High-affinity Anti-mertk antibody and uses thereof

Abstract

To provide high-affinity anti-MERTK antibodies and uses thereof.SOLUTION: The present disclosure provides antibodies (e.g., humanized antibodies) that specifically bind Mer tyrosine kinase (MERTK; e.g., human MERTK) and a composition comprising such antibodies. The present disclosure also provides (i) an anti-MERTK antibody or an antigen-binding fragment thereof set forth in the present description that specifically binds to MERTK (e.g., human MERTK), and (ii) an antibody-drug conjugate containing a cytotoxic agent directly conjugated to the antibody or conjugated to the antibody via a linker, and a composition containing such an antibody-drug conjugate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] 1. Field This application claims the benefit of U.S. Provisional Application No. 62 / 810,841, filed February 26, 2019, which is incorporated herein by reference in its entirety.

[0002] This application incorporates by reference the Sequence Listing submitted herewith as an ASCII formatted text file entitled "13256-008-228_SEQ_LISTING.txt", created on February 19, 2020, and having a size of 94,274 bytes.

[0003] The present disclosure provides antibodies (e.g., humanized antibodies) that specifically bind to Mer tyrosine kinase (MERTK; e.g., human MERTK), and compositions comprising such antibodies. The present disclosure also provides antibody-drug conjugates comprising (i) an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK), and (ii) a cytotoxic agent conjugated directly to the antibody or via a linker, as well as compositions comprising such antibody-drug conjugates. The present disclosure also provides a method for treating cancer, comprising administering to a human subject in need thereof (a) an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) described herein, or (b) an antibody-drug conjugate comprising (i) an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), and (ii) a cytotoxic agent conjugated directly to the antibody or via a linker. [Background technology]

[0004] 2.Background Mer tyrosine kinase (MERTK), also known as c-mer, MER, proto-oncogene c-Mer, receptor tyrosine kinase MerTK, tyrosine-protein kinase Mer, STK kinase, RP38, or MGC133349, is a member of the TAM family of receptor tyrosine kinases, which also includes AXL and TYRO3 kinase. MERTK transduces signals from the extracellular space through activation by binding of ligands, most notably the soluble protein Gas-6. Binding of Gas-6 to MERTK induces autophosphorylation of MERTK at its intracellular domain, resulting in downstream signal activation (Cummings CT et al., (2013) Clin Cancer Res 19: 5275-5280; Verma A et al., (2011) Mol Cancer Ther 10: 1763-1773).

[0005] MERTK exists in both membrane-bound and soluble forms. The extracellular domain can be cleaved to generate a soluble extracellular domain, which is hypothesized to act as a decoy receptor that negatively regulates the activation of MERTK receptors on cells by reducing the ability and / or availability of soluble Gas-6 ligands to bind to membrane-bound MERTK (Sather S et al., (2007) Blood 109: 1026-1033). As a result, MERTK plays a dual role in cancer progression, angiogenesis, and metastasis. Gas-6 activation of MERTK in endothelial cells inhibits endothelial cell recruitment by cancer cells in a coculture system. Endothelial recruitment is a key feature of cancer cells that enables tumor angiogenesis, tumor growth, and metastasis. Downregulation of MERTK in metastatic breast cancer cells also inhibits endothelial recruitment (Png KJ et al., (2012) Nature 481: 190-194). However, MERTK also plays an opposite role in cancer cells, and its overexpression leads to increased metastasis, possibly by releasing cleaved MERTK to generate soluble MERTK ectodomain protein as a decoy receptor. Furthermore, ligand-dependent activation of MERTK in cancer cells stimulates oncogenic pathways, including the AKT pathway (Linger RM, Cohen RA, Cummings CT, Sather S, Migdall-Wilson J, Middleton DH, Lu X, Baron AE, Franklin WA, Merrick DT, Jedlicka P, DeRyckere D, Heasley LE, Graham DK. Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth, and enhances chemosensitivity of human non-small cell lung cancer (Oncogene. 2013 Jul 18;32(29):3420-31)). Therefore, tumor cells overexpress MERTK and promote oncogenic pathways. Tumor cells also secrete a soluble form of the extracellular MERTK receptor that acts as a decoy receptor, reducing the ability (and / or availability) of soluble Gas-6 ligand to activate MERTK on endothelial cells, ultimately leading to endothelial recruitment, angiogenesis, and cancer progression (Png KJ et al., (2012) Nature 481: 190-194).

[0006] MERTK is also involved in modulating macrophage homeostasis and maintaining anti-inflammatory state.In macrophages, MERTK mediates the phagocytic clearance of apoptotic cells and the release of IL-10 and acute inflammatory cytokines, the expression of which is stimulated by Gas-6-dependent binding to MERTK (Zizzo et al., (2012) J. Immunology Oct 1;189(7):3508-20;Cook et al., J Clin Invest. 2013;123(8):3231-3242).

[0007] Historically, because MERTK was thought to function solely as an oncogene, efforts have been made to generate inhibitors of MERTK for the treatment of cancer (e.g., the compound UNC1062, a potent small molecule MERTK inhibitor developed as an anticancer compound) (Liu J et al., (2013) Eur J Med Chem 65: 83-93; Cummings CT et al., (2013) Clin Cancer Res 19: 5275-5280; Verma A et al., (2011) Mol Cancer Ther 10: 1763-1773). In recent years, antibody-drug conjugates (ADCs) have become the most rapidly They have become one of the fastest growing classes of cancer drugs (Beck A et al., (2017) Nat Rev Drug Discov 16: 315-337; Peters C and Brown S, (2015) Biosci Rep 35: art:e00225). The citation of a reference herein should not be construed as an admission that it is prior art to the present disclosure. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Cummings CT et al., (2013) Clin Cancer Res 19: 5275-5280 [Non-licensed document 2] Verma A et al., (2011) Mol Cancer Ther 10: 1763-1773 [Non-licensed document 3] Sather S et al., (2007) Blood 109: 1026-1033

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

[0009] 3. Overview Disclosed herein are antibodies and antigen-binding fragments thereof that specifically bind to MERTK (e.g., human MERTK) with high affinity. In specific embodiments of any of the antibodies or antigen-binding fragments thereof described herein, the antibody specifically recognizes the extracellular domain of MERTK (e.g., human MERTK), and the extracellular domain comprises the amino acid sequence of SEQ ID NO: 132.

[0010] In a specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof specifically binds to MERTK (e.g., human MERTK) and leads to the internalization of MERTK from the cell surface. In a specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof blocks Gas-6-induced phosphorylation of AKT. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof prevents MERTK activation. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein specifically recognizes the extracellular portion of human MERTK. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof reduces colonization by cancer cells. In certain embodiments, the anti-MERTK antibody or antigen-binding fragment described herein is monoclonal. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein is an immunoglobulin comprising two identical light chains and two identical heavy chains. In a specific embodiment, the anti-MERTK antibody is a humanized antibody.

[0011] In certain embodiments, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 105.

[0012] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 107.

[0013] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 108.

[0014] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (eg, human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:109.

[0015] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 110.

[0016] In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 111.

[0017] In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises (a) a VH comprising the amino acid sequence of SEQ ID NO: 105, and (b) a VL comprising the amino acid sequence of SEQ ID NO: 106. In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises (a) a VH comprising the amino acid sequence of SEQ ID NO: 107, and (b) a VL comprising the amino acid sequence of SEQ ID NO: 106. In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises (a) a VH comprising the amino acid sequence of SEQ ID NO: 108, and (b) a VL comprising the amino acid sequence of SEQ ID NO: 106. In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises (a) a VH comprising the amino acid sequence of SEQ ID NO: 109, and (b) a VL comprising the amino acid sequence of SEQ ID NO: 106. In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises (a) a VH comprising the amino acid sequence of SEQ ID NO: 110, and (b) a VL comprising the amino acid sequence of SEQ ID NO: 111.

[0018] In certain embodiments, the antibodies provided herein that specifically bind to MERTK (e.g., human MERTK) comprise a heavy chain constant region or a light chain constant region, or both. In some embodiments, the heavy chain constant region is selected from the group of human immunoglobulins consisting of IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In certain embodiments, the light chain constant region is selected from the group of human immunoglobulins consisting of IgGκ and IgGλ. In some embodiments, the antibody comprises a constant region that has increased binding affinity to one or more human Fc gamma receptors.

[0019] In some embodiments, the antibody comprises a constant region that has reduced binding affinity to one or more human Fc gamma receptors.

[0020] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, each of the heavy chains comprises a variable region (VH) comprising the amino acid sequence of SEQ ID NO: 105. In a further embodiment of such a specific embodiment, each of the light chains comprises a variable region (VL) comprising the amino acid sequence of SEQ ID NO: 106.

[0021] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, each of the heavy chains comprises a variable region (VH) comprising the amino acid sequence of SEQ ID NO: 107. In a further embodiment of such a specific embodiment, each of the light chains comprises a variable region (VL) comprising the amino acid sequence of SEQ ID NO: 106.

[0022] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, each of the heavy chains comprises a variable region (VH) comprising the amino acid sequence of SEQ ID NO: 108. In a further embodiment of such a specific embodiment, each of the light chains comprises a variable region (VL) comprising the amino acid sequence of SEQ ID NO: 106.

[0023] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, each of the heavy chains comprises a variable region (VH) comprising the amino acid sequence of SEQ ID NO: 110. In a further embodiment of such a specific embodiment, each of the light chains comprises a variable region (VL) comprising the amino acid sequence of SEQ ID NO: 111.

[0024] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, each of the heavy chains comprises a variable region (VH) comprising the amino acid sequence of SEQ ID NO: 109. In a further embodiment of such a specific embodiment, each of the light chains comprises a variable region (VL) comprising the amino acid sequence of SEQ ID NO: 106.

[0025] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, the light chain comprises a variable region (VL) comprising SEQ ID NO:106.

[0026] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, the light chain comprises a variable region (VL) comprising SEQ ID NO:111.

[0027] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, the heavy chain comprises a variable region (VH) comprising SEQ ID NO:105.

[0028] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, the heavy chain comprises a variable region (VH) comprising SEQ ID NO:107.

[0029] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, the heavy chain comprises a variable region (VH) comprising SEQ ID NO:108.

[0030] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, the heavy chain comprises a variable region (VH) comprising SEQ ID NO:109.

[0031] In a specific embodiment of the embodiment in which the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, the heavy chain comprises a variable region (VH) comprising SEQ ID NO:110.

[0032] In specific embodiments of any of the antibodies or antigen-binding fragments thereof provided herein, where the antibody is an immunoglobulin comprising two identical light chains and two identical heavy chains, the antibody or antigen-binding fragment thereof comprises a human-derived constant region. In a further embodiment of such a specific embodiment, the heavy chain constant region has an isotype selected from the group consisting of gamma 1, gamma 2, gamma 3, and gamma 4.

[0033] In specific embodiments of any of the antibodies or antigen-binding fragments thereof provided herein, the antibody binds to MERTK (e.g., human MERTK) on a cell with an EC50 in the range of about 1 nM to 15 nM (e.g., 6.5 nM to 8 nM).

[0034] In specific embodiments of any of the antibodies or antigen-binding fragments thereof provided herein, the antibody or antigen-binding fragment reduces the expression level of MERTK in cancer cells (e.g., the melanoma cell line SKMEL5). In another specific embodiment of any of the antibodies or antigen-binding fragments thereof provided herein, the antibody or antigen-binding fragment reduces the expression level of MERTK in human M2 macrophages. In another specific embodiment of any of the antibodies or antigen-binding fragments thereof provided herein, the antibody or antigen-binding fragment reduces the level of MERTK in in vitro differentiated human M2 macrophages.

[0035] In specific embodiments of any of the antibodies or antigen-binding fragments thereof provided herein, the antibody or antigen-binding fragment thereof comprises a human-derived constant region. In a further embodiment of such specific embodiments, the antibody or antigen-binding fragment thereof is a humanized immunoglobulin.

[0036] In specific embodiments of any of the antibodies or antigen-binding fragments thereof provided herein, where the antibody is not a monoclonal antibody or an immunoglobulin comprising two identical light chains and two identical heavy chains, the antibody or antigen-binding fragment thereof is a bispecific antibody.

[0037] In another aspect, provided herein is an immunoglobulin that specifically binds to MERTK (e.g., human MERTK), comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105; and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106.

[0038] In another aspect, provided herein is an immunoglobulin that specifically binds to MERTK (e.g., human MERTK), comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107; and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106.

[0039] In another aspect, provided herein is an immunoglobulin that specifically binds to MERTK (e.g., human MERTK), comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108; and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106.

[0040] In another aspect, provided herein is an immunoglobulin that specifically binds to MERTK (e.g., human MERTK), comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109; and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106.

[0041] In another aspect, provided herein is a humanized immunoglobulin that specifically binds to MERTK (e.g., human MERTK), comprising: (A) (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; or (B) (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; or (C) (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; or (D) (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106. The present invention provides a humanized immunoglobulin comprising:

[0042] In some embodiments, the antibodies provided herein are IgG. In some embodiments, the antigen-binding fragments provided herein are Fab, F(ab')2, or scFv fragments.

[0043] In another aspect, provided herein is a chimeric antibody or antigen-binding fragment thereof that binds to MERTK (e.g., human MERTK). In some embodiments, the chimeric antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 110. In some embodiments, the chimeric antibody comprises a variable light chain region (VL) comprising the amino acid sequence of SEQ ID NO: 111. In a specific embodiment, the chimeric antibody comprises a VH of SEQ ID NO: 110 and a VL of SEQ ID NO: 111.

[0044] In another specific embodiment, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, 114, 115, 116 or 117. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 113 or 118. In another specific embodiment, the anti-MERTK antibody comprises (A) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, and a light chain comprising the amino acid sequence of SEQ ID NO: 113; or (B) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114, and a light chain comprising the amino acid sequence of SEQ ID NO: 113; or (C) a heavy chain comprising the amino acid sequence of SEQ ID NO: 115, and a light chain comprising the amino acid sequence of SEQ ID NO: 113; or (D) a heavy chain comprising the amino acid sequence of SEQ ID NO: 116, and a light chain comprising the amino acid sequence of SEQ ID NO: 113; or (E) a heavy chain comprising the amino acid sequence of SEQ ID NO: 117, and a light chain comprising the amino acid sequence of SEQ ID NO: 113. Includes.

[0045] In certain embodiments, the anti-MERTK antibody is a bispecific antibody, which comprises two different antigen-binding regions, one binding region specifically binding to MERTK (e.g., human MERTK) and the other binding region binding to an antigen of interest (e.g., an immune cell receptor, a checkpoint receptor, or a tumor-associated antigen).

[0046] In specific embodiments, the binding region that binds to MERTK comprises the variable region of the z10, z11, or z13 antibody described herein (e.g., those shown in Tables 11, 12, and 13 below). In some specific embodiments, the other binding region of the bispecific antibody binds to CD3. In other specific embodiments, the other binding region of the bispecific antibody binds to PD-L1. In other specific embodiments, the other binding region of the bispecific antibody binds to LRP1. In other specific embodiments, the other binding region of the bispecific antibody binds to LPR8. In other specific embodiments, the other binding region of the bispecific antibody binds to TGF-β. In other specific embodiments, the other binding region of the bispecific antibody binds to ICOS. In other specific embodiments, the other binding region of the bispecific antibody binds to CD40. In other specific embodiments, the other binding region of the bispecific antibody binds to NKGD2. In other specific embodiments, the other binding region of the bispecific antibody binds to TIGIT. In certain embodiments, the binding region that binds to CD40 is an antagonist antibody. In another specific embodiment, the binding region that binds ICOS is an antagonist antibody. In another specific embodiment, the binding region that binds PD-L1 is a blocking antibody.

[0047] In another embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof (e.g., a humanized or human antibody, or an antigen-binding fragment thereof) that binds to the same epitope of MERTK (e.g., human MERTK) as the anti-MERTK antibody described herein. In another embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof (e.g., a humanized or human antibody, or an antigen-binding fragment thereof) that competes with the anti-MERTK antibody or antigen-binding fragment thereof described herein for binding to MERTK (e.g., human MERTK). In another specific embodiment, provided herein is a first anti-MERTK antibody or antigen-binding fragment thereof that competes with an anti-MERTK antibody or antigen-binding fragment thereof described herein for binding to MERTK (e.g., human MERTK), wherein the competition is demonstrated by a reduction in binding of the first anti-MERTK antibody or antigen-binding fragment thereof to MERTK (e.g., human MERTK) by more than 80% (e.g., 85%, 90%, 95%, or 98%, or between 80% and 85%, 80% and 90%, 85% and 90%, or 85% and 95%) in the presence of the anti-MERTK antibody or antigen-binding fragment described herein. In a specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof that binds to the same epitope as MERTK (or competes with binding to the anti-MERTK antibody or antigen-binding fragment thereof) is not a murine antibody or antigen-binding fragment thereof.

[0048] In certain embodiments, the anti-MERTK antibodies provided herein have an EC20 activity in the range of about 1 nM to 10 nM in an assay as described herein. 50In some embodiments, the anti-MERTK antibody or antigen-binding fragment thereof specifically binds to MERTK (e.g., human MERTK). In specific embodiments, the anti-MERTK antibody or antigen-binding fragment thereof specifically binds to human MERTK. In specific embodiments, the antibody or antigen-binding fragment thereof provided herein does not bind or does not appreciably bind to human Axl, human Tyro3, ​​or mouse MERTK, as assessed by assays described herein or known to those of skill in the art. In some embodiments, the anti-MERTK antibody or antigen-binding fragment thereof binds to human MERTK and cynomolgus monkey MERTK. In specific embodiments, the antibody provided herein is isolated. In specific embodiments, the antibody provided herein is a monoclonal antibody. In specific embodiments, the anti-MERTK antibody or antigen-binding fragment thereof provided herein is bivalent and can bind to two MERTK molecules (e.g., human MERTK molecules).

