

[0996] Randomization: Once the tumors reached about 200 mm3, animals were randomly assigned to different experimental groups, ensuring homogenous distribution of tumor sizes.

[0997] Treatment: Animals were treated with 1 mg / kg mAb#01-ADC with a double intravenous (IV) injection into the caudal vein.

[0998] Monitoring: Health status was monitored throughout the study. Body temperature and weight were regularly measured to assess well-being, detect fever, and identify significant signs of toxicity or disease progression. Periodic evaluations assessed tumor size reduction as a marker of therapeutic efficacy.

[0999] Briefly, Nude mice were engrafted subcutaneously with 5 million human THP-1 cells in a 50 hydrogel (Geltrex™). After -21 days, when tumors reached and average of ~ 200 mm3, an i.v. injection of mAb#01-ADC at 1 mg / kg was performed. Tumor volume was tracked with tri-weekly measurements. A second dosing of mAb#01-ADC at 1 mg / kg was performed at day 26. FIG. 11 B, show that animals treated with mAb#01-ADC achieve complete remissions with the first dose of the ADC, and remained in complete remission for up to 7 weeks. Mice were euthanized in the control arm when tumors reached -1000 mm3. For the data presented in FIG. 11C, the tolerability of the treatment is shown in comparison to the control arm.

[1000] Accordingly, the preceding merely illustrates the principles of the present disclosure. 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 equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalentsand equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein.

Claims

CLAIMSWE CLAIM:

1. An antibody that specifically binds CD64, wherein the antibody competes for binding to CD64 with an antibody comprising:a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 1 , and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 2; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 3, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 4; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 5, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 6; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 7, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 8; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 9, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 10;a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 11 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 12;a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 13, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 14;a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 15, and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 16; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 17, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 18; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 19, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 20; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 21 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 22; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 23, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 24; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 25, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 26; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 27, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 28; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 29, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 30; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 31 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and V CDR3 of the V set forth in SEQ ID NO: 32; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 33, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 34; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 35, and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO:

36. a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 37, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 38; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 39, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 40; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 41 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 42; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 43, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 44; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 45, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 46; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 47, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 48; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 49, and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 50; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 51 , and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 52; or a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 53, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:

54. a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 55, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 56; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 57, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 58; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 59, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 60; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 61 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 62; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 63, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 64; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 65, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and V CDR3 of the V set forth in SEQ ID NO: 66; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 67, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 68; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 69, and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 70; or a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 71 , and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:

72. a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 73, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 74; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 75, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 76; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 77, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 78; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 79, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 80; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 81 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 82; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 83, and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 84; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 85, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 86; or a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 87, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 88.

2. The antibody of claim 1 , wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 1 , and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 2; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 3, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 4; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 5, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 6; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 7, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 8; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 9, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 10; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 11 , and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 12; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 13, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 14; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 15, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 16; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 17, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 18; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 19, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 20; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 21 , and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 22; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 23, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 24; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 25, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 26; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 27, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and V CDR3 of the V set forth in SEQ ID NO: 28; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 29, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 30; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 31 , and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 32; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 33, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 34; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 35, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:

36. a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 37, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 38; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 39, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 40; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 41 , and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 42; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 43, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 44; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 45, and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 46; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 47, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 48; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 49, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 50; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 51 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 52; or a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 53, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:

54. a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 55, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 56; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 57, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 58; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 59, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 60; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 61 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and V CDR3 of the V set forth in SEQ ID NO: 62; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 63, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 64; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 65, and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 66; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 67, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 68; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 69, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 70; or a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 71 , and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:

72. a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 73, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 74; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 75, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 76; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 77, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 78; a variable heavy chain (VH) polypeptide comprisingthe VHCDR1 , VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO: 79, and a variable light chain (VL) polypeptide comprisingthe V CDR1 , V CDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 80; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 81 , and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 82; a variable heavy chain (VH) polypeptide comprisingthe V CDR1 , V CDR2 and V CDR3 of the V set forth in SEQ ID NO: 83, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 84; a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 85, and a variable light chain (VL) polypeptide comprisingthe VLCDR1 , VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO: 86; or a variable heavy chain (VH) polypeptide comprisingthe VH CDR1 , VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO: 87, and a variable light chain (VL) polypeptide comprisingthe VL CDR1 , VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO: 88.

3. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 1 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 2.

4. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 3; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 4.

5. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 5; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 6.

6. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 7; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% orgreater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 8.

7. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 9; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 10.

8. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 11 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 12.

9. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% orgreater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 13; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 14.

10. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 15; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 16.

11. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 17; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 18.

12. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 19; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 20.

13. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 21 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 22.

14. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 23; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 24.

15. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 25; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 26.

16. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 27; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 28.

17. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 29; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% orgreater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 30.

18. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 31 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 32.

19. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 33; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 34.

20. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 35; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 36.

21. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 37; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 38.

22. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 39; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 40.

23. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% orgreater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 41 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 42.

24. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 43; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 44.

25. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 45; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 46.

26. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 47; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 48.

27. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 49; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 50.

28. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 51 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 52.

29. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 53; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 54.

30. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 55; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 56.

31. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 57; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% orgreater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 58.

32. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 59; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 60.

33. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 61 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 62.

34. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 63; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 64.

35. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 65; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 66.

36. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 67; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 68.

37. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% orgreater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 69; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 70.

38. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 71 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 72.

39. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 73; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 74.

40. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 75; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 76.

41. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 77; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 78.

42. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 79; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% orgreater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 80.

43. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 81 ; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 82.

44. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 83; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 84.

45. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% orgreater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 85; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 86.

46. The antibody of claim 1 or claim 2, wherein the antibody comprises:a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 87; anda variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 88.

47. The antibody of any one of claims 1 to 46, wherein the antibody is a fully human antibody, a humanized antibody, or a chimeric antibody.

48. The antibody of any one of claims 1 to 47, wherein the antibody is an IgG.

49. The antibody of claim 48, wherein the IgG is an IgG 1.

50. The antibody of any one of claims 1 to 49, wherein the antibody comprises an Fc region, and the Fc region is heterologous to the VHof the antibody.

51. The antibody of claim 50, wherein the Fc region is a variant Fc region.

52. The antibody of claim 51 , wherein the variant Fc region comprises one or more amino acid substitutions, one or more amino acid insertions, one or more amino acid deletions, or any combination thereof, relative to a wild-type Fc region.

53. The antibody of any one of claims 1 to 47, wherein the antibody is a Fab.

54. The antibody of any one of claims 1 to 47, wherein the antibody is a single chain antibody.

55. The antibody of claim 54, wherein the antibody is an scFv.

56. The antibody of any one of claims 1 to 55, wherein the antibody is a multi-specific antibody comprising a first antigen-binding domain and a second antigen-binding domain, and wherein the first antigen binding domain comprises a VHpolypeptide-VLpolypeptide pair as defined in any one of claims 1 to 46.