[0049] In another aspect, provided herein is a polynucleotide sequence encoding an antibody or antigen-binding fragment thereof. In a specific embodiment, provided herein is a polynucleotide sequence comprising a nucleic acid molecule encoding a heavy chain variable region, wherein the nucleic acid molecule comprises the nucleic acid sequence of SEQ ID NO: 119, SEQ ID NO: 121, SEQ ID NO: 122, or SEQ ID NO: 123. In another specific embodiment, provided herein is a polynucleotide sequence comprising a nucleic acid molecule encoding a light chain variable region, wherein the nucleic acid molecule comprises the nucleic acid sequence of SEQ ID NO: 120 or SEQ ID NO: 124. In a specific embodiment, the nucleic acid molecule or polynucleotide sequence is isolated.

[0050] In another aspect, provided herein is a vector comprising a polynucleotide sequence encoding an antibody or antigen-binding fragment described herein. In certain embodiments, a vector (e.g., an isolated vector) comprises a polynucleotide encoding the heavy chain variable region and / or light chain variable region, or the heavy chain and / or light chain, of an anti-MERTK antibody described herein. In certain embodiments, a host cell comprises the polynucleotide or vector. Exemplary host cells include E. coli, Pseudomonas, Bacillus, Streptomyces, yeast, 293F, CHO, YB / 20, NS0, PER-C6, HEK-293, HEK-293T, NIH-3T3, HeLa, BHK, Hep G2, SP2 / 0, R1.1, BW, LM, COS1, COS7, BSC1, BSC40, BMT10 cells, plant cells, insect cells, and human cells in tissue culture. In a specific embodiment, provided herein is a method for producing an anti-MERTK antibody or an antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), the method comprising culturing a host cell such that a polynucleotide is expressed and an antibody is produced.

[0051] In another aspect, provided herein is an ex vivo cell containing one or more polynucleotides encoding any of the antibodies or antigen-binding fragments thereof described herein, or any of the immunoglobulins described herein. In a specific embodiment, the ex vivo cell is (a) a first immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; (b) a second immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; and (c) a third immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; (d) a fourth immunoglobulin comprising (i) a heavy chain region comprising the amino acid sequence of SEQ ID NO: 109, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; and (e) a fifth immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 111. The antibody comprises one or more polynucleotides encoding an antibody selected from the group consisting of:

[0052] In another aspect, provided herein is an ex vivo cell containing a polynucleotide encoding any of the heavy chains of the antibodies described herein.

[0053] In another aspect, provided herein is an ex vivo cell containing a polynucleotide encoding any of the light chains of the antibodies described herein. In another aspect, provided herein is a method of producing an antibody or antigen-binding fragment thereof, comprising culturing an ex vivo cell containing one or more polynucleotides encoding any of the antibodies or antigen-binding fragments described herein under conditions such that the one or more polynucleotides are expressed by the cell to produce the antibody or antigen-binding fragment encoded by the polynucleotide. In a specific embodiment, the method of producing an antibody or antigen-binding fragment thereof comprises: (a) a first immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; (b) a second immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; (c) a third immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; (d) a fourth immunoglobulin comprising (i) a heavy chain region comprising the amino acid sequence of SEQ ID NO: 109, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; and (e) a fifth immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 111; and culturing ex vivo cells containing one or more polynucleotides encoding an antibody selected from the group consisting of:

[0054] In another aspect, provided herein is a method of producing an antibody heavy chain, the method comprising culturing an ex vivo cell containing a polynucleotide encoding any of the antibody heavy chains described herein under conditions such that the polynucleotide is expressed by the cell to produce the antibody heavy chain encoded by the polynucleotide.

[0055] In another aspect, provided herein is a method of producing an antibody light chain, the method comprising culturing an ex vivo cell containing a polynucleotide encoding any of the antibody light chains described herein under conditions such that the polynucleotide is expressed by the cell to produce the antibody light chain encoded by the polynucleotide.

[0056] In another aspect, provided herein is an antibody-drug conjugate comprising: (a) an antibody moiety described herein that is an antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK); (b) one or more drug moieties, each drug moiety being a cytotoxic agent; and (c) optionally, a linker, wherein the cytotoxic agent is conjugated directly to the antibody moiety or via a linker.

[0057] In a specific embodiment, the molar ratio of antibody moiety to drug moiety is between 1:1 and 1:12.

[0058] In a specific embodiment, the molar ratio of antibody moiety to drug moiety is between 1:1 and 1:8.

[0059] In another specific embodiment, the molar ratio of antibody moiety to drug moiety is between 1:3 and 1:5.

[0060] In another specific embodiment, the molar ratio of antibody moiety to drug moiety is 1:9.

[0061] In a specific embodiment, the antibody-drug conjugate comprises a linker, wherein the linker is a cleavable linker.

[0062] In another specific embodiment, the antibody-drug conjugate comprises a linker, wherein the linker is a non-cleavable linker.

[0063] In another specific embodiment, the antibody-drug conjugate comprises a linker, and the linker is maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (also known as "mc-vc-PABC") (see Figure 13A for the structure of mc-vc-PABC). In another specific embodiment, the antibody-drug conjugate comprises a linker, and the linker is CL2 (see Figure 13B and Cardillo et al. 2011, Clin Cancer Res; 17(10); 3157-69 for the structure of CL2). In another specific embodiment, the antibody-drug conjugate comprises a linker, and the linker is CL2A (see Figure 13B and Goldberg et al. 2018, Oncotarget; 9(48); 28989-29006, and Cardillo et al. 2011, Clin Cancer Res; 17(10); 3157-69 for the structure of CL2A).

[0064] In specific embodiments, the cytotoxic agent is a small molecule, a nucleotide, a peptide, or a non-antibody protein. In a further embodiment of such specific embodiments, the cytotoxic agent is a small molecule.

[0065] In another specific embodiment, the cytotoxic agent is an auristatin, a maytansinoid, a pyrrolobenzodiazepine, an indolinobenzodiazepine, a calicheamicin, a camptothecin analog, a duocarmycin, a tubulin inhibitor, a tublysin or tublysin analog, amberstatin 269, doxorubicin, an antibiotic, an anthracycline, a microtubule inhibitor, a splicehostatin, or a tylanstatin. In a further embodiment of such a specific embodiment, the cytotoxic agent is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). In another further embodiment of such a specific embodiment, the cytotoxic agent is DM1 or DM4. In another further embodiment of such a specific embodiment, the cytotoxic agent is SN-38.

[0066] In another aspect, provided herein is a method of producing an antibody-drug conjugate described herein, wherein a linker is absent, the method comprising the steps of: (a) conjugating a cytotoxic agent directly to the antibody moiety to produce the antibody-drug conjugate; and (b) purifying the antibody-drug conjugate.

[0067] In another aspect, provided herein is a method of producing an antibody-drug conjugate described herein, wherein the antibody-drug conjugate comprises a linker, and the method comprises the following steps, in the order stated: (a) conjugating the linker directly to the antibody moiety to produce a linker-antibody moiety, (b) conjugating the linker of the linker-antibody moiety directly to a cytotoxic agent to produce the antibody-drug conjugate, and (c) purifying the antibody-drug conjugate.

[0068] In another aspect, provided herein is a method of producing an antibody-drug conjugate described herein, wherein the antibody-drug conjugate comprises a linker, and the method comprises the following steps, in the order stated: (a) conjugating the linker directly to a cytotoxic agent to produce a linker-cytotoxic agent moiety, (b) conjugating the linker of the linker-cytotoxic agent moiety directly to the antibody moiety to produce the antibody-drug conjugate, and (c) purifying the antibody-drug conjugate.

[0069] In another aspect, provided herein is a pharmaceutical composition comprising an anti-MERTK antibody or antigen-binding fragment thereof described herein, or an antibody-drug conjugate described herein. In a specific embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of any of the antibodies or antigen-binding fragments described herein, or any of the antibody-drug conjugates described herein. In a specific embodiment, the pharmaceutical composition comprises: (a) a first immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; (b) a second immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; (c) a third immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; (d) a fourth immunoglobulin comprising (i) a heavy chain region comprising the amino acid sequence of SEQ ID NO: 109, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; or (e) a fourth immunoglobulin comprising (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; and a pharmaceutically acceptable carrier.

[0070] In some embodiments, the pharmaceutical composition comprises a polynucleotide sequence comprising a nucleic acid sequence encoding an antibody or antigen-binding fragment thereof.

[0071] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an anti-MERTK antibody or antigen-binding fragment thereof described herein, or an antibody-drug conjugate described herein. In a specific embodiment, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject any of the pharmaceutical compositions described herein.

[0072] In some embodiments, the tumor sample from the subject is evaluated for overexpression of phosphorylated MERTK before treatment according to the methods described herein.In certain embodiments, the subject is treated when the tumor sample overexpresses phosphorylated MERTK.

[0073] In specific embodiments of the preceding aspects of the method for treating cancer, the cancer is cancer of the head and neck, lung, breast, bone, ovary, stomach, pancreas, larynx, esophagus, testis, liver, parotid gland, bile duct, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, or thyroid.In certain embodiments of these specific embodiments, the cancer is breast cancer.In further embodiments of these certain embodiments, the cancer is triple-negative breast cancer.

[0074] In specific embodiments of the preceding aspects of the method of treating cancer, the cancer is sarcoma, squamous cell carcinoma, melanoma, glioma, glioblastoma, neuroblastoma, gastric cancer, colorectal cancer, non-small cell lung cancer, or Kaposi's sarcoma. In specific embodiments of the aspects of the method of treating cancer, the cancer is leukemia or lymphoma. In a further specific embodiment, the cancer is acute myeloid leukemia. In another further specific embodiment, the cancer is acute lymphocytic leukemia. In another further embodiment, the cancer is multiple myeloma.

[0075] In a specific embodiment, the cancer treated according to the methods described herein overexpresses MERTK, is associated with constitutively active MERTK (e.g., human MERTK), or both. In another specific embodiment, the cancerous cells overexpress phosphorylated MERTK.

[0076] In specific embodiments of the methods of treating cancer, the method further comprises administering to the subject an additional therapeutic agent.

[0077] In specific embodiments of the embodiments in which the method further comprises administering an additional therapeutic agent to the subject, the additional therapeutic agent is for treating cancer. The additional therapeutic agent may be administered in the same pharmaceutical composition or in a different pharmaceutical composition other than the anti-MERTK antibody or antigen-binding fragment thereof, or antibody-drug conjugate.

[0078] In specific embodiments of the present invention, the additional therapeutic agent is a drug used to treat breast cancer, a drug used to treat melanoma, immunotherapy, or an angiogenesis inhibitor. In a further embodiment of this specific embodiment, the additional therapeutic agent is a drug used to treat breast cancer selected from the group consisting of tamoxifen, raloxifene, paclitaxel, cyclophosphamide, docetaxel, vinblastine, fluorouracil, everolimus, trastuzumab, trastuzumab-emtansine, pertuzumab, and lapatinib ditosylate. In another further embodiment of this specific embodiment, the additional therapeutic agent is a drug used to treat melanoma selected from the group consisting of a BRAF inhibitor, a MEK inhibitor, and dacarbazine. In another further embodiment of this specific embodiment, the additional therapeutic agent is a drug that blocks immune checkpoint signaling. In another further embodiment, the additional therapeutic agent is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. In another further embodiment of such specific embodiment, the additional therapeutic agent is an angiogenesis inhibitor selected from the group consisting of a VEGF inhibitor, a VEGFR2 inhibitor, sunitinib, and sorafenib.

[0079] In a specific embodiment of the method for treating cancer, the subject is a human. In a specific embodiment, provided herein is an antibody-drug conjugate comprising an antibody portion comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 105 and the VL comprises the amino acid sequence of SEQ ID NO: 106, and the antibody portion is linked to MMAE via an mc-vc-PABC linker. In another specific embodiment, provided herein is an antibody-drug conjugate comprising an antibody portion comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 105 and the VL comprises the amino acid sequence of SEQ ID NO: 106, and the antibody portion is linked to SN-38 via a CL2A linker.

[0080] In certain embodiments, the antibody-drug conjugate comprises an antibody portion that is an immunoglobulin, hi some embodiments, the antibody-drug conjugate comprises an antibody portion, the antibody portion is an immunoglobulin, and the immunoglobulin comprises a human constant region. 4. Brief description of the drawings [Brief explanation of the drawings]

[0081] [Figure 1] Determination of the dissociation rate (Kd) for humanized and chimeric anti-MERTK antibodies using surface plasmon resonance (SPR) measurements.

[0082] [Figure 2] Summary of protein purification for three humanized anti-MERTK antibodies (z10, z11 and z13) and a chimeric anti-MERTK antibody (xAb).

[0083] [Figure 3] Figure 3A. Flow cytometry analysis of the binding affinity of the z10 antibody to human MERTK expressed by melanoma cells. Figure 3B. SPR measurement of the binding of the z10 antibody to human extracellular MERTK.

[0084] [Figure 4] The z10 antibody specifically binds to human MERTK (Figure 4A), as measured in an affinity binding assay using ELISA. However, the z10 antibody does not bind to the extracellular domains of human Axl (Figure 4B), human Tyro3 (Figure 4C), or mouse MERTK (Figure 4D), as assessed in an affinity binding assay using ELISA. The extracellular domains of human MERTK, human Axl, and mouse MERTK were conjugated to the IgG Fc domain and used in ELISA.

[0085] [Figure 5A]The z10 antibody induces degradation of human MERTK in cancer cells (particularly SKMEL5 cells). SKMEL5 cells were incubated with various concentrations of z10 antibody for 24 hours (Figure 5A) or with 0.3 μg / mL of antibody for various periods (Figure 5B) before assessing the levels of human MERTK by Western blot analysis. [Figure 5B] The z10 antibody induces degradation of human MERTK in cancer cells (particularly SKMEL5 cells). SKMEL5 cells were incubated with various concentrations of z10 antibody for 24 hours (Figure 5A) or with 0.3 μg / mL of antibody for various periods (Figure 5B) before assessing the levels of human MERTK by Western blot analysis.

[0086] [Figure 6] The z10 antibody degrades human MERTK in differentiated human M2 macrophages in vitro. In vitro M2 macrophages were treated with 0.3 μg / mL of z10 antibody or control IgG, and the cells were incubated for various periods before assessing the levels of human MERTK by Western blot analysis. Figure 6A provides the results of the Western blot, and Figure 6B provides the relative quantification of human MERTK to tubulin.

[0087] [Figure 7] Degradation of human MERTK is mediated by internalization of human MERTK in SKMEL5 cells. SKMEL5 cells were incubated with control IgG or z10 antibody, both labeled with pHrodo, which is measurable only at low pH conditions upon uptake into lysosomes. Surface human MERTK was measured using a commercially available MERTK antibody. Figure 7A shows fluorescence over time, and Figure 7B is a representative image.

[0088] [Figure 8]The z10 antibody blocks Gas6-induced AKT phosphorylation in human cancer cells. SKMEL5 cells were incubated with 0.3 μl / mL of z10 antibody or control IgG for 2 hours, followed by incubation with 200 nM Gas6 for 10 minutes. Figure 8A shows the results of Western blot analysis, Figure 8B shows the amount of human MERTK relative to tubulin, and Figure 8C shows the amount of phosphorylated AKT relative to tubulin.

[0089] [Figure 9-1] The z10 antibody inhibits colony formation of human cancer cells. The figures show the reduction in the number of colonies observed after culturing 500 SKMEL5 cells for 12 days in the presence of 0.3 μg / mL or 1 μg / mL of z10 antibody, compared to the number of colonies observed when 500 SKMEL5 cells were cultured for 12 days with control IgG. Figure 9A shows colony formation of cancer cells after 12 days of incubation with 0.3 μg / mL of z10 antibody or control IgG antibody. Figure 9B shows colony formation of cancer cells after 12 days of incubation with 1 μg / mL of z10 antibody or control IgG antibody. Figure 9C shows the number of colonies formed after 12 days of incubation with 0.3 μg / mL of z10 antibody or control IgG antibody. Figure 9D shows the number of colonies formed after 12 days of incubation with 1 μg / mL of z10 antibody or control IgG antibody. [Figure 9-2]The z10 antibody inhibits colony formation of human cancer cells. The figures show the reduction in the number of colonies observed after culturing 500 SKMEL5 cells for 12 days in the presence of 0.3 μg / mL or 1 μg / mL of z10 antibody, compared to the number of colonies observed when 500 SKMEL5 cells were cultured for 12 days with control IgG. Figure 9A shows colony formation of cancer cells after 12 days of incubation with 0.3 μg / mL of z10 antibody or control IgG antibody. Figure 9B shows colony formation of cancer cells after 12 days of incubation with 1 μg / mL of z10 antibody or control IgG antibody. Figure 9C shows the number of colonies formed after 12 days of incubation with 0.3 μg / mL of z10 antibody or control IgG antibody. Figure 9D shows the number of colonies formed after 12 days of incubation with 1 μg / mL of z10 antibody or control IgG antibody.

[0090] [Figure 10] The z10 antibody induces cytokine responses in M2 macrophages and CD14+ monocytes.

[0091] [Figure 11] z10 inhibits cancer cell survival in vitro. 1,000 RPMI8226 multiple myeloma cells (Figure 11A) or 200 SKMEL5 melanoma cells (Figure 11B) were cultured in the presence of either IgG control or z10. On day 6 (RPMI8226) or day 4 (SKMel5), viability was assessed using the CellTiter-Glo 2.0 cell viability assay.

[0092] [Figure 12]Anti-tumor efficacy of naked antibody MDA-MB-231-LM2:z10. 50,000 MDA-MB-231-LM2 TNBC cells were injected into the tail vein of NSG mice. Treatment was initiated on the day of tumor cell inoculation, i.p., twice weekly for the duration of the study. Figure 12A shows lung colonization of MDA-MB-231 LM2 triple-negative breast cancer cells using IVIS imaging. Figure 12B quantifies lung colonization of MDA-MB-231 LM2 triple-negative breast cancer cells. * represents a p-value less than 0.05.

[0093] [Figure 13A] Figure 13A shows the structure of maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethylauristatin E (mc-vc-PABC-MMAE) conjugated to an antibody (Ab). Figure 13B shows the structure of SN-38 conjugated to an antibody (Ab) via a CL2 or CL2A linker. "Ab" represents antibody, which may be, by way of example and not limitation, z10 or control IgG. The CL2 linker has a cathepsin B cleavage site (where AA is phenylalanine-lysine, see Figure 13B), while the CL2A linker does not have a cathepsin B cleavage site (where AA is lysine, see Figure 13B). [Figure 13B] Figure 13A shows the structure of maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethylauristatin E (mc-vc-PABC-MMAE) conjugated to an antibody (Ab). Figure 13B shows the structure of SN-38 conjugated to an antibody (Ab) via a CL2 or CL2A linker. "Ab" represents antibody, which may be, by way of example and not limitation, z10 or control IgG. The CL2 linker has a cathepsin B cleavage site (where AA is phenylalanine-lysine, see Figure 13B), while the CL2A linker does not have a cathepsin B cleavage site (where AA is lysine, see Figure 13B).

[0094] [Figure 14A] Figures 14A and 14B show the results of size-exclusion high-pressure liquid chromatography measuring the purity of z10 conjugated to MMAE via an mc-vc-PABC linker (z10-MMAE, see Figure 13A, where the Ab is z10) (Figure 14A) and z10 conjugated to SN-38 via a CL2A linker (z10-SN-38, see Figure 13B, where the Ab is z10 and AA is lysine) (Figure 14B). [Figure 14B] Figures 14A and 14B show the results of size-exclusion high-pressure liquid chromatography measuring the purity of z10 conjugated to MMAE via an mc-vc-PABC linker (z10-MMAE, see Figure 13A, where the Ab is z10) (Figure 14A) and z10 conjugated to SN-38 via a CL2A linker (z10-SN-38, see Figure 13B, where the Ab is z10 and AA is lysine) (Figure 14B).

[0095] [Figure 15] The z10-ADC binds to MERTK with a Kd similar to that of z10. Figure 15 provides binding affinity data for the z10-ADC. hMER recombinant protein (Mer-Fc conjugate) (50 nM to 0.05 nM) was equilibrated with 0.3 nM of z10, z10-MMAE, or z10-SN-38, respectively, and then added to an ELISA plate pre-coated with hMER recombinant protein. Antibody binding was detected using an AP-conjugated anti-human IgG secondary antibody and developed using a GloMax microplate reader.

[0096] [Figure 16]Figures 16A and 16B show that MERTK is internalized by SKMel5 cells after incubation with z10, z10-MMAE, or z10-SN-38 (Figure 16A), and MERTK is degraded (Figure 16B). z10, z10-MMAE, and z10-SN-38 degrade MERTK to a similar extent. SKMel5 cells were incubated with 6.7 nM pHrodo-labeled z10, z10-MMAE, or z10-SN-38. pHrodo signals are only measurable under low pH conditions, e.g., upon uptake into lysosomes. Surface MERTK was stained with BV421-conjugated MERTK antibody. Binding was measured by flow cytometry.

[0097] [Figure 17-1] z10-MMAE and z10-SN-38 kill MERTK-expressing cancer cells. SKMel5 (FIG. 17A) or RPMI8226 (FIG. 17B) cells were incubated with an IgG control, an IgG control conjugated to MMAE via a mc-mv-PABC linker (IgG-MMAE, see FIG. 13A; Ab is IgG), or z10-MMAE for 7 days. Cell viability was measured using CellTiterGlo. SKMel5 (FIG. 17C) or RPMI8226 (FIG. 17D) cells were incubated with the indicated concentrations of an IgG control, an IgG control conjugated to SN-38 via a CL2A linker (IgG-SN-38, see FIG. 13B; Ab is IgG, AA is lysine), or z10-SN-38 for 7 days. Cell viability was measured using CellTiterGlo. FIG. 17E shows Western blot analysis of whole cell lysates prepared from SKMel5 or RPMI8226 cells. [Figure 17-2]z10-MMAE and z10-SN-38 kill MERTK-expressing cancer cells. SKMel5 (FIG. 17A) or RPMI8226 (FIG. 17B) cells were incubated with an IgG control, an IgG control conjugated to MMAE via a mc-mv-PABC linker (IgG-MMAE, see FIG. 13A; Ab is IgG), or z10-MMAE for 7 days. Cell viability was measured using CellTiterGlo. SKMel5 (FIG. 17C) or RPMI8226 (FIG. 17D) cells were incubated with the indicated concentrations of an IgG control, an IgG control conjugated to SN-38 via a CL2A linker (IgG-SN-38, see FIG. 13B; Ab is IgG, AA is lysine), or z10-SN-38 for 7 days. Cell viability was measured using CellTiterGlo. FIG. 17E shows Western blot analysis of whole cell lysates prepared from SKMel5 or RPMI8226 cells. [Figure 17-3] z10-MMAE and z10-SN-38 kill MERTK-expressing cancer cells. SKMel5 (FIG. 17A) or RPMI8226 (FIG. 17B) cells were incubated with an IgG control, an IgG control conjugated to MMAE via a mc-mv-PABC linker (IgG-MMAE, see FIG. 13A; Ab is IgG), or z10-MMAE for 7 days. Cell viability was measured using CellTiterGlo. SKMel5 (FIG. 17C) or RPMI8226 (FIG. 17D) cells were incubated with the indicated concentrations of an IgG control, an IgG control conjugated to SN-38 via a CL2A linker (IgG-SN-38, see FIG. 13B; Ab is IgG, AA is lysine), or z10-SN-38 for 7 days. Cell viability was measured using CellTiterGlo. FIG. 17E shows Western blot analysis of whole cell lysates prepared from SKMel5 or RPMI8226 cells.

[0098] [Figure 18]z10-MMAE inhibits lung colonization of MDA-MB-231-LM2 TNBC cells. Figure 18A shows lung colonization of MDA-MB-231-LM2 triple-negative breast cancer cells using IVIS imaging. Figure 18B quantifies lung colonization of MDA-MB-231-LM2 triple-negative breast cancer cells. 50,000 MDA-MB-231-LM2 TNBC cells were injected into the tail vein of NSG mice. Treatment began on the day of tumor cell inoculation, and lung metastatic colonization was monitored by bioluminescence imaging. The arrow in Figure 18B indicates the day of dosing. ** indicates a p-value less than 0.01.

[0099] [Figure 19] z10 / z10-ADC does not affect the viability of MERTK-expressing M1 macrophages (Figure 19A) or M2 macrophages (Figure 19B). M2 macrophages were differentiated by culturing 8 x 10 monocytes in PBMC medium with M-CSF (50 ng / mL) for 8 days. M1 macrophages were differentiated by culturing 8 x 10 monocytes in PBMC medium with GM-CSF (20 ng / mL) for 5 days, followed by culturing with GM-CSF (20 ng / mL), IFNg (20 ng / mL), IL-6 (20 ng / mL), and LPS (10 pg / mL) for an additional 3 days. M2 and M1 macrophages were treated with the indicated antibodies or ADCs in differentiation medium for 4 days, and viability was assessed using the CellTiter-Glo 2.0 cell viability assay. DETAILED DESCRIPTION OF THE INVENTION

[0100] 5. Detailed Description Provided herein are anti-MERTK antibodies (eg, monoclonal antibodies) and antigen-binding fragments thereof that specifically bind to MERTK (eg, human MERTK).

[0101] In certain embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein specifically recognize the extracellular domain of MERTK (e.g., human MERTK). In certain embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein do not bind to human Axl, human Tyro3, ​​or mouse MERTK, as detected by techniques known to those of skill in the art or described herein. In specific embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein do not bind to human Axl, human Tyro3, ​​or mouse MERTK, as assessed in an affinity binding assay using ELISA, as described in Section 6.2, below.

[0102] In a specific embodiment, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein specifically binds to a human MERTK protein comprising the amino acid sequence of SEQ ID NO: 131. In another specific embodiment, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein specifically binds to an extracellular region of human MERTK comprising the amino acid sequence of SEQ ID NO: 132. In another specific embodiment, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein specifically binds to SEQ ID NO: 132. In a specific embodiment, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein is bivalent. In a specific embodiment, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein comprises two antigen-binding sites that bind to MERTK (e.g., human MERTK). In certain embodiments, the two antigen-binding sites bind to the same epitope on MERTK (e.g., human MERTK). In certain embodiments, the two antigen-binding sites comprise identical CDRs.

[0103] In certain embodiments, the anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof has a K of about 1 pM to 10 nM, as determined using techniques known to those of skill in the art or described herein. DIn a specific embodiment, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein have a K of about 1 pM to about 6 pM, as determined using surface plasmon resonance (SPR) as described in Section 6 below. D In certain embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein have an EC of about 1 nM to 20 nM using assays described herein or known to those skilled in the art. 50 In certain embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein bind to MERTK (e.g., human MERTK) with a K of about 1 nM to 10 nM in the assay described in Section 6 below. D and binds to MERTK (e.g., human MERTK).

[0104] In certain embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antibody fragments thereof described herein have an EC of about 1 nM to 20 nM, as assessed, for example, by flow cytometry as described herein or known to one of skill in the art. 50 and bind to human MERTK-expressing cells (e.g., human MERTK cancer cells or M2 macrophages). In specific embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein have an EC of 1 nM to 10 nM, as assessed, for example, by flow cytometry as described in Section 6.2 below. 50 and binds to human MERTK-expressing cells (e.g., human MERTK cancer cells or M2 macrophages).

[0105] In certain embodiments, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein reduces the expression level of human MERTK in cancer cells, as assessed by an assay described herein (e.g., in Section 6.2 below) or known to one of skill in the art. In certain embodiments, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein reduces the expression level of human MERTK in the melanoma cell line SKMEL5, as assessed by an assay described herein (e.g., in Section 6.2 below) or known to one of skill in the art. In certain embodiments, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof reduces the expression level of human MERTK in human M2 macrophages, as assessed by an assay described herein (e.g., in Section 6.2 below) or known to one of skill in the art. In certain embodiments, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof reduces the expression level of human MERTK through MERTK internalization, as assessed by an assay described herein (e.g., in Section 6.2 below) or known to one of skill in the art. In certain embodiments, the anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof reduces the expression level of human MERTK by internalization into lysosomes, as assessed by an assay described herein (e.g., in Section 6.2 below) or an assay known to one of skill in the art.

[0106] In certain embodiments, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein reduces Gas-6-induced phosphorylation of AKT in human MERTK-expressing cells (e.g., cancer cells), as assessed by an assay described herein (e.g., in Section 6.2, below) or known to one of skill in the art. In specific embodiments, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein prevents Gas-6-induced phosphorylation of AKT in human MERTK-expressing cancer cells, such as melanoma SKMEL5 cells, as assessed by an assay described herein (e.g., in Section 6.2, below) or known to one of skill in the art. In certain embodiments, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein reduces Gas-6-induced phosphorylation of human MERTK in human MERTK-expressing cells, as assessed by an assay known to one of skill in the art. In a specific embodiment, the anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein blocks Gas6-induced MERTK activation in human MERTK-expressing cancer cells (e.g., melanoma cells, e.g., SKMEL5, etc.), as assessed by an assay known to one skilled in the art.

[0107] In certain embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments described herein reduce the colony-forming ability of cancer cells, as assessed by an assay described herein (e.g., in Section 6.2, below) or an assay known to one of skill in the art. In certain embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein inhibit colony formation of cancer cells (e.g., melanoma cells such as SKMEL5).

[0108] In certain embodiments, the anti-MERTK antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof described herein induce a cytokine response in M2 macrophages, CD14+ monocytes, or both, as assessed using assays described herein or known to one of skill in the art, e.g., as provided in FIG. 10.

[0109] In a specific embodiment, the anti-MERTK antibodies (eg, humanized antibodies) or antigen-binding fragments thereof described herein are isolated.

[0110] The antibodies described herein may include monoclonal or polyclonal antibodies. In specific embodiments, the antibody may be an immunoglobulin, a tetrameric antibody comprising two heavy chain molecules and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, a single domain antibody, a monovalent antibody, a single chain antibody, a single chain Fv (scFv), a disulfide-linked Fv (scFv), and an anti-idiotypic (anti-Id) antibody (including, for example, an anti-Id antibody).

[0111] In certain embodiments, the antibodies described herein may be multispecific or bispecific. In certain embodiments, the antibodies described herein are bispecific monoclonal antibodies. In certain embodiments, the antibodies described herein are monovalent. In specific embodiments, the antibodies described herein are bivalent. In certain embodiments, the antibodies described herein bind to human MERTK on cells. In some embodiments, the antibodies described herein are monospecific. In certain embodiments, the antibodies described herein are recombinantly produced. In some embodiments, the antibodies described herein are synthetic antibodies. In specific embodiments, the antibodies described herein are humanized antibodies. In other embodiments, the antibodies described herein may be human antibodies.

[0112] The antibodies described herein may be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG 2a or IgG 2b ). In certain embodiments, the antibodies described herein are IgG antibodies, or classes or subclasses thereof. In specific embodiments, the antibodies described herein (e.g., humanized antibodies) are monoclonal antibodies. In specific embodiments, the anti-MERTK antibodies described herein are IgG antibodies.

[0113] As used herein, the terms "antigen-binding fragment," "antigen-binding region," and similar terms refer to a portion of an antibody molecule comprising amino acid residues that confer its specificity for an antigen to the antibody molecule (e.g., complementarity-determining region (CDR)). The antigen-binding region may be derived from any animal species, including rodents (e.g., mice, rats, or hamsters) and humans. By way of example, antigen-binding fragments include Fab fragments, F(ab')2 fragments, and antigen-binding fragments of any of the antibodies described above. In a specific embodiment, the antigen-binding fragment of a humanized antibody comprises the variable heavy chain region, the variable light chain region, or both, of the z10, z11, or z13 antibody described herein.

[0114] As used herein, the terms "variable region" and "variable domain" are used interchangeably and are common in the art. A variable region typically refers to a portion of an antibody, generally a portion of the light or heavy chain, which generally differs significantly in sequence between antibodies and is used in the binding and specificity of a particular antibody to a particular antigen. The variability in sequence is concentrated in regions called complementarity-determining regions (CDRs), while the more highly conserved regions in the variable domain are called framework regions (FRs). Without wishing to be bound by a particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of an antibody with an antigen.

[0115] CDRs are defined in various ways in the art, including the Kabat, Chothia, AbM, contact, IMGT, and Exemplary definitions. The Kabat definition is based on sequence variability and is the most commonly used definition for predicting CDR regions (Kabat, Elvin A. et al., Sequences of Proteins of Immunological Interest. Bethesda: National Institutes of Health, 1983). The Chothia definition is based on the location of structural loop regions (Chothia et al., (1987) J Mol Biol 196: 901-917). The AbM definition, a compromise between the Kabat and Chothia definitions, is an integrated suite of programs for antibody structure modeling created by the Oxford Molecular Group (bioinf.org.uk / abs) (Martin ACR et al., (1989) PNAS 86: 9268-9272). The contact definition is based on the analysis of available complex crystal structures (bioinf.org.uk / abs) (see MacCallum RM et al., (1996) J Mol Biol 5: 732-745). The IMGT definition is from IMGT (IMGT®, the international ImMunoGeneTics information system® website imgt.org, Founder and Director: Marie-Paule Lefranc, Montpellier, France). The Exemplary definition is a combination of AbM and Kabat (Presta et al., (1997) Cancer Res 57: 4593-4599).

[0116] In a specific embodiment, the humanized antibody or antigen-binding fragment thereof described herein comprises a variable heavy chain region, a variable light chain region, or both, wherein the variable heavy chain region, the variable light chain region, or both, is the variable heavy chain region, the variable heavy chain region, or both, of the z10, z11, or z12 antibody, which are provided in Tables 11, 12, and 13, respectively. In another specific embodiment, the humanized antibody or antigen-binding fragment thereof described herein comprises a variable heavy chain region, a variable light chain region, or both, wherein the variable heavy chain comprises the amino acid sequence of the variable heavy chain region in Table 14, and the variable light chain region comprises the amino acid sequence of the variable light chain region in Tables 11, 12, or 13, below. In a specific embodiment, the humanized antibody is monoclonal. In some embodiments, the humanized antibody is an immunoglobulin, a tetrameric antibody comprising two heavy chain molecules and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, and an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, a single domain antibody, a single chain antibody, a single chain Fv, a disulfide-linked Fv, or an anti-idiotype antibody. Humanized antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA, or IgA2), or any subclass (e.g., IgG 2a or IgG 2b In a specific embodiment, the humanized antibodies described herein are IgG, or a class or subclass thereof.

[0117] The present application contemplates not only antibodies and antigen-binding fragments thereof comprising the sequences disclosed herein (e.g., CDRs, framework regions, variable regions), but also antibodies and antigen-binding fragments thereof that consist of or consist essentially of the sequences disclosed herein. For example, the antibody may consist of the light and heavy chain sequences of the z10, z11, or z13 antibodies described herein.

[0118] In specific embodiments, provided herein is a chimeric anti-MERTK antibody or antigen-binding fragment thereof comprising a variable heavy chain region, a variable light chain region, or both, wherein the variable light chain comprises the amino acid sequence of a variable light chain region in Table 15 below, and the variable heavy chain comprises the amino acid sequence of a variable heavy chain region in Table 15 below. In specific embodiments, the chimeric antibody is monoclonal. In some embodiments, the chimeric antibody is an immunoglobulin, a tetrameric antibody comprising two heavy chain molecules and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, a single domain antibody, a single chain antibody, a single chain Fv, a disulfide-linked Fv, or an anti-idiotype antibody. Chimeric antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA, or IgA2), or any subclass (e.g., IgG 2a or IgG 2b In certain embodiments, the chimeric antibodies described herein are IgG antibodies, or classes or subclasses thereof.

[0119] In another aspect, multispecific antibodies and heteroconjugate antibodies are provided herein. In a specific embodiment, a bispecific antibody is provided herein comprising two different antigen-binding regions, one of which binds to MERTK (e.g., human MERTK) and comprises the variable heavy chain region, variable light chain region, or both of an antibody described herein (e.g., z10, z11, z13, or xAb antibody), and the other binding region binds to an antigen of interest. In some embodiments, the bispecific antibody comprises two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other binding region binds to an antigen of interest, the binding region specifically binding to MERTK (e.g., human MERTK) comprising the variable heavy chain region and variable light chain region of the z10, z12, or z13 antibody described herein. In a specific embodiment, the antigen of interest is an immune cell receptor or a tumor-associated antigen. For more information on bispecific antibodies, see Section 5.1.3 below.