57. The antibody of claim 56, wherein the second antigen-binding domain specifically binds an antigen other than CD64.

58. The antibody of claim 57, wherein the antigen other than CD64 is a tumor antigen.

59. The antibody of claim 58, wherein the tumor antigen is CD3, major histocompatibility class II (MHC II), 5T4, AXL receptor tyrosine kinase (AXL), B-cell maturation antigen (BCMA), c-MET, C4.4a, carbonic anhydrase 6 (CA6), carbonic anhydrase 9 (CA9), Gadherin-6, CD19, CD20, CD22, CD25, CD27L, CD30, CD33, CD37, CD44v6, CD56, CD70, CD74, CD79b, CD123, CD138, carcinoembryonic antigen (CEA), cKit, Cripto protein, CS1, delta-like canonical Notch ligand 3 (DLL3), endothelin receptor type B (EDNRB), EpCAM, ephrin A4 (EFNA4), epidermal growth factor receptor (EGFR), EGFRvlll, ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3), EPH receptor A2 (EPHA2), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), FMS-like tyrosine kinase 3 (FLT3), folate receptor 1 (FOLR1), GLUT3, glycoprotein non-metastatic B (GPNMB), guanylate cyclase 2 C (GUCY2C), HCAM, human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), Integrin alpha, lysosomal-associated membrane protein 1 (LAMP-1), Lewis Y, LIV-1, leucine rich repeat containing 15 (LRRC15),mesothelin (MSLN), sodium-dependent phosphate transport protein 2B (NaPi2b), Nectin-4, NMB, NOTCH3, p-cadherin (p-CAD), prostate-specific membrane antigen (PSMA), protein tyrosine kinase 7 (PTK7), solute carrier family 44 member 4 (SLC44A4), SLIT like family member 6 (SLITRK6), STEAP family member 1 (STEAP1), tissue factor (TF), T cell immunoglobulin and mucin protein-1 (TIM-1), trophoblast cell-surface antigen (TROP-2), or VEGF-A.

60. A nucleic acid encoding a variable heavy chain (VH) polypeptide, a variable light chain (VL) polypeptide, or both, of the antibody of any one of claims 1 to 59.

61. The nucleic acid of claim 60, wherein the antibody is a single chain antibody, and wherein the nucleic acid encodes the single chain antibody.

62. An expression construct comprising the nucleic acid of claim 60 or 61 operably linked to a promoter.

63. A cell comprising the expression construct of claim 62.

64. A cell comprising:(1) an expression construct comprising a nucleic acid that encodes a variable heavy chain (VH) polypeptide and a variable light chain (VL) polypeptide of the antibody of any one of claims 1 to 59; or(2) a first expression construct comprising a nucleic acid that encodes a variable heavy chain (VH) polypeptide of the antibody of any one of claims 1 to 59, and a second expression construct comprising a nucleic acid that encodes a variable light chain (VL) polypeptide of the antibody.

65. A method of making the antibody of any one of claims 1 to 59, comprising culturing the cell of claim 63 or 64 under conditions suitable for the cell to express the antibody, wherein the antibody is produced.

66. A conjugate comprising:an antibody of any one of claims 1 to 59; andan agent conjugated to the antibody.

67. The conjugate of claim 66, wherein the agent is selected from the group consisting of: a chemotherapeutic agent, a toxin, a cytotoxic agent, a radiation sensitizing agent, a radioactive isotope, a detectable label, and a half-life extending moiety.

68. The conjugate of claim 67, wherein the agent is a chemotherapeutic agent.

69. The conjugate of claim 68, wherein the chemotherapeutic agent is PNU-159682.

70. The conjugate of claim 67, wherein the agent is a cytotoxic agent.

71. The conjugate of claim 70, wherein the cytotoxic agent is Ricin-A, Pseudomonas exotoxin A, Granzyme B, angiogenin, or microtubule-associated protein tau.

72. A conjugate comprising an antibody that specifically binds CD64 and an agent, wherein the agent is an anthracycline.

73. The conjugate of claim 72, wherein the anthracycline is PNU-159682.

74. The conjugate of any one of claims 66 to 73, wherein the agent is conjugated to the antibody via a cleavable linker.

75. The conjugate any one of claims 66 to 73, wherein the agent is conjugated to the antibody via a non-cleavable linker.

76. The conjugate of claim 75, wherein the non-cleavable linker comprises a maleimide group.

77. The conjugate of claim 76, wherein the conjugate comprising the maleimide group has the following formula:wherein:Ab is the anti-CD64 antibody;AN is the anthracycline or the anthracycline derivative;each Rxxis independently hydrogen or C1-3 alkyl;n1 is an integer from 0 to 4;each AA is independently selected from the group consisting of alanine, glycine, lysine, serine, aspartic acid, aspartate methyl ester, N,N-dimethyl-lysine, phenylalanine, citrulline, valine, asparagine, homoserine methyl ether, isoleucine, leucine, glutamic acid, histidine, arginine, threonine, O-methylserine, O-methylaspartic acid, O-methylglutamic acid, N-methyllysine, O-methyltyrosine, O-methylhistidine, and O-methylthreonine; andn2 is an integer from 1 to 4.