[0120] Also provided herein are heteroconjugate antibodies. In specific embodiments, the heteroconjugate antibody comprises two monoclonal antibodies with specificity for two different antigens, wherein one of the monoclonal antibodies comprises a variable heavy chain region and a variable light chain region described herein (e.g., a z10, z11, z13, or xAb antibody).

[0121] Also provided are isolated nucleic acids (polynucleotides), such as complementary DNAs (cDNAs), encoding the anti-MERTK antibodies and antigen-binding fragments thereof described herein. In certain embodiments, provided herein are polynucleotides comprising the nucleic acid sequence of the VH, VL, or both, of a z10, z11, z13, or xAb antibody set forth in Table 21, 22, 23, or 24. In some embodiments, provided herein are polynucleotides comprising the heavy chain, light chain, or both, of a z10, z11, z13, or xAb antibody set forth in Table 25, 26, 27, or 28.

[0122] Additionally, vectors (e.g., expression vectors) and cells (e.g., host cells) containing nucleic acids (polynucleotides) encoding the anti-MERTK antibodies or antigen-binding fragments thereof described herein are provided. Methods for producing such antibodies are also provided.

[0123] In another aspect, provided herein is an antibody-drug conjugate comprising: (a) an antibody moiety that is an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) described herein, (b) one or more drug moieties, each drug moiety being a cytotoxic agent, and (c) optionally a linker, wherein the cytotoxic agent is conjugated directly to the antibody moiety or via a linker. As used in this disclosure, the term "conjugated" is intended to mean covalently bonded, which may be directly or through an intervening covalent bond structure.

[0124] Nucleic acids encoding the antibody-drug conjugates are also provided when the cytotoxic agent is a peptide or protein, or when the cytotoxic agent and the linker, if present, are peptides or proteins. In another aspect, provided herein is a method of producing an antibody-drug conjugate comprising (i) an anti-MERTK antibody or antigen-binding fragment thereof, and (ii) a cytotoxic agent conjugated directly to the anti-MERTK antibody or antigen-binding fragment or conjugated to the anti-MERTK antibody or antigen-binding fragment via a linker.

[0125] In another aspect, provided herein is a composition (e.g., a pharmaceutical composition) comprising an anti-MERTK antibody or antigen-binding fragment thereof described herein. In a specific embodiment, the pharmaceutical composition comprises an anti-MERTK antibody or antigen-binding fragment thereof described herein, one or more pharmaceutically acceptable carriers, excipients, or both, and optionally one or more other therapeutic agents.

[0126] In another aspect, provided herein are compositions (e.g., pharmaceutical compositions) comprising the antibody-drug conjugates described herein. In specific embodiments, the pharmaceutical compositions comprise the antibody-drug conjugates described herein, one or more pharmaceutically acceptable carriers, excipients, or both, and, optionally, one or more other therapeutic agents.

[0127] In another aspect, provided herein is a method of treating cancer in a subject, comprising administering to the subject an effective amount of an anti-MERTK antibody or antigen-binding fragment thereof described herein, or a composition thereof. In specific embodiments, the anti-MERTK antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment described herein. In other embodiments, the anti-MERTK antibody or antigen-binding fragment thereof is a bispecific antibody or heteroconjugate antibody described herein. In some embodiments, the anti-MERTK antibody or antigen-binding fragment thereof is a chimeric antibody or antigen-binding fragment thereof.

[0128] In another aspect, provided herein is a method of treating cancer in a subject, comprising administering to the subject an effective amount of an antibody-drug conjugate described herein. In a specific embodiment, provided herein is a method of treating cancer in a subject, comprising administering to the subject an effective amount of an antibody-drug conjugate comprising: (i) an anti-MERTK antibody or antigen-binding fragment thereof, and (ii) a cytotoxic agent conjugated directly to the anti-MERTK antibody or antigen-binding fragment thereof or conjugated to the anti-MERTK antibody or antigen-binding fragment thereof via a linker. 5.1. Antibodies 5.1.1. Sequences and Variants

[0129] Tables 1, 7, and 8 below provide the VH CDRs and VL CDRs, respectively, of anti-MERTK antibodies or antigen-binding fragments thereof defined using different systems. Tables 2, 3, 4, 5, and 6 below provide VH framework regions defined using different systems that may be combined with the CDRs of Table 1. In specific embodiments, the CDRs of Table 1 are combined with VH framework region 3 of the consensus sequence, using one numbering system, along with VH framework regions 1, 2, and 4 using the same numbering system, as provided in Tables 2, 3, 4, or 6. Tables 9 and 10 below provide VL framework regions defined using different systems that may be combined with the CDRs of Table 7 or 8. Tables 11, 12, 13, and 15 provide the amino acid sequences of the VH and VL of particular antibodies. Table 14 provides the amino acid sequences of the VH that may be combined with the VL provided in Tables 11, 12, 13, or 15. Tables 16, 17, 18, and 20 provide amino acid sequences of the heavy and light chains of particular antibodies. Table 19 provides heavy chain amino acid sequences that may be combined with the light chain amino acid sequences of Tables 16, 17, or 18. Tables 21, 22, 23, and 24 provide nucleic acid sequences encoding the variable regions of particular antibodies. Tables 25, 26, 27, and 28 provide nucleic acid sequences encoding the heavy and light chains of particular antibodies. Tables 29 and 30 provide exemplary human MERTK amino acid sequences to which the anti-MERTK antibodies or antigen-binding fragments thereof described herein can bind.

[0130] In specific embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof provided herein comprise a VH CDR1 of an antibody in Table 1, as defined by Kabat, Chothia, AbM, Contact, IMGT, or Exemplary. In some embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof provided herein comprise a VH CDR2 of an antibody in Table 1, as defined by Kabat, Chothia, AbM, Contact, IMGT, or Exemplary. In some embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof provided herein comprise a VH CDR3 of an antibody in Table 1, as defined by Kabat, Chothia, AbM, Contact, IMGT, or Exemplary. In some embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof provided herein comprise one, two, or all three of the VH CDRs of an antibody in Table 1, as determined by a single numbering system.

[0131] In specific embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof provided herein comprise a VL CDR1 of an antibody in Table 7 as defined by Kabat, Chothia, AbM, Contact, IMGT, or Exemplary. In some embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof provided herein comprise a VL CDR2 of an antibody in Table 7 as defined by Kabat, Chothia, AbM, Contact, IMGT, or Exemplary. In some embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof provided herein comprise a VL CDR3 of an antibody in Table 7 as defined by Kabat, Chothia, AbM, Contact, IMGT, or Exemplary. In some embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof provided herein comprise one, two, or all three of the VL CDRs of an antibody in Table 7 as determined by a single numbering system.

[0132] [Table 1]

[0133]

Table 2-1

Table 2-2

[0134]

Table 3

[0135]

Table 4

[0136]

Table 5-1

Table 5-2

[0137]

Table 6

[0138]

Table 7-1

Table 7-2

[0139]

Table 8

[0140]

Table 9-1

Table 9-2

[0141]

Table 10

[0142]

Table 11-1

Table 11-2

[0143]

Table 12

[0144]

Table 13

[0145]

Table 14

[0146]

Table 15

[0147] Table 16

[0148] Table 17

[0149]

Table 18-1

Table 18-2

[0150]

Table 19

[0151] Table 20

[0152]

Table 21-1

Table 21-2

[0153] Table 22

[0154] Table 23

[0155]

Table 24-1

Table 24-2

[0156] Table 25

[0157]

Table 26-1

Table 26-2

[0158] Table 27

[0159] Table 28

[0160]

Table 29-1

Table 29-2

[0161] In a specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable heavy region (VH) CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the Exemplary numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the Exemplary numbering system. In another specific embodiment, provided herein is an anti-MERTK or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable heavy region (VH) CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the Kabat numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the Kabat numbering system.In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable heavy region (VH) CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the Chothia numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the Chothia numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable heavy region (VH) CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the AbM numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the AbM numbering system.In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable heavy region (VH) CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the Contact numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the Contact numbering system. In another specific embodiment, the present specification provides an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment comprises a framework region (FR) 1, a variable heavy chain region (VH) CDR1, FR2, a VH CDR2, FR3, a VH. and FR1, FR2, FR3 and FR4, wherein VH CDR1, VH CDR2 and VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 shown in Table 1 using the IMGT numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 shown in Table 2, 3, 4 or 5 using the IMGT numbering system.

[0162] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable heavy region (VH) CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using one numbering system, FR1, FR2 and FR4 comprise the amino acid sequences of FR1, FR2 and FR4 set forth in Table 2, 3 or 4 using the same numbering system, and FR3 comprises the amino acid sequence of FR3 set forth in Table 5 using the same numbering system.

[0163] In a specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH), wherein the VH comprises framework region (FR) 1, VH CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the Exemplary numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the Exemplary numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH), wherein the VH comprises framework region (FR) 1, VH CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein the VH CDR1, VH CDR2, VH CDR3 are as set forth in Table 1 using the Kabat numbering system. and FR3, wherein FR1, FR2, FR3, and FR4 comprise the amino acid sequences of FR1, FR2, FR3, and FR4 set forth in Table 2, 3, 4, or 5 using the Kabat numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH), wherein the VH comprises framework region (FR) 1, VH CDR1, FR2, VH CDR2, FR3, VH CDR3, and FR4, wherein VH CDR1, VH CDR2, VH CDR3 are set forth in Table 1 using the Chothia numbering system. An anti-MERTK antibody or antigen-binding fragment thereof is provided, comprising the amino acid sequence of CDR3, wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 shown in Table 2, 3, 4 or 5 using the Chothia numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH), wherein the VH comprises framework region (FR) 1, VH CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the AbM numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the AbM numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH), wherein the VH comprises framework region (FR) 1, VH CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the Contact numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the Contact numbering system.In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH), wherein the VH comprises framework region (FR) 1, VH CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the IMGT numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 2, 3, 4 or 5 using the IMGT numbering system.

[0164] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH), wherein the VH comprises framework region (FR) 1, VH CDR1, FR2, VH CDR2, FR3, VH CDR3 and FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using one numbering system, wherein FR1, FR2 and FR4 comprise the amino acid sequences of FR1, FR2 and FR4 set forth in Table 2, 3 or 4 using the same numbering system, and wherein FR3 comprises the amino acid sequence of FR3 set forth in Table 5 using the same numbering system.

[0165] In a specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 shown in Table 7 using the Exemplary numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 shown in Table 9 using the Exemplary numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable light chain region (VL) CDR1, FR2, a VL CDR2, FR3, a VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 are as set forth in Table 7 using the Kabat numbering system. Provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable light region (VL) CDR1, FR2, a VL CDR2, FR3, a VL CDR3 and FR4, and wherein the VL CDR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 as set forth in Table 9 using the Kabat numbering system. Provided herein is an anti-MERTK antibody or antigen-binding fragment thereof, wherein CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 set forth in Table 7 using the Chothia numbering system, and FR1, FR2, FR3, and FR4 comprise the amino acid sequences of FR1, FR2, FR3, and FR4 set forth in Table 9 using the Chothia numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises framework region (FR) 1, variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3, and FR4, and VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR3 set forth in Table 7 using the AbM numbering system. An anti-MERTK antibody or antigen-binding fragment thereof is provided, comprising the amino acid sequences of CDR2 and VL CDR3, and FR1, FR2, FR3 and FR4, wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 shown in Table 9 using the AbM numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 set forth in Table 7 using the Contact numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 9 using the Contact numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a framework region (FR) 1, a variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 set forth in Table 7 using the IMGT numbering system, and FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 9 using the IMGT numbering system.

[0166] In a specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region (VL), wherein the VL comprises framework region (FR) 1, variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 shown in Table 7 using the Exemplary numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 shown in Table 9 using the Exemplary numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region (VL), the VL comprising framework regions (FR) 1, variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL The present invention provides an anti-MERTK antibody or antigen-binding fragment thereof, wherein the antibody comprises VL CDR1, VL CDR2, and VL CDR3, and FR4, wherein VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 shown in Table 7 using the Kabat numbering system, and FR1, FR2, FR3, and FR4 comprise the amino acid sequences of FR1, FR2, FR3, and FR4 shown in Table 9 using the Kabat numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region (VL), wherein the VL comprises framework region (FR) 1, variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 set forth in Table 7 using the Chothia numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 9 using the Chothia numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region (VL), wherein the VL comprises framework region (FR) 1, variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 set forth in Table 7 using the AbM numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 9 using the AbM numbering system.In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region (VL), wherein the VL comprises framework region (FR) 1, variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 set forth in Table 7 using the Contact numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 9 using the Contact numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region (VL), wherein the VL comprises framework region (FR) 1, variable light chain region (VL) CDR1, FR2, VL CDR2, FR3, VL CDR3 and FR4, wherein VL CDR1, VL CDR2, VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 set forth in Table 7 using the IGMT numbering system, and wherein FR1, FR2, FR3 and FR4 comprise the amino acid sequences of FR1, FR2, FR3 and FR4 set forth in Table 9 using the IMGT numbering system.

[0167] In a specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH framework region (FR) 1, a VH CDR1, a VH FR2, a VH CDR2, a VH FR3, a VH CDR3 and a VH FR4, and the VL comprises a VL FR1, a VL CDR2, a VL CDR3 and a VL FR4. CDR1、VL FR2、VL CDR2、VL FR3、VL CDR3およびVL VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 set forth in Table 1 using the exemplary numbering system; VH FR1, VH FR2, VH FR3, and VH FR4 comprise the amino acid sequences of VH FR1, VH FR2, VH FR3, and VH FR4 set forth in Tables 2, 3, 4, or 5 using the exemplary numbering system; VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 set forth in Table 7 using the exemplary numbering system; and VL FR1, VL FR2, VL FR3, and VL FR4 set forth in Table 9 using the exemplary numbering system. An anti-MERTK antibody or an antigen-binding fragment thereof is provided, which comprises the amino acid sequence of FR4. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH framework region (FR) 1, VH CDR1, VH FR2, VH CDR2, VH FR3, VH CDR3 and VH FR4, wherein the VL comprises VL FR1, VL CDR1, VL FR2, VL CDR2, VL FR3, VL CDR3 and VL FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the Kabat numbering system, and wherein the VH FR1, VH FR2, VH FR3 and VH wherein FR4 comprises the amino acid sequences of VH FR1, VH FR2, VH FR3 and VH FR4 set forth in Table 2, 3, 4 or 5 using the Kabat numbering system; VL CDR1, VL CDR2 and VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 set forth in Table 7 using the Kabat numbering system; VL FR1, VL FR2, VL FR3 and VL FR4 are shown in Table 9 using the Kabat numbering system. An anti-MERTK antibody or an antigen-binding fragment thereof is provided, which comprises the amino acid sequence of FR4. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH framework region (FR) 1, VH CDR1, VH FR2, VH CDR2, VH FR3, VH CDR3 and VH FR4, wherein the VL comprises VL FR1, VL CDR1, VL FR2, VL CDR2, VL FR3, VL CDR3 and VL FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the Chothia numbering system, and wherein the VH FR1, VH FR2, VH FR3 and VH The present invention provides an anti-MERTK antibody or antigen-binding fragment thereof, wherein VH CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of VH FR1, VH FR2, VH FR3, and VH FR4 set forth in Table 2, 3, 4, or 5 using the Chothia numbering system; VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 set forth in Table 7 using the Chothia numbering system; and VL FR1, VL FR2, VL FR3, and VL FR4 comprise the amino acid sequences of VL FR1, VL FR2, VL FR3, and VL FR4 set forth in Table 9 using the Chothia numbering system.In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH framework region (FR) 1, VH CDR1, VH FR2, VH CDR2, VH FR3, VH CDR3, and VH FR4, wherein the VL comprises VL FR1, VL CDR1, VL FR2, VL CDR2, VL FR3, VL CDR3, and VL FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 set forth in Table 1 using the AbM numbering system, and wherein the VH FR1, VH FR2, VH FR3, and VH VL CDR1, VL FR4 comprises the amino acid sequences of VH FR1, VH FR2, VH FR3 and VH FR4 shown in Table 2, 3, 4 or 5 using the AbM numbering system, and VL CDR1, VL CDR2 and VL CDR3 are shown in Table 7 using the AbM numbering system. An anti-MERTK antibody or antigen-binding fragment thereof is provided, wherein the antibody comprises the amino acid sequences of VL CDR2 and VL CDR3, and VL FR1, VL FR2, VL FR3 and VL FR4 set forth in Table 9 using the AbM numbering system. In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH framework region (FR) 1, VH CDR1, VH FR2, VH CDR2, VH FR3, VH CDR3, and VH FR4, wherein the VL comprises VL FR1, VL CDR1, VL FR2, VL CDR2, VL FR3, VL CDR3, and VL FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 set forth in Table 1 using the Contact numbering system, and wherein the VH FR1, VH FR2, VH FR3, and VH The present invention provides an anti-MERTK antibody or antigen-binding fragment thereof, wherein VH CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of VH FR1, VH FR2, VH FR3, and VH FR4 set forth in Table 2, 3, 4, or 5 using the Contact numbering system; VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 set forth in Table 7 using the Contact numbering system; and VL FR1, VL FR2, VL FR3, and VL FR4 comprise the amino acid sequences of VL FR1, VL FR2, VL FR3, and VL FR4 set forth in Table 9 using the Contact numbering system.In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH framework region (FR) 1, VH CDR1, VH FR2, VH CDR2, VH FR3, VH CDR3 and VH FR4, wherein the VL comprises VL FR1, VL CDR1, VL FR2, VL CDR2, VL FR3, VL CDR3 and VL FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using the IMGT numbering system, and wherein the VH FR1, VH FR2, VH FR3 and VH wherein VH FR1, VH FR2, VH FR3 and VH FR4 comprise the amino acid sequences of VH FR1, VH FR2, VH FR3 and VH FR4 set forth in Table 2, 3, 4 or 5 using the IMGT numbering system, and VL CDR1, VL CDR2 and VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 set forth in Table 7 using the IMGT numbering system, and VL FR1, VL FR2, VL FR3 and VL. FR4 is VL FR1, VL The present invention provides an anti-MERTK antibody or antigen-binding fragment thereof, comprising the amino acid sequences of VL FR2, VL FR3 and VL FR4.

[0168] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH framework region (FR) 1, VH CDR1, VH FR2, VH CDR2, VH FR3, VH CDR3 and VH FR4, wherein the VL comprises VL FR1, VL CDR1, VL FR2, VL CDR2, VL FR3, VL CDR3 and VL FR4, wherein the VH CDR1, VH CDR2, VH CDR3 comprise the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3 set forth in Table 1 using one numbering system, and wherein the VH FR1, VH FR2, VH FR3 and VH and VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 set forth in Table 7 using the same numbering system, and VL FR1, VL FR2, VL FR3, and VL FR4 comprise the amino acid sequences of VL FR1, VL FR2, VL FR3, and VL FR4 set forth in Table 9 using the same numbering system.

[0169] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), and wherein the VH An anti-MERTK antibody or antigen-binding fragment thereof is provided, wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 1, VH CDR2 comprises the amino acid sequence of SEQ ID NO: 6, VH CDR3 comprises the amino acid sequence of SEQ ID NO: 11, VL CDR1 comprises the amino acid sequence of SEQ ID NO: 68, VL CDR2 comprises the amino acid sequence of SEQ ID NO: 69, and VL CDR3 comprises the amino acid sequence of SEQ ID NO: 70.

[0170] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), and wherein the VH An anti-MERTK antibody or antigen-binding fragment thereof is provided, wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 2, VH CDR2 comprises the amino acid sequence of SEQ ID NO: 7, VH CDR3 comprises the amino acid sequence of SEQ ID NO: 12, VL CDR1 comprises the amino acid sequence of SEQ ID NO: 71, VL CDR2 comprises the amino acid sequence of SEQ ID NO: 72, and VL CDR3 comprises the amino acid sequence of SEQ ID NO: 73.

[0171] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), and wherein the VH An anti-MERTK antibody or antigen-binding fragment thereof is provided, wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 3, VH CDR2 comprises the amino acid sequence of SEQ ID NO: 8, VH CDR3 comprises the amino acid sequence of SEQ ID NO: 11, VL CDR1 comprises the amino acid sequence of SEQ ID NO: 68, VL CDR2 comprises the amino acid sequence of SEQ ID NO: 69, and VL CDR3 comprises the amino acid sequence of SEQ ID NO: 70.

[0172] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), and wherein the VH An anti-MERTK antibody or antigen-binding fragment thereof is provided, wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 4, VH CDR2 comprises the amino acid sequence of SEQ ID NO: 9, VH CDR3 comprises the amino acid sequence of SEQ ID NO: 13, VL CDR1 comprises the amino acid sequence of SEQ ID NO: 74, VL CDR2 comprises the amino acid sequence of SEQ ID NO: 75, and VL CDR3 comprises the amino acid sequence of SEQ ID NO: 76.

[0173] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), and wherein the VH An anti-MERTK antibody or antigen-binding fragment thereof is provided, wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 5, VH CDR2 comprises the amino acid sequence of SEQ ID NO: 10, VH CDR3 comprises the amino acid sequence of SEQ ID NO: 14, VL CDR1 comprises the amino acid sequence of SEQ ID NO: 77, VL CDR2 comprises the amino acid sequence of SEQ ID NO: 72, and VL CDR3 comprises the amino acid sequence of SEQ ID NO: 70.

[0174] In another specific embodiment, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), and wherein the VH An anti-MERTK antibody or antigen-binding fragment thereof is provided, wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 3, VH CDR2 comprises the amino acid sequence of SEQ ID NO: 6, VH CDR3 comprises the amino acid sequence of SEQ ID NO: 11, VL CDR1 comprises the amino acid sequence of SEQ ID NO: 68, VL CDR2 comprises the amino acid sequence of SEQ ID NO: 69, and VL CDR3 comprises the amino acid sequence of SEQ ID NO: 70.

[0175] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 105. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 107. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 108. In another specific embodiment, a humanized anti-MERTK or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 109.

[0176] In certain embodiments, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 110.

[0177] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 106. In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a variable light chain region (VL) comprising the amino acid sequence of SEQ ID NO: 111.

[0178] In a specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 105 and the VL comprises the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 107 and the VL comprises the amino acid sequence of SEQ ID NO: 106. In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 108 and the VL comprises the amino acid sequence of SEQ ID NO: 106. In another embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 110 and the VL comprises the amino acid sequence of SEQ ID NO: 111.

[0179] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 109 and the VL comprises the amino acid sequence of SEQ ID NO: 106 or 111.

[0180] In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of VH shown in Table 11, and the VL comprises the amino acid sequence of VL shown in Table 11. In another specific embodiment, a humanized anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of VH shown in Table 12, and the VL comprises the amino acid sequence of VL shown in Table 12. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of VH shown in Table 13, and the VL comprises the amino acid sequence of VL shown in Table 13. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of VH shown in Table 14, and the VL comprises the amino acid sequence of VL shown in Table 11, 12, or 13.

[0181] In certain embodiments, the antibodies described herein may be described by their VH domain alone or their VL domain alone. For example, see Rader, incorporated herein by reference in its entirety, which describes that humanization of a murine anti-αvβ3 antibody by identifying complementary light or heavy chains from a library of human light or heavy chains, respectively, results in humanized antibody variants with high affinity or higher affinity than that of the original antibody. See C et al., (1998) PNAS 95: 8910-8915. Clackson T et al., (1991) Nature 8:111-114, which is incorporated herein by reference in its entirety, describes a method for producing antibodies that bind to a specific antigen by using a complementary variable domain (VL domain) and screening a library for complementary variable domains. 352: 624-628. Kim SJ & Hong HJ, (2007), which is incorporated herein by reference in its entirety, describe a method for producing antibodies that bind to a specific antigen by screening a library (e.g., a human VL library) for VH domains, which selected VL domains can then be used to guide the selection of additional complementary (e.g., human) VH domains. See also J Microbiol 45: 572-577.

[0182] As used herein, the terms "immunospecifically bind," "immunospecifically recognize," "specifically bind," and "specifically recognize" are similar terms in the context of antibodies, as understood by those skilled in the art, and refer to antibodies and antigen-binding fragments thereof that bind to an antigen (e.g., an epitope or immune complex) via an antigen-binding site, and do not exclude cross-reactivity of the antibody or antigen-binding fragment with other antigens. Any method known in the art can be used to determine whether immunospecific binding to MERTK (e.g., human MERTK) is maintained.

[0183] In a specific aspect, provided herein is an anti-MERTK antibody or antigen-binding fragment thereof comprising a heavy chain and / or a light chain of the antibody, for example, a heavy chain alone, a light chain alone, or both a heavy chain and a light chain. With respect to the light chain, in a specific embodiment, the light chain of the anti-MERTK antibody or antigen-binding fragment thereof described herein is a kappa light chain. In another specific embodiment, the light chain of the anti-MERTK antibody or antigen-binding fragment thereof described herein is a lambda light chain. In yet another specific embodiment, the light chain of the anti-MERTK antibody or antigen-binding fragment thereof described herein is a human kappa light chain or a human lambda light chain.

[0184] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a light chain, wherein the light chain comprises the amino acid sequence of a variable light region (VL) and a kappa light chain constant region, wherein the VL comprises the amino acid sequence of SEQ ID NO: 106 or SEQ ID NO: 111. As used herein, the terms "constant region" or "constant domain" are interchangeable and have their common meaning in the art. The constant region is the part of an antibody, e.g., the carboxyl-terminal portion of the light chain and / or heavy chain, that is not directly involved in binding the antibody to an antigen but may exhibit various effector functions, such as interaction with Fc receptors. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence than the immunoglobulin variable domain.

[0185] In a specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a light chain, wherein the light chain comprises a variable light region (VL) and a human kappa or lambda light chain constant region, wherein the VL comprises the amino acid sequence of SEQ ID NO: 106 or SEQ ID NO: 111. Non-limiting examples of human constant region sequences are described in the art, see, e.g., Kabat EA et al., (1991). I want to be done that.

[0186] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a light chain, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 113 or SEQ ID NO: 118.

[0187] With respect to the heavy chain, in specific embodiments, the heavy chain of the anti-MERTK antibody or antigen-binding fragment thereof described herein may be a human alpha (α), delta (δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In specific embodiments, the anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain, wherein the heavy chain comprises a constant region or portion thereof (e.g., C) described herein or known in the art. H 1. C H 2 or C H 3, or a combination thereof), and the variable heavy chain region (VH) of an anti-MERTK antibody described herein (e.g., SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 108, 109 or SEQ ID NO: 110).

[0188] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain, wherein the heavy chain comprises a variable heavy chain region (VH) of an anti-MERTK antibody described herein (e.g., SEQ ID NOs: 105, 107, 108, 109, or 110) and a constant region or portion thereof (e.g., C H 1. C H 2 or C H 3, or a combination thereof). In a specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequence of SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, or SEQ ID NO: 117. Non-limiting examples of human constant region sequences have been described in the art, see, e.g., Kabat EA et al., (1991), supra.

[0189] In specific embodiments, an anti-MERTK antibody described herein that specifically binds to MERTK (e.g., human MERTK) comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, and (ii) a light chain comprising the amino acids of SEQ ID NO: 113. In specific embodiments, an anti-MERTK antibody described herein that specifically binds to MERTK (e.g., human MERTK) comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114, and (ii) a light chain comprising the amino acids of SEQ ID NO: 113. In specific embodiments, an anti-MERTK antibody described herein that specifically binds to MERTK (e.g., human MERTK) comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 115, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 113. In specific embodiments, an anti-MERTK antibody described herein that specifically binds to MERTK (e.g., human MERTK) comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 116, and (ii) a light chain comprising the amino acids of SEQ ID NO: 113. In a specific embodiment, an anti-MERTK antibody described herein that specifically binds to MERTK (e.g., human MERTK) comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 117, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 118.

[0190] In a specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein that immunospecifically binds to MERTK (e.g., human MERTK) comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising any amino acid sequence described herein, and the constant region comprises an amino acid sequence of a constant region of a human IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein that immunospecifically binds to MERTK (e.g., human MERTK) comprises a VH and a VL comprising any amino acid sequence described herein, and the constant region comprises an amino acid sequence of a human IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class of immunoglobulin molecule (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (e.g., IgG 2a and IgG2b ) (e.g., those shown in Tables 11, 12, 13, or 15).

[0191] In certain embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an anti-MERTK antibody or antigen-binding fragment thereof described herein to alter one or more functional properties of the antibody.

[0192] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are present in the Fc region (e.g., C as numbered according to the Kabat numbering system (e.g., EU index of Kabat)) of an anti-MERTK antibody or antigen-binding fragment thereof described herein. H 2 domain (residues 231-340 of human IgG1) and / or C H 3 domain (residues 341-447 of human IgG1) and / or hinge region) to increase or decrease the affinity of the antibody or its antigen-binding fragment for an Fc receptor (e.g., an activating Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an anti-MERTK antibody or its antigen-binding fragment that decrease or increase the affinity of the antibody for an Fc receptor, and techniques for introducing such mutations into an Fc receptor or its fragment, are known to those skilled in the art. Examples of mutations in the Fc receptor of an anti-MERTK antibody or its antigen-binding fragment that can change the affinity of the antibody or its antigen-binding fragment for an Fc receptor are described, for example, in Smith P et al., (2012) PNAS 109: 6181-6186, U.S. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.

[0193] In some embodiments, the antibodies or antigen-binding fragments thereof described herein comprise a glycosylated constant region. In some embodiments, the antibodies or antigen-binding fragments thereof described herein comprise an unglycosylated constant region. Antibodies with reduced fucose content have been reported to have increased affinity for Fc receptors, such as FcγRIIIa. Thus, in certain embodiments, the antibodies or antigen-binding fragments thereof described herein have reduced or no fucose content. Such antibodies or antigen-binding fragments thereof can be produced using techniques known to those skilled in the art. For example, antibodies or antigen-binding fragments thereof can be expressed in cells that have insufficient or no fucosylation capacity. In a specific example, a cell line with knockout of both alleles of α1,6-fucosyltransferase can be used to produce antibodies or antigen-binding fragments thereof with reduced fucose content. The Potelligent® system (Lonza) is an example of such a system that can be used to produce antibodies or antigen-binding fragments thereof with reduced fucose content. Alternatively, antibodies or antigen-binding fragments with reduced or no fucose content can be produced, for example, by (i) culturing cells under conditions that prevent or reduce fucosylation; (ii) post-translational removal of fucose (e.g., using a fucosidase enzyme); (iii) post-translational addition of a desired carbohydrate, for example, after recombinant expression of a non-glycosylated glycoprotein; or (iv) purification of the glycoprotein to select for non-fucosylated antibodies or antigen-binding fragments thereof. For methods of producing antibodies or antigen-binding fragments thereof with reduced or no fucose content, see, for example, Longmore GD & Schachter H (1982) Carbohydr Res 100: 365-92 and Imai-Nishiya H et al., (2007) BMC Biotechnol. 7: 84.

[0194] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain or a light chain, wherein (i) the heavy chain comprises (a) a variable region comprising the amino acid sequence of SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 108 or SEQ ID NO: 109, and (b) a constant heavy chain domain comprising the amino acid sequence of the constant domain of human IgG; or (ii) the light chain comprises (a) a variable region comprising the amino acid sequence of SEQ ID NO: 106, and (b) a constant light chain domain comprising the amino acid sequence of the constant domain of a human light chain.

[0195] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises (a) a variable region comprising the amino acid sequence of SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 108 or SEQ ID NO: 109, and (b) a constant heavy chain domain comprising the amino acid sequence of the constant domain of human IgG; and (ii) the light chain comprises a variable region comprising the amino acid sequence of SEQ ID NO: 106, and (b) a constant light chain domain comprising the amino acid sequence of the constant domain of human kappa light chain.

[0196] In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain or a light chain, wherein (i) the heavy chain comprises (a) a variable region comprising the amino acid sequence of SEQ ID NO: 110, and (b) a constant heavy chain domain comprising the amino acid sequence of the constant domain of human IgG; or (ii) the heavy chain comprises (a) a variable region comprising the amino acid sequence of SEQ ID NO: 111, and (b) a constant light chain domain comprising the amino acid sequence of the constant domain of human kappa light chain. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises (a) a variable region comprising the amino acid sequence of SEQ ID NO: 110, and (b) a constant heavy chain domain comprising the amino acid sequence of the constant domain of human IgG; and (ii) the light chain comprises (a) a variable region comprising the amino acid sequence of SEQ ID NO: 111, and (b) a constant light chain domain comprising the amino acid sequence of the constant domain of human kappa light chain.

[0197] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can also be accomplished using a mathematical algorithm. A specific, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87: 2264-2268, as modified in Karlin S & Altschul SF (1993) PNAS 90: 5873-5877. Such an algorithm is exemplified by the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215: 403. The program is incorporated into the BLAST nucleotide search program. BLAST nucleotide searches can be performed, for example, using the parameters of the NBLAST nucleotide program set to a score of 100 and a word length of 12 to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed, for example, using the parameters of the XBLAST program set to a score of 50 and a word length of 3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, gapped BLAST can be used as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402. Alternatively, PSI BLAST can be used to perform an iterative search that detects distant relationships between molecules (see above). When using BLAST, gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used (see, for example, the National Center for Biotechnology Information (NCBI) on the World Wide Web at ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for comparing sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11 17. Such an algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When utilizing the ALIGN program to compare amino acid sequences, a weight residual table of PAM120, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0198] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0199] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises a VH having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of the VH of SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 108, or SEQ ID NO: 109. In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof comprises a VH having at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of the VH of SEQ ID NO: 110.

[0200] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that immunospecifically binds to MERTK (e.g., human MERTK) comprises a VL having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of the VL of SEQ ID NO: 106. In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof comprises a VL having at least 99% sequence identity to the VH of SEQ ID NO: 111.

[0201] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises (i) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of the VH domain of SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 108, or SEQ ID NO: 109; and (ii) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity with the amino acid sequence of the VL domain of SEQ ID NO: 106.

[0202] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) comprises (i) a VH domain having at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the VH domain of SEQ ID NO: 110, and (ii) a VL domain having at least 99% sequence identity with the VL domain of SEQ ID NO: 111.