78. The conjugate of claim 77, wherein: each Rxxis hydrogen, n1 is 3, AA is glycine, and n2 is 1 .

79. The conjugate of claim in or 78, wherein the maleimide based linker has the following structure:

80. The conjugate of any one of claims 77 to 79, wherein AN is PNU-159682.

81. The conjugate of any one of claims 77 to 80, wherein the conjugate has the following formula.wherein Ab is an anti-CD64 antibody.

82. A composition comprising the conjugate of any one of claims 66 to 81.

83. The composition of claim 82, wherein the composition is formulated for administration to a subject in need thereof.

84. The composition of claim 83, wherein the composition is formulated for parenteral administration.

85. A method of targeting a CD64 expressing cell in a subject, the method comprising administering to the subject the conjugate of any one of claims 66 to 81 or the composition of any one of claims 82 to 84.

86. The method of claim 85, wherein the antibody is conjugated to a chemotherapeutic agent or a cytotoxic agent, and wherein the targeting kills the CD64 expressing cell.

87. The method of claim 86, wherein the CD64 expressing cell in the subject is an inflammatory cell or an autoimmune cell in the subject.

88. The method of claim 87, wherein the inflammatory or the autoimmune cell is involved in the development of an inflammatory disease or an autoimmune disease.

89. The method of any one of claims 86 to 88, wherein the antibody is conjugated to the cytotoxic agent.

90. The method of claim 89, wherein the cytotoxic agent is Ricin-A, Pseudomonas exotoxin A, Granzyme B, angiogenin, or microtubule-associated protein tau.

91. The method of claim 90, wherein the inflammatory disease or the autoimmune disease is graft versus host disease (GVHD), chronic cutaneous inflammation, atopic dermatitis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, or systemic lupus erythematosus (SLE).

92. The method according to any one of claims 86 to 91 , wherein the method is a method of treating the inflammatory disease or the autoimmune disease in the subject.

93. The method of claim 86, wherein the antibody is conjugated to the chemotherapeutic agent.

94. The method of claim 93, wherein the chemotherapeutic agent is PNU-159682.

95. The method of claim 93 or 94, wherein the CD64 expressing cell is a cell of a cancer in the subject.

96. The method of claim 95, wherein the cancer is a leukemia, a lymphoma, or a solid tumor.

97. The method of claim 96, wherein the cancer is the leukemia.

98. The method of claim 97, wherein the leukemia is a monocytic leukemia.

99. The method of claim 98, wherein the monocytic leukemia is chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute monocytic leukemia, or acute myelomonocytic leukemia.

100. The method of claim 96, wherein the cancer is the lymphoma.

101. The method of claim 100, wherein the lymphoma is T-cell lymphoma or Hodgkin lymphoma.

102. The method of claim 101 , wherein the cancer is the solid tumor.

103. The method of claim 101 , wherein the solid tumor is glioblastoma, thyroid cancer, lung cancer, hepatic cancer, renal cancer, ovarian cancer, head and neck cancer, breast cancer, prostate cancer, or melanoma.

104. The method of any one of claims 93 to 103, further comprising administering to the subject a second agent.

105. The method of claim 104, wherein the second agent is an immune check-point inhibitor.

106. The method of claim 105, wherein the immune check-point inhibitor is: a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a programmed cell death-1 (PD-1) inhibitor, a programmed cell death ligand-1 (PD-L1) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, a T-cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor, an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIG IT) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA) inhibitor, a B7-H3 inhibitor, and any combination thereof.

107. The method according to any one of claims 95 to 106, wherein the method is a method of treating the cancer in the subject.

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