[0203] In another aspect, the present invention provides antibodies that bind to the same or overlapping epitopes of MERTK (e.g., human MERTK) as the antibodies described herein. As used herein, "epitope" is a term used in the art and refers to a localized region of an antigen to which an antibody can specifically bind. An epitope can be, for example, contiguous amino acids of a polypeptide (linear or contiguous epitope), or an epitope can be, for example, comprised of two or more non-contiguous regions of a polypeptide(s) (conformational, non-linear, discontinuous, or non-contiguous epitope). In certain embodiments, the epitope of an antibody can be determined by, for example, NMR spectroscopy, X-ray diffraction crystallography, ELISA assay, hydrogen / deuterium exchange combined with mass spectrometry (e.g., MALDI mass spectrometry), array-based oligopeptide scanning assay, and / or mutagenesis mapping (e.g., site-directed mutagenesis mapping). For X-ray crystallography, crystallization can be achieved using any method known in the art (e.g., Giege R et al., (1994) Acta Crystallogr D Biol Crystallogr 50(Pt 4): 339-350; McPherson A (1990) Eur J Biochem 189: 1-23; Chayen NE (1997) Structure 5: 1269-1274; McPherson A (1976) J Biol Chem 251: 6300-6303).Antibody:antigen crystals may be studied using well-known X-ray diffraction techniques and refined using computer software such as X-PLOR (Yale University, 1992, distributed by Molecular Simulations, Inc.; see, e.g., Meth Enzymol (1985) volumes 114 & 115, eds. Wyckoff HW et al.; U.S. Patent Application No. 2004 / 0014194), and BUSTER (Bricogne G (1993) Acta Crystallogr D Biol Crystallogr 49(Pt 1): 37-60; Bricogne G (1997) Meth Enzymol 276A: 361-423, ed. Carter CW; Roversi P et al., (2000) Acta Crystallogr D Biol Crystallogr 56(Pt 10): 1316-1323). Mutagenesis mapping studies may be accomplished using any method known to those skilled in the art. For example, for a description of mutagenesis techniques, including alanine scanning mutagenesis techniques, see Champe M et al., (1995) and Cunningham BC & Wells JA (1989). In addition, antibodies that recognize and bind to the same or overlapping epitopes of MERTK (e.g., human MERTK) can be identified using routine techniques such as immunoassays, for example, by demonstrating the ability of one antibody to block the binding of another antibody to a target antigen, i.e., competitive binding assays. Competitive binding assays can also be used to determine whether two antibodies have similar binding specificities for an epitope. Competitive binding can be determined in an assay in which the immunoglobulin under test inhibits the specific binding of a reference antibody to a common antigen, such as MERTK. There are many types of competitive binding assays, such as solid-phase direct or indirect radioimmunoassays (RIA), solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competition assays (Stahli C et al., (1983) Methods Enzymol. 9:242-253); solid-phase direct biotin-avidin EIA (Kirkland TN et al., (1986) J Immunol 137: 3614-9); solid-phase direct labeling assay, solid-phase direct labeling sandwich assay (see Harlow E & Lane D, (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Press); solid-phase direct labeling RIA using I-125 label (see Morel GA et al., (1988) Mol Immunol 25(1): 7-15); solid-phase direct biotin-avidin EIA (Cheung RC et al., (1990) Virology 176: 546-52); and direct labeling RIA (Moldenhauer G et al., (1990) Scand J Immunol 32: 77-82). Typically, such assays involve the use of purified antigen (e.g., MERTK (e.g., human MERTK)) or cells bearing either of these bound to a solid surface, an unlabeled test immunoglobulin, and a labeled reference immunoglobulin. Competitive inhibition can be measured by determining the amount of label bound to the solid surface or cells in the presence of the test immunoglobulin. The test immunoglobulin is usually present in excess. Typically, when a competing antibody is present in excess, it inhibits specific binding of the reference antibody to the common antigen by at least 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, or more. Competitive binding assays can be configured in a number of different formats, using either labeled antigen or labeled antibody. In a common version of this assay, the antigen is immobilized on a 96-well plate. The ability of unlabeled antibodies to block the binding of the labeled antibody to the antigen is then measured using radioactive or enzyme labels.For further details, see, e.g., Wagener C et al., (1983) J Immunol 130: 2308-2315; Wagener C et al., (1984) J Immunol Methods 68: 269-274; Kuroki M et al., (1990) Cancer Res 50: 4872-4879; Kuroki M et al., (1992) Immunol Invest 21: 523-538; Kuroki M et al., (1992) Hybridoma 11: 391-407 and Antibodies: A Laboratory Manual, Ed Harlow E & Lane D editors, supra, pp. 386-389.

[0204] In certain aspects, when two antibodies recognize the same or sterically overlapping epitopes, a competitive binding assay, such as a competitive ELISA assay, which can be configured in several different formats using either labeled antigen or labeled antibody, can be used to determine whether an antibody is competitively blocked, e.g., in a dose-dependent manner, by another antibody, e.g., an antibody that binds to essentially the same epitope as the reference antibody or an overlapping epitope. In certain embodiments, antibodies can be tested in competitive binding assays using antibodies described herein (e.g., antibodies z10, z11, or z13).

[0205] In another aspect, provided herein is an antibody that competes (e.g., in a dose-dependent manner) for binding between MERTK (e.g., human MERTK) and an anti-MERTK antibody described herein (e.g., z10, z11, z13, or xAb) as determined using an assay known to one of skill in the art or described herein (e.g., an ELISA competition assay or surface plasmon resonance). In another aspect, provided herein is an antibody that competitively inhibits (e.g., in a dose-dependent manner) the binding of an anti-MERTK antibody described herein (e.g., z10, z11, z13, or xAb) to MERTK (e.g., human MERTK) as determined using an assay known to one of skill in the art or described herein (e.g., an ELISA competition assay, or suspension array, or surface plasmon resonance).

[0206] In certain embodiments, provided herein are anti-MERTK antibodies that compete with antibodies described herein for binding to MERTK (e.g., human MERTK) to the same extent as the antibodies described herein self-compete for binding to MERTK (e.g., human MERTK). In certain embodiments, provided herein are first antibodies that compete with anti-MERTK antibodies described herein for binding to MERTK (e.g., human MERTK), wherein the competition is demonstrated by a reduction in binding of the first antibody to MERTK (e.g., human MERTK) of more than 80% (e.g., 85%, 90%, 95%, or 98%, or between 80% and 85%, 80% and 90%, 85% and 90%, or 85% and 95%).

[0207] In a specific aspect, provided herein is an anti-MERTK antibody that competes (e.g., in a dose-dependent manner) for specific binding to MERTK (e.g., human MERTK) with an antibody comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109 or SEQ ID NO: 110, and a VL domain comprising the amino acid sequence of SEQ ID NO: 106 or SEQ ID NO: 111.

[0208] In a specific embodiment, an anti-MERTK antibody (e.g., a humanized antibody or a human antibody) or antigen-binding fragment thereof specifically binds to the same or overlapping epitope of an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 105 and a VL domain having the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein immunospecifically binds to the same or overlapping epitope of an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 107 and a VL domain having the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein immunospecifically binds to the same or overlapping epitope of an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 108 and a VL domain having the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof described herein immunospecifically binds to the same or overlapping epitope of an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 110 and a VL domain having the amino acid sequence of SEQ ID NO: 111. Assays known to those skilled in the art or described herein (e.g., X-ray crystallography, ELISA assays, etc.) can be used to determine whether two antibodies bind to the same epitope. In a specific embodiment, an antibody or antigen-binding fragment thereof that competes with an antibody described herein for binding to MERTK (e.g., human MERTK) is not a murine antibody. In a specific embodiment, an antibody or antigen-binding fragment thereof that binds to the same or overlapping epitope as an antibody described herein (e.g., human MERTK) is not a murine antibody.

[0209] Affinity can be expressed by, but not limited to, the equilibrium dissociation constant (K D ) and the equilibrium association constant (K A K D can be determined by techniques known to those skilled in the art, such as biolayer interferometry or surface plasmon resonance.

[0210] In certain embodiments, an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein that competes with an antibody described herein for binding to MERTK (e.g., human MERTK), or an anti-MERTK antibody or antigen-binding fragment thereof that binds to the same or overlapping epitope as an anti-MERTK antibody described herein, has a K of about 8 nM, 7 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.25 nM, or 0.1 nM. D In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein that competes with an antibody described herein for binding to MERTK (e.g., human MERTK), or an anti-MERTK antibody or antigen-binding fragment thereof that binds to the same or overlapping epitope as an antibody described herein, has a K of 0.1 nM to 10 nM, 0.5 nM to 10 nM, 1 nM to 10 nM, 2 nM to 10 nM, 2 nM to 5 nM, or 4 nM to 10 nM in an assay such as those described herein or known to one of skill in the art. D In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein that competes with an antibody described herein for binding to MERTK (e.g., human MERTK), or an anti-MERTK antibody or antigen-binding fragment thereof that binds to the same or overlapping epitope as an antibody described herein, has a K of about 2 pM to 8 pM using assays described herein or known to one of skill in the art. D It binds to MERTK (e.g., human MERTK) with avidity.

[0211] In a specific embodiment, the anti-MERTK antibodies or antigen-binding fragments thereof described herein have a K of about 3 nM in an assay described herein or known to one of skill in the art. DIn some embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof described herein bind to MERTK (e.g., human MERTK) with a K of about 1 pM to 15 pM in assays described herein or known in the art. D In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein binds to MERTK (e.g., human MERTK) with an avidity of about 1.46 nM in an assay described herein or known to one of skill in the art. D In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein binds to MERTK (e.g., human MERTK) with an avidity of about 5.74 pM in an assay described herein or known to one of skill in the art. D In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein binds to MERTK (e.g., human MERTK) with an avidity of about 3.68 pM in an assay described herein or known to one of skill in the art. D In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof described herein binds to MERTK (e.g., human MERTK) with an avidity of about 2.99 pM in an assay described herein or known to one of skill in the art. D It binds to MERTK (e.g., human MERTK) with avidity. As used herein, the term "about," when used to modify a numerical value or numerical range, indicates that a deviation of 5% to 10% above and below the value or range remains within the intended meaning of the recited value or range.

[0212] In a specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof binds to MERTK (e.g., human MERTK) with an EC50 of 1 nM to 20 nM, as assessed by an assay described herein or known in the art. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof binds to MERTK (e.g., human MERTK) with an EC50 of 1 nM to 10 nM, as assessed by an assay described herein or known in the art. In another specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof binds to MERTK (e.g., human MERTK) with an EC50 of about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, or about 10 nM, as assessed by an assay described herein or known in the art.

[0213] In specific embodiments, the anti-MERTK antibody or antigen-binding fragment thereof is one described in Section 6 below. 5.1.2. Functional Features

[0214] In some aspects, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) reduces the expression level of human MERTK in cancer cells (e.g., SKMEL5 melanoma cells) by more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 85%, as assessed by assays known to those of skill in the art or described herein. In some aspects, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to human MERTK reduces the expression level of human MERTK in human M2 macrophages by more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%, as assessed by an assay known to one of skill in the art or described herein. In a specific embodiment, the anti-MERTK antibody or antigen-binding fragment thereof binds to MERTK (e.g., human MERTK) but does not bind to human Axl, human Tyro3, ​​or mouse MERTK, as assessed by a method described herein or known in the art.

[0215] In some embodiments, the anti-MERTK antibody or antigen-binding fragment thereof binds to human MERTK and cynomolgus monkey MERTK.

[0216] In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) induces a cytokine secretion response by M2 macrophages, CD14+ monocytes, or both, as shown in Figure 10. In certain embodiments, the anti-MERTK antibody or antigen-binding fragment thereof alters expression of a certain cytokine by M2 macrophages, CD14+ monocytes, or both, as shown in Figure 10, by more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% (e.g., the antibody or antigen-binding fragment thereof increases expression of a certain cytokine) as assessed by assays known to one of skill in the art or described herein.

[0217] In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) blocks (e.g., partially or completely) the level of MERTK phosphorylation induced by Gas-6 in human MERTK-expressing cells, such as cancer cells (e.g., melanoma cells), M2 macrophages, or both, in an assay known to one of skill in the art. In a specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) reduces the level of Gas-6-induced human MERTK phosphorylation in human MERTK-expressing cells, such as cancer cells (e.g., melanoma cells), M2 macrophages, or both, in an assay known to one of skill in the art by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%.

[0218] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) induces degradation of human MERTK in human MERTK-expressing cells, such as, for example, cancer cells (e.g., melanoma cells), M2 macrophages, or both. In a specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) reduces the level of human MERTK on the surface of human MERTK-expressing cells, such as, for example, cancer cells (e.g., melanoma cells), M2 macrophages, or both, by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% in an assay described herein or known to one of skill in the art.

[0219] In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) induces internalization of human MERTK in human MERTK-expressing cells, such as, for example, cancer cells (e.g., melanoma cells), M2 macrophages, or both. In a specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) increases internalization of human MERTK by human MERTK-expressing cells, such as, for example, cancer cells (e.g., melanoma cells), M2 macrophages, or both, by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% in an assay described herein or known to one of skill in the art.

[0220] In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) inhibits (e.g., partially or completely) colony formation by cancer cells (e.g., melanoma cells) in an assay described herein or known to one of skill in the art. In a specific embodiment, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) reduces the level of colony formation by cancer cells (e.g., melanoma cells) by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% in an assay described herein or known to one of skill in the art. In some aspects, an anti-MERTK antibody or antigen-binding fragment thereof described herein that immunospecifically binds to MERTK (e.g., human MERTK) reduces the colony-forming ability of cancer cells (e.g., SKMEL5 melanoma cells) by more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 85%, as assessed by an assay known to one of skill in the art or described herein.

[0221] In some aspects, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) prevents Gas6-induced phosphorylation of AKT in an assay described herein or known in the art. In certain embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) competes with Gas-6 (e.g., human Gas-6) for binding to human MERTK. In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein inhibits (e.g., completely inhibits or only partially inhibits) Gas-6 from binding to human MERTK. In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK) inhibits binding of Gas-6 (e.g., human or mouse Gas-6) to human MERTK by more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%, as assessed by an assay known to one of skill in the art or described herein. In a specific embodiment, the assay used to assess inhibition of Gas-6 (e.g., human Gas-6) binding to human MERTK in the presence of an anti-MERTK antibody or antigen-binding fragment thereof described herein is an antibody capture ELISA known to one of skill in the art, such as that described in WO2016 / 106221 (e.g., Example 1 of WO2016 / 106221).

[0222] In some embodiments, an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) reduces the level of Gas-6-induced AKT phosphorylation in human MERTK-expressing cancer cells (e.g., melanoma cells) by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 85% in an assay described herein or known to one of skill in the art.

[0223] In specific embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof described herein that specifically bind to MERTK (e.g., human MERTK) inhibit angiogenesis in tumors. In some embodiments, the inhibition of angiogenesis is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In specific embodiments, the inhibition of angiogenesis is at least 50%, 55%, 60%, 65%, or 70%. Inhibition of angiogenesis can be assessed by methods described herein and / or known to those skilled in the art. Inhibition can be compared to the level of angiogenesis without any antibody or with an irrelevant antibody (e.g., an antibody that does not immunospecifically bind to MERTK).

[0224] In certain embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof described herein that specifically bind to MERTK (e.g., human MERTK) inhibit tumor progression. Inhibition of tumor progression is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. Tumor progression can be assessed by methods known to those skilled in the art. Tumor progression can be compared to the cancer state without any antibody or with an irrelevant antibody (e.g., an antibody that does not specifically bind to human MERTK). In specific embodiments, the anti-MERTK antibody or antigen-binding fragment thereof has one, two, three, or more characteristics of the antibodies described in Section 6 below. 5.1.3. Bispecific antibodies

[0225] In a specific aspect, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to human MERTK and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) is an anti-MERTK antibody or antigen-binding fragment thereof described herein. In a specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the variable heavy chain region of an anti-MERTK antibody or antigen-binding fragment thereof described herein. In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequence of the variable heavy chain region of antibody z10 shown in Table 11. In another specific embodiment, provided herein is a bispecific antibody comprising two different binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequence of the variable heavy chain region of antibody z11 shown in Table 12. In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other binding region which binds to another antigen of interest, wherein the binding region which specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequence of the variable heavy chain region of antibody z13 shown in Table 13.In another specific embodiment, provided herein is a bispecific antibody comprising two different binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other binding region binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises a variable heavy chain region comprising an amino acid sequence as set forth in Table 14.

[0226] In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the variable light chain region of an anti-MERTK antibody or antigen-binding fragment thereof described herein. In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequence of the variable light chain region of antibody z10 shown in Table 11. In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequence of the variable light chain region of antibody z11 shown in Table 12. In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequence of the variable light chain region of antibody z13 shown in Table 13. In another specific embodiment, provided herein is a bispecific antibody comprising two different binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other binding region binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises a variable light chain region, and the variable light chain region comprises the amino acid sequence of a VL shown in Table 11, 12 or 13.

[0227] In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the variable light chain region and variable heavy chain region of an anti-MERTK antibody or antigen-binding fragment thereof described herein. In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequence of the variable light chain region and variable heavy chain region of antibody z10 shown in Table 11. In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequences of the variable light and heavy chain regions of antibody z11 shown in Table 12. In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other of which binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises the amino acid sequences of the variable light and heavy chain regions of antibody z13 shown in Table 13.In another specific embodiment, provided herein is a bispecific antibody comprising two different antigen-binding regions, one of which specifically binds to MERTK (e.g., human MERTK) and the other binding region binds to another antigen of interest, wherein the binding region that specifically binds to MERTK (e.g., human MERTK) comprises a variable light chain region and a variable heavy chain region, wherein the variable heavy chain region comprises an amino acid sequence set forth in Table 14, and the variable light chain region comprises an amino acid sequence of a VL set forth in Table 11, 12, or 13.

[0228] In certain embodiments, the antigen of interest bound by the other binding region of a bispecific antibody described herein is an antigen present on an immune cell (e.g., a T cell, an NK cell, or a dendritic cell). In some embodiments, the antigen of interest bound by the other binding region of a bispecific antibody described herein is an immune checkpoint receptor (e.g., PD-1, PD-L1, CTLA-4, LAG3, Tim3, ICOS, CD40, GITR, or OX40). In specific embodiments, the other binding region of a bispecific antibody described herein comprises an agonist anti-GITR antibody, an agonist anti-OX40 antibody, or an agonist anti-CD40 antibody. In specific embodiments, the other binding region of a bispecific antibody comprises a blocking antibody or antigen-binding fragment thereof that binds to PD-1, PD-L1, CTLA-4, or LAG3. In certain embodiments, the antigen of interest bound by the other binding region of a bispecific antibody described herein is a T cell receptor. In specific embodiments, the antigen of interest bound by the other binding region of the bispecific antibody described herein is CD3, PD-L1, LRP1, LRP8, TGF-β, NKGD2, or TIGIT. In some embodiments, the antigen of interest is a tumor-associated antigen.

[0229] In a specific embodiment, the other binding region of the bispecific antibody described herein is nivolumab or an antigen-binding fragment thereof. In another specific embodiment, the other binding region of the bispecific antibody described herein is lambrolizumab or an antigen-binding fragment thereof. In another specific embodiment, the other binding region of the bispecific antibody described herein is MEDI-4736 or an antigen-binding fragment thereof. In another specific embodiment, the other binding region of the bispecific antibody described herein is ipilimumab or an antigen-binding fragment thereof. In another specific embodiment, the other binding region of the bispecific antibody described herein is MPDL-3280A or an antigen-binding fragment thereof. In another specific embodiment, the other binding region of the bispecific antibody described herein is pidilizumab or an antigen-binding fragment thereof. In another specific embodiment, the other binding region of the bispecific antibody described herein is avelumab or an antigen-binding fragment thereof. In another specific embodiment, the other binding region of the bispecific antibody described herein is pembrolizumab or an antigen-binding fragment thereof. 5.2. Antibody-Drug Conjugates

[0230] Provided herein are antibody-drug conjugates comprising: (a) an antibody portion that is an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK); (b) one or more drug moieties, each drug moiety being a cytotoxic agent; and (c) optionally, a linker, wherein the cytotoxic agent is conjugated directly to the antibody portion or via a linker. As used in this disclosure, the term "conjugated" is intended to mean covalently bonded, which may be direct or through an intervening covalent bond structure. The antibody portion of the antibody-drug conjugates provided herein may be an antibody described in Section 5.1 or Section 6. The antibody-drug conjugate may be an antibody-drug conjugate described in Section 6.

[0231] In certain embodiments, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is between 1:1 and 1:20. In a specific embodiment, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is between 1:1 and 1:15. In a specific embodiment, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is between 1:1 and 1:12. In a specific embodiment, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is between 1:1 and 1:8. In a preferred embodiment, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is between 1:3 and 1:5. In a specific embodiment, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is 1:3. In another specific embodiment, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is 1:4. In another specific embodiment, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is 1:5. In another specific embodiment, the antibody-drug conjugates provided herein have a molar ratio of antibody moiety to drug moiety that is 1:9.

[0232] The drug moiety is conjugated to one or more chains of the antibody moiety. In some embodiments, the drug moiety is conjugated to one chain of the antibody moiety (e.g., when the antibody moiety is an scFv or when the antibody moiety is a multi-chain antibody such as an immunoglobulin (which is a tetramer) or an antigen-binding fragment thereof). In other embodiments, the drug moiety is conjugated to two or more chains of the antibody moiety (when the antibody moiety is a multi-chain antibody such as an immunoglobulin or an antigen-binding fragment thereof). In specific embodiments, the drug moiety is conjugated to two identical chains of the immunoglobulin, e.g., the heavy chain or the light chain. In other embodiments, the drug moiety is conjugated to all chains of the antibody moiety (when the antibody moiety is a multi-chain antibody such as an immunoglobulin or an antigen-binding fragment thereof). In some embodiments, the drug moiety is conjugated to the antibody by the methods described in Section 6.4, below.

[0233] In specific embodiments, the drug moiety is conjugated to one or more sites in the constant region of the antibody. In specific embodiments, the drug moiety is conjugated to one or more sites in the variable region of the antibody. In specific embodiments, the drug moiety is conjugated to one or more lysine residues in the antibody. In specific embodiments, the drug moiety is conjugated to one or more cysteine ​​residues in the antibody, for example, when MMAE or SN-38 is the drug moiety. In certain embodiments, the drug moiety is conjugated to the Fc region of an antibody that is an immunoglobulin. In specific embodiments, the drug moiety is a peptide or protein fused (directly or via a linker that is a peptide or protein) to the N-terminus or C-terminus of one or more chains of the antibody moiety.

[0234] For example, if the antibody moiety is an scFv, the drug moiety can be fused (directly or via a peptide or protein linker) to the N- or C-terminus of the scFv. In specific embodiments, if the antibody moiety is a multi-chain antibody or antigen-binding fragment thereof, the drug moiety can be fused (directly or via a peptide or protein linker) to one of the chains of the antibody moiety. In the case of an antibody that is an immunoglobulin, in specific embodiments, both heavy chains can be fused (directly or via a peptide or protein linker) to the drug moiety, and / or both light chains can be fused (directly or via a peptide or protein linker) to the drug moiety. In such specific embodiments, provided herein are vectors (e.g., expression vectors) comprising a polynucleotide comprising a nucleotide sequence encoding a fusion protein comprised of a drug moiety and an antibody moiety or chain thereof, and a linker, if any, between the drug moiety and the antibody moiety, for recombinant expression in a host cell, preferably a mammalian cell. Also provided herein are ex vivo host cells comprising such vectors for recombinantly expressing a fusion protein comprised of a drug moiety and an antibody moiety or chain thereof, and a linker, if any, between the drug moiety and the antibody moiety. The characteristics and methods for producing such vectors and ex vivo host cells may be the same as those described below for anti-MERTK antibodies. Also provided herein is a method for producing a fusion protein composed of a drug moiety and an antibody moiety or chain thereof, and a linker, if present, between the drug moiety and the antibody moiety, comprising culturing such ex vivo host cells under conditions such that a polynucleotide comprising a nucleotide sequence encoding the fusion protein is expressed by the ex vivo host cells to produce the fusion protein. The antibody-drug conjugates described herein can be produced by methods known in the art or described in Section 6 below.

[0235] In some embodiments, the antibody-drug conjugate has the structure shown in Figure 13A or Figure 13B, particularly Figure 13A. Figure 13A shows the structure of MMAE linked to an antibody (Ab) via an mc-vc-PABC linker. Figure 13B shows the structure of SN-38 linked to an antibody (Ab) via a CL2 or CL2A linker. If "AA" in Figure 13B is phenylalanine-lysine, Figure 13B shows the antibody linked to SN-38 via a CL2 linker (which contains a cathepsin B cleavage site). If "AA" in Figure 13B is lysine, Figure 13B shows the antibody linked to SN-38 via a CL2A linker (which does not contain a cathepsin B cleavage site).

[0236] In a specific embodiment, the antibody portion of the antibody-drug conjugate comprises the variable region of antibody z10. In a specific embodiment, an antibody-drug conjugate provided herein comprises an antibody portion comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 105 and the VL comprises the amino acid sequence of SEQ ID NO: 106, and the antibody portion is conjugated to MMAE via an mc-vc-PABC linker. In another specific embodiment, an antibody-drug conjugate provided herein comprises an antibody portion comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 105 and the VL comprises the amino acid sequence of SEQ ID NO: 106, and the antibody portion is conjugated to SN-38 via a CL2A linker.

[0237] In alternative embodiments of the antibody-drug conjugates described throughout this disclosure, the drug moiety is not necessarily a cytotoxic agent. For example, the drug moiety can be any drug known in the art suitable for use, including but not limited to those described in Section 5.2.3 below, or can be an imaging agent, e.g., for purposes of diagnosing or monitoring disease.

[0238] In preferred embodiments of the antibody-drug conjugates described throughout this disclosure, the drug moiety is conjugated to the antibody (also referred to herein as the "antibody moiety") via a linker. 5.2.1. Functional Characteristics of Antibody-Drug Conjugates

[0239] In certain embodiments, the antibody-drug conjugates described herein have a K of about 8 nM, 7 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.25 nM, 0.17 nM, 0.1 nM, 0.081 nM, or 0.021 nM. D and binds to MERTK (e.g., human MERTK). In some aspects, the antibody-drug conjugates provided herein reduce the expression level of human MERTK in cancer cells (e.g., SKMEL5 melanoma cells) by more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%, as assessed by assays known to those of skill in the art or described herein, e.g., as described in Section 6 below. In specific embodiments, the antibody-drug conjugates provided herein bind to MERTK (e.g., bind to human MERTK but do not bind to human Axl, human Tyro3, ​​or mouse MERTK), as assessed by methods described herein or known in the art. In certain embodiments, the antibody-drug conjugates provided herein comprise an antibody moiety, and the antibody-drug conjugate binds to MERTK with a higher affinity than the unconjugated antibody moiety.

[0240] In certain embodiments, the antibody-drug conjugates provided herein cause cell death of MERTK (e.g., human MERTK)-expressing cells (e.g., M2 macrophages, cancer cells, or both) in vitro. In some specific embodiments, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of MERTK-expressing cells cultured for a period of time in the presence of an antibody-drug conjugate described herein are dead at the end of the period, as assessed by methods known to those skilled in the art for measuring cell death in vitro. In other specific embodiments, the percentage of MERTK-expressing cells (e.g., M2 macrophages, cancer cells, or both) that undergo cell death is at least 50%, 100%, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, or 1000-fold higher when cultured in the presence of an antibody-drug conjugate described herein for a period of time compared to culture without the antibody-drug conjugate (e.g., cultured without any antibody-drug conjugate, or cultured with an antibody-drug conjugate comprising an irrelevant antibody (e.g., an antibody that does not immunospecifically bind to MERTK (e.g., human MERTK)), or cultured with an unconjugated anti-MERTK antibody or unconjugated anti-MERTK antigen-binding fragment described herein). The period of time can be, for example, about 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week.

[0241] In some embodiments, the antibody-drug conjugates provided herein do not affect the viability of MERTK-expressing macrophages as assessed by methods known to those of skill in the art for measuring cell death in vitro or as described herein, e.g., in Section 6, infra. In some embodiments, the antibody-drug conjugates provided herein do not affect the viability of M1 macrophages as assessed by methods known to those of skill in the art for measuring cell death in vitro or as described herein, e.g., in Section 6, infra. In some embodiments, the antibody-drug conjugates provided herein do not affect the viability of M2 macrophages as assessed by methods known to those of skill in the art for measuring cell death in vitro or as described herein, e.g., in Section 6, infra.

[0242] In certain embodiments, the antibody-drug conjugates provided herein induce degradation of MERTK in MERTK-expressing cells, such as cancer cells (e.g., melanoma cells). In specific embodiments, the antibody-drug conjugates provided herein reduce the level of human MERTK on the surface of human MERTK-expressing cells, such as cancer cells (e.g., melanoma cells), by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% in an assay described herein or known to those skilled in the art. In certain embodiments, the antibody-drug conjugates provided herein induce greater degradation of MERTK in MERTK-expressing cells than the unconjugated antibody moiety, as assessed in an assay described herein or known in the art.

[0243] In certain embodiments, the antibody-drug conjugates provided herein induce the internalization of MERTK in MERTK-expressing cells, such as cancer cells (e.g., melanoma cells). In specific embodiments, the antibody-drug conjugates provided herein increase the internalization of human MERTK by human MERTK-expressing cells, such as cancer cells (e.g., melanoma cells), by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% in an assay described herein or known to one skilled in the art. In certain embodiments, the antibody-drug conjugates provided herein comprise an antibody moiety, and the antibody-drug induces higher internalization of MERTK-expressing cells than the unconjugated antibody moiety, as assessed by an assay described herein or known to one skilled in the art.

[0244] In certain embodiments, the antibody-drug conjugates provided herein inhibit tumor progression. Inhibition of tumor progression is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. Tumor progression can be assessed by methods known to those skilled in the art. Tumor progression can be compared to cancer conditions treated without any antibody, with an unrelated antibody (e.g., an antibody that does not specifically bind to human MERTK), with SN-38, with MMAE, or with the unconjugated antibody portion of the antibody-drug conjugate. In specific embodiments, the anti-MERTK antibody or antigen-binding fragment thereof has one, two, three, or more characteristics of the antibodies described in Section 6 below.

[0245] In specific embodiments, the antibody-drug conjugates described herein inhibit angiogenesis in tumors. In some embodiments, the inhibition of angiogenesis is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In specific embodiments, the inhibition of angiogenesis is at least 50%, 55%, 60%, 65%, or 70%. Inhibition of angiogenesis can be assessed by methods described herein and / or known to those skilled in the art. The inhibition can be compared to the level of angiogenesis without the antibody-drug conjugate (e.g., cultured without any antibody-drug conjugate, or cultured with an antibody-drug conjugate that includes an irrelevant antibody (e.g., an antibody that does not specifically bind to MERTK (e.g., human MERTK)), or cultured with an unconjugated anti-MERTK antibody or unconjugated anti-MERTK antigen-binding fragment described herein).

[0246] In certain embodiments, the antibody-drug conjugates described herein inhibit the progression of tumors (e.g., tumors of human breast cancer cells). The inhibition of tumor progression is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. Tumor progression can be assessed by methods known to those skilled in the art. Tumor progression can be compared to the state of the cancer without the antibody-drug conjugate (e.g., cultured without any antibody-drug conjugate, or cultured with an antibody-drug conjugate comprising an irrelevant antibody (e.g., an antibody that does not specifically bind to MERTK (e.g., human MERTK)), or cultured with an unconjugated anti-MERTK antibody or unconjugated anti-MERTK antigen-binding fragment described herein). In a specific embodiment, the assay used to assess tumor progression is a mouse tumor transplant model. 5.2.2. Antibody part

[0247] The antibody-drug conjugates provided herein may comprise any of the anti-MERTK antibodies provided herein. For example, see Section 5.1.1 for examples of antibody moieties of the antibody-drug conjugates provided herein. In a specific embodiment, the antibody moiety is an immunoglobulin, e.g., an immunoglobulin comprising a human constant domain or a humanized immunoglobulin. In another specific embodiment, the antibody moiety is an scFv comprising the VH and VL domains of, for example, an antibody described in Section 5.1.1 herein.

[0248] In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated, optionally via a linker, to an antibody moiety comprising a VH disclosed herein, e.g., a VH described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated, optionally via a linker, to an antibody moiety comprising a VL disclosed herein, e.g., a VL described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated, optionally via a linker, to an antibody moiety comprising a VH and VL of an antibody disclosed herein, e.g., as described in Section 5.1.1.

[0249] In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated, optionally via a linker, to an antibody moiety comprising a VH comprising the amino acid sequence of SEQ ID NO: 105. In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated, optionally via a linker, to an antibody moiety comprising a VL comprising the amino acid sequence of SEQ ID NO: 106. In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated, optionally via a linker, to an antibody moiety comprising (i) a VH comprising the amino acid sequence of SEQ ID NO: 105, and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 106.

[0250] In some embodiments, an antibody-drug conjugate provided herein comprises MMAE conjugated via a linker to an antibody moiety comprising a VH, wherein the VH comprises the amino acid sequence of SEQ ID NO: 105. In some embodiments, an antibody-drug conjugate provided herein comprises MMAE conjugated via a linker to an antibody moiety comprising a VL, wherein the VL comprises the amino acid sequence of SEQ ID NO: 106. In some embodiments, an antibody-drug conjugate provided herein comprises SN-38 conjugated via a linker to an antibody moiety comprising a VH, wherein the VH comprises the amino acid sequence of SEQ ID NO: 105. In some embodiments, an antibody-drug conjugate provided herein comprises SN-38 conjugated via a linker to an antibody moiety comprising a VL, wherein the VL comprises the amino acid sequence of SEQ ID NO: 106.

[0251] In a specific embodiment, an antibody-drug conjugate provided herein comprises MMAE conjugated via a linker to an antibody portion comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 105 and the VL comprises the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, an antibody-drug conjugate provided herein comprises SN-38 conjugated via a linker to an antibody portion comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 105 and the VL comprises the amino acid sequence of SEQ ID NO: 106.

[0252] In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated via a linker to an antibody moiety comprising a heavy chain provided herein, e.g., a heavy chain described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise MMAE conjugated via a linker to an antibody moiety comprising a heavy chain provided herein, e.g., a heavy chain described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise SN-38 conjugated via a linker to an antibody moiety comprising a heavy chain provided herein, e.g., a heavy chain described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated via a linker to an antibody moiety comprising a light chain provided herein, e.g., a light chain described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise MMAE conjugated via a linker to an antibody moiety comprising a light chain provided herein, e.g., a light chain described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise SN-38 conjugated via a linker to an antibody moiety comprising a light chain provided herein, e.g., a light chain described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise (i) a heavy chain provided herein, and (ii) a light chain provided herein, e.g., a drug moiety conjugated via a linker to an antibody moiety comprising a heavy chain and a light chain described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise (i) a heavy chain provided herein, and (ii) a light chain provided herein, e.g., an antibody moiety comprising a heavy chain and a light chain described in Section 5.1.1, MMAE conjugated via a linker to an antibody moiety comprising a heavy chain and a light chain described in Section 5.1.1. In some embodiments, the antibody-drug conjugates provided herein comprise (i) a heavy chain provided herein, and (ii) a light chain provided herein, e.g., an antibody moiety comprising a heavy chain and a light chain described in Section 5.1.1.

[0253] In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated via a linker to an antibody moiety comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 112. In some specific embodiments, the antibody-drug conjugates provided herein comprise MMAE conjugated via a linker to an antibody moiety comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 112. In some specific embodiments, the antibody-drug conjugates provided herein comprise SN-38 conjugated via a linker to an antibody moiety comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated via a linker to an antibody moiety comprising a light chain comprising the amino acids of SEQ ID NO: 113. In some specific embodiments, the antibody-drug conjugates provided herein comprise MMAE conjugated via a linker to a light chain comprising the amino acids of SEQ ID NO: 113. In some specific embodiments, the antibody-drug conjugates provided herein comprise SN-38 conjugated via a linker to a light chain comprising the amino acids of SEQ ID NO: 113. In some embodiments, the antibody-drug conjugates provided herein comprise a drug moiety conjugated via a linker to an antibody moiety comprising (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, and (ii) a light chain comprising the amino acids of SEQ ID NO: 113. In a specific embodiment, the antibody-drug conjugates provided herein comprise MMAE conjugated via a linker to an antibody moiety comprising (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, and (ii) a light chain comprising the amino acids of SEQ ID NO: 113. In another specific embodiment, the antibody-drug conjugates provided herein comprise SN-38 conjugated via a linker to an antibody moiety comprising (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 112, and (ii) a light chain comprising the amino acids of SEQ ID NO: 113. 5.2.3. Drug Moieties and Linkers

[0254] The cytotoxic agents used in antibody-drug conjugates are often also called payloads or warheads. Most of the cytotoxic agents used in antibody-drug conjugates target DNA or microtubules and have high cytotoxic potency (approximately 10 -10 ~10 -12 M IC 50 range) (see Beck A et al., (2017) Nat Rev Drug Discov 16: 315-337). However, the use of less potent cytotoxic agents The cytotoxic agent may be a small molecule, a nucleotide, a peptide, or a non-antibody protein. In a specific embodiment, the cytotoxic agent is a small molecule. In another specific embodiment, the cytotoxic agent is a non-antibody protein. Non-limiting exemplary cytotoxic agents that can be used in the antibody-drug conjugates according to the present invention include those described in Beck A et al., (2017) Nat Rev Drug Discov 16: 315-337; Peters C and Brown S, (2015) Biosci Rep 35: art:e00225; McCombs JR and Owen SC (2015) The AAPS Journal 17: 339-351; Jackson DY (2016) Org Process Res Dev 20: 852-866; and Olivier KJ and Hurvitz SA ed., (2016) Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical, Wiley.

[0255] In certain embodiments, the cytotoxic agent is one of the agents listed in Table 30 or 31. In specific embodiments, the cytotoxic agent used in the antibody-drug conjugate is an auristatin (such as monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), AurO101, PF06380101, auristatin W, or auristatin F) or a derivative thereof, a maytansinoid (such as DM1 or DM4), a pyrrolobenzodiazepine (PBD) (such as SGD1882 or SG3199), an indolinobenzodiazepine (such as DGN462 or DGN549), a calicheamicin (ozogamicin) (such as CM1), a camptothecin analog (SN-38, DX DX-8951f or DX-8951f derivatives), duocarmycins (such as seco-duocarmycin-hydroxy-benzamide-azaindole (seco-DUBA), minor groove binding alkylating agents (MGBA) or MED-2460), tubulin inhibitors (such as cryptophycin), tubulysin or tubulysin analogs (such as AZ13599185), amberstatin 269, doxorubicin, antibiotics (such as rifalogs), anthracyclines (such as PNU-159682), microtubule inhibitors (such as rhizoxin), splicostatin, or tylanstatin. In a specific embodiment, the cytotoxic agent used in the antibody-drug conjugate is MMAE or MMAF. In a specific embodiment, the cytotoxic agent used in the antibody-drug conjugate is MMAE (see, e.g., Figure 13A). In another specific embodiment, the cytotoxic agent used in the antibody-drug conjugate is DM1 or DM4. In another specific embodiment, the cytotoxic agent used in the antibody-drug conjugate is SN-38. In another specific embodiment, the cytotoxic agent used in the antibody-drug conjugate is SN-38, as shown in Figure 13B. [Table 30-1] [Table 30-2] [Table 30-3] [Table 30-4] [Table 31-1] [Table 31-2]

[0256] As used herein, the term "small molecule" refers to an organic or inorganic compound (which may be, for example, a heteroorganic or organometallic compound) having a molecular weight of less than about 10,000 grams per mole. In specific embodiments, a small molecule has a molecular weight of less than about 5,000 grams per mole, or less than about 2,000 grams per mole, or less than about 1,000 grams per mole, or less than about 500 grams per mole, or less than about 100 grams per mole.

[0257] In some embodiments, the cytotoxic agent is conjugated directly to the antibody moiety. In other embodiments, the cytotoxic agent is conjugated to the antibody moiety via a linker. Suitable linkers for use in accordance with the present invention are preferably stable in the bloodstream to limit off-target toxicity and unstable at the site of cancer to allow release of the cytotoxic agent (see Peters C and Brown S, (2015) Biosci Rep 35: art:e00225). Non-limiting exemplary linkers that can be used in accordance with the present invention include Beck A et al., (2017) Nat Rev Drug Discov 16: 315-337;Peters C and Brown S, (2015) Biosci Rep 35: art:e00225; McCombs JR and Owen SC (2015) The AAPS Journal 17: 339-351; Jackson DY (2016) Org Process Res Dev 20: 852-866; and Olivier KJ and Hurvitz SA ed., (2016) Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical, Wiley. In some embodiments, the linker is a cleavable linker, for example, having a motif sensitive to lysosomal proteases (e.g., cathepsin B), a motif sensitive to acidic pH (e.g., hydrazone), or a motif containing a disulfide bridge that can be reduced by glutathione. In other embodiments, the linker is a non-cleavable linker. By way of example and not limitation, the linker can be a small molecule, a nucleotide, a peptide, or a non-antibody protein. In specific embodiments, the linker is a small molecule. In specific embodiments, the linker used in the antibody-drug conjugate is cathepsin B, hydrazone, succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), maleimidocaproic acid (mc), valine-citrulline (vc), N-hydroxysuccinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfoSPDB), N-hydroxysuccinimidyl 4-(2-pyridydithio)butanoate (SPDB), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), valine-alanine (va), polyethylene glycol 8-valine-citrulline (PEG8-va), mb-vc, CL2A, a cleavable vc-based linker, or a Fleximer polymer linker. In specific embodiments, the linker selected for use in the antibody-drug conjugates described herein does not interfere with the binding of the antibody moiety to its antigen, cytotoxic agent, or both.In specific embodiments, the linker selected for use in the antibody-drug conjugates described herein is maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC). In other specific embodiments, the linker selected for use in the antibody-drug conjugates described herein is CL2. In other specific embodiments, the linker selected for use in the antibody-drug conjugates described herein is CL2A. In some specific embodiments, the linker selected for use in the antibody-drug conjugates described herein is the linker shown in Figure 13A. In other specific embodiments, the linker selected for use in the antibody-drug conjugates described herein is the linker shown in Figure 13B, in which AA is lysine. In other specific embodiments, the linker selected for use in the antibody-drug conjugates described herein is the linker shown in Figure 13B, in which AA is phenylalanine-lysine. In a specific embodiment, the antibody-drug conjugate comprises a linker, and the linker is maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (also known as "mc-vc-PABC") (see Figure 13A for the structure of mc-vc-PABC). In another specific embodiment, the antibody-drug conjugate comprises a linker, and the linker is CL2 (see Figure 13B and Cardillo et al. 2011, Clin Cancer for the structure of CL2). Res; 17(10); 3157-69). In another specific embodiment, the antibody-drug conjugate comprises a linker, and the linker is CL2A (for the structure of CL2A, see Figure 13B and Goldberg et al. 2018, Oncotarget; 9(48); 28989-29006, and Cardillo et al. 2011, Clin Cancer Res; 17(10); 3157-69).

[0258] In some embodiments, the linker selected for use in the antibody-drug conjugates described herein comprises one or more cleavage sites. In specific embodiments, the linker selected for use in the antibody-drug conjugates described herein contains a cathepsin B protease site. In other specific embodiments, the linker selected for use in the antibody-drug conjugates described herein contains a cathepsin B protease site and a pH-dependent cleavage site.

[0259] Non-limiting exemplary linker-drug moiety pairs that can be used in the antibody-drug conjugates described herein are described in Beck A et al., (2017) Nat Rev Drug Discov 16: 315-337; Peters C and Brown S, (2015) Biosci Rep 35: art:e00225; McCombs JR and Owen SC (2015) The AAPS Journal 17: 339-351; Jackson DY (2016) Org Process Res Dev 20: 852-866; and Olivier KJ and Hurvitz SA ed., (2016) Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical, Wiley. In specific embodiments, the linker-drug moiety pair in the antibody-drug conjugate is vc-MMAE, mc-MMAF, SMCC-DM1, sulfoSPDB-DM4, SPDB-DM4, SPP-DM1, va-SGD1882, polyethylene glycol 8 (PEG8)-va-SG3199, sulfoSPDB-DGN462, hydrazone-CM1, vc-seco-DUBA, mb-vc-MGBA, CL2A-SN38, a peptide linker with a DX-8951 derivative, hydrazone-doxorubicin, a cleavable vc-based linker with Aur0101, vc-PF06380101, a fleximer polymer linker with auristatin F, a cleavable linker-tubulin inhibitor, or vc-refalogue. In specific embodiments, the linker-drug moiety pair in the antibody-drug conjugate is mc-vc-PABC-MMAE (as shown in Figure 13A). In another specific embodiment, the linker-drug moiety pair in the antibody-drug conjugate is CL2-SN-38 (where AA is phenylalanine-lysine, as shown in Figure 13B). In another specific embodiment, the linker-drug moiety pair in the antibody-drug conjugate is CL2A-SN-38 (where AA is lysine, as shown in Figure 13B).

[0260] In specific embodiments, the drug moiety of the antibody-drug conjugates described herein does not interfere with the binding of the antibody moiety to its antigen (eg, MERTK (eg, human MERTK)). 5.3. Antibody Production 5.3.1. Antibody Production and Screening

[0261] In another aspect, provided herein is a method for producing an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK).

[0262] The antibodies or antigen-binding fragments thereof described herein can be produced by any method known in the art for the synthesis of antibodies, for example, by chemical synthesis or recombinant expression technology. The methods described herein, unless otherwise indicated, use conventional techniques in molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields within the skill of the art. These techniques are described, for example, in the references cited herein and are fully explained in the literature. For example, Maniatis T et al., (1982) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press; Sambrook J et al., (1989) Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press; Sambrook J et al., (2001) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel FM et al., Current Protocols in Molecular Biology, John Wiley & Sons (1987 and annual updates);Current Protocols in Immunology, John Wiley & Sons (1987 and annual updates) Gait (ed.) (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press;Eckstein (ed.) (1991) Oligonucleotides and Analogues: A Practical Approach, IRL Press;Birren B et al., (eds.) (1999) Genome Analysis: A Laboratory Manual, Cold Spring Harbor Laboratory Press.

[0263] In specific embodiments, the antibodies described herein are antibodies (e.g., recombinant antibodies) prepared, expressed, produced, or isolated by any means, including, for example, synthesis of DNA sequences, production via genetic engineering. In certain embodiments, such antibodies comprise a sequence encoded by a DNA sequence that does not naturally occur within the in vivo antibody germline repertoire of an animal or mammal (e.g., a human). In specific embodiments, the antibodies described herein are produced by a method comprising using human MERTK (SEQ ID NO: 131) or its extracellular domain (SEQ ID NO: 132) as an immunogen.

[0264] In certain aspects, provided herein are methods for producing an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), comprising culturing a cell or host cell described herein. In certain aspects, provided herein are methods for producing an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), comprising expressing (e.g., recombinantly expressing) the antibody or antigen-binding fragment thereof using a cell or host cell described herein (e.g., a cell or host cell comprising a polynucleotide encoding an antibody described herein). In certain embodiments, the cell is an isolated cell. In certain embodiments, an exogenous polynucleotide has been introduced into the cell. In certain embodiments, the method further comprises purifying the antibody or antigen-binding fragment thereof obtained from the cell or host cell.

[0265] Methods for producing polyclonal antibodies are known in the art (see, for example, Chapter 11 in: Short Protocols in Molecular Biology, (2002) 5th Ed., See Ausubel FM et al., eds., John Wiley and Sons, New York).

[0266] The term "monoclonal antibody," as used herein, is not limited to antibodies produced by hybridoma technology. Monoclonal antibodies can be prepared using a wide variety of techniques known in the art, including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be recombinantly produced from host cells that exogenously express an antibody described herein or a fragment thereof, e.g., the light chain and / or heavy chain of such an antibody. Methods for preparing clonal cell lines and the monoclonal antibodies expressed thereby are well known in the art (see, e.g., Chapter 11 in Short Protocols in Molecular Biology, (2002) 5th Ed., Ausubel FM et al., supra). For example, For example, monoclonal antibodies can be produced using techniques known in the art and described, for example, in Harlow E. & Lane D, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling GJ et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563 681 (Elsevier, NY, 1981); and Kohler Antibodies can be produced using hybridoma techniques, including those taught in G & Milstein C (1975) Nature 256: 495. Methods for producing and screening specific antibodies using hybridoma techniques are routine and well known in the art. In some embodiments, a mouse (or other animal, such as a rat, monkey, donkey, pig, sheep, hamster, or dog) can be immunized with an antigen (e.g., a human), and once an immune response is detected, for example, once antibodies specific to the antigen are detected in the mouse serum, the mouse spleen is harvested and splenocytes are isolated. The splenocytes are then fused to any suitable myeloma cells, for example, cells from cell line SP2 / 0 available from the American Type Culture Collection (ATCC®) (Manassas, VA), by well-known techniques to form hybridomas. Hybridomas are selected and cloned by limiting dilution.

[0267] The hybridoma cells thus prepared are seeded and grown in a suitable culture medium, preferably containing one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. The culture medium in which the hybridoma cells are growing is assayed for the production of monoclonal antibodies against MERTK (e.g., human MERTK). After hybridoma cells that produce antibodies of the desired specificity, affinity, and / or activity are identified, the clones are subcloned, grown, and isolated from the culture medium by standard methods (Goding JW (Ed), supra, Monoclonal Antibodies: Principles and Practice). The binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by methods known in the art, such as immunoprecipitation or in vitro binding assays, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).

[0268] In specific embodiments, disclosed herein are monoclonal antibodies produced by a single cell (e.g., a hybridoma or host cell producing a recombinant antibody), wherein the antibody immunospecifically binds to MERTK (e.g., human MERTK), e.g., as determined by ELISA or other antigen-binding or competitive binding assays known in the art or described in Section 6 herein. In certain embodiments, the monoclonal antibody is a monovalent antibody or a multivalent (e.g., bivalent) antibody. In certain embodiments, the monoclonal antibody is a monospecific antibody or a multispecific antibody (e.g., a bispecific antibody).

[0269] Antibody fragments that recognize MERTK (e.g., human MERTK) can be generated by any technique known to those skilled in the art. For example, the Fab and F(ab')2 fragments described herein can be produced by proteolytic cleavage of immunoglobulin molecules using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments). The Fab fragment corresponds to one of the two identical arms of an antibody molecule and contains an intact light chain paired with the VH and CH1 domains of the heavy chain. The F(ab')2 fragment contains the two antigen-binding arms of an antibody molecule linked by disulfide bonds in the hinge region.

[0270] Furthermore, the anti-MERTK antibodies or antigen-binding fragments thereof described herein can also be generated using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of phage particles carrying the polynucleotide sequences encoding them. In particular, DNA sequences encoding VH and VL domains are amplified from animal cDNA libraries (e.g., human or mouse cDNA libraries of affected tissues). The DNA encoding the VH and VL domains is recombined with an scFv linker by PCR and cloned into a phagemid vector. The vector is electroporated into E. coli cells, and the E. coli is infected with helper phage. The phages used in these methods are typically filamentous phages, including fd and M13, and the VH and VL domains are usually recombinantly fused to either gene III or gene VIII of the phage. Phage expressing antigen-binding domains that bind to a specific antigen can be selected or identified by antigen, for example, using labeled antigen or antigen bound or captured to a solid surface or bead. Examples of phage display methods that can be used to generate the antibodies described herein include those described in Brinkman U et al., (1995) J Immunol Methods 182: 41-50; Ames RS et al., (1995) J Immunol Methods 184: 177-186; Kettleborough CA et al., (1994) Eur J Immunol 24: 952-958;Persic L et al., (1997) Gene 187: 9-18;Burton DR & Barbas CF (1994) Advan Immunol 57: 191-280; PCT Application No. PCT / GB91 / 001134; International Publication Nos. WO90 / 02809, WO91 / 10737, WO92 / 01047, 92 / 18619, WO93 / 11236, WO95 / 15982, WO95 / 20401 and WO97 / 13844; and U.S. Pat. Nos. 5,698,426, 5,223, 409, 5,403,484, 5,580,717, 5,427,908, 5,750,753, 5,821,047, 5,571,698, 5,427,908, 5,516,637, 5,780,225, 5,658,727, 5,733,743 and 5,969,108.

[0271] As described in the above references, after phage selection, the antibody coding region from the phage can be isolated and used to generate whole antibodies, including humanized antibodies, chimeric antibodies, or any other desired antigen-binding fragments, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, as described below. Methods for the production of whole antibodies can be described in accordance with techniques disclosed in PCT Publication No. WO92 / 22324; Mullinax RL et al., (1992) BioTechniques 12(6): 864-9; Sawai H et al., (1995) Am J Reprod Immunol 34: 26-34; and Better M et al., (1988) Science 240: 1041-1043. Techniques may also be used to recombinantly produce antibody fragments, such as Fab, Fab' and F(ab')2 fragments, using methods known in the art.

[0272] In one embodiment, to generate a whole antibody, a VH or VL sequence can be amplified from a template, e.g., an scFv clone, using PCR primers containing the VH or VL nucleotide sequence, a restriction site, and flanking sequences that protect the restriction site. Using cloning techniques known to those skilled in the art, the PCR-amplified VH domain can be cloned into a vector expressing a VH constant region, and the PCR-amplified VL domain can be cloned into a vector expressing a VL constant region, e.g., a human kappa or lambda constant region. The VH and VL domains can also be cloned into a single vector expressing the necessary constant regions. The heavy chain conversion vector and the light chain conversion vector are then co-transfected into a cell line using techniques known to those skilled in the art to generate a stable or transient cell line expressing a full-length antibody, e.g., an IgG.

[0273] A chimeric antibody is a molecule in which different portions of the antibody are derived from different immunoglobulin molecules. For example, a chimeric antibody can contain the variable region of a mouse or rat monoclonal antibody fused to the constant region of a human antibody. Methods for producing chimeric antibodies are known in the art. For example, see Morrison SL (1985) Science 229: 1202-7; Oi VT & Morrison SL (1986) BioTechniques 4: 214-221; Gillies SD et al., (1989) J Immunol Methods 125: 191-202; and U.S. Patent No. 5,807,777. 15, 4,816,567, 4,816,397, and 6,331,415. In a specific embodiment, the chimeric antibody comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH and VL comprise the VH and VL amino acid sequences, respectively, set forth in Table 13.

[0274] A humanized antibody can bind to a predetermined antigen and comprises a framework region having substantially the amino acid sequence of a human immunoglobulin and a CDR having substantially the amino acid sequence of a non-human immunoglobulin (e.g., a murine immunoglobulin). In certain embodiments, a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The antibody may also comprise the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. The humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including IgG1, IgG2, IgG3, and IgG4. Humanized antibodies can be prepared by a variety of techniques, including, but not limited to, CDR grafting (European Patent No. EP239400, International Publication No. WO91 / 09967; and U.S. Patent Nos. 5,225,539, 5,530,101, and 5,585,089), veneering, or resurfacing (European Patent Nos. EP592106 and EP519596; Padlan EA (1991) Mol Immunol 28(4 / 5): 489-498; Studnicka GM et al., (1994) Prot Engineering 7(6): 805-814; and Roguska MA et al., (1994) PNAS 91: 969-973), chain shuffling (U.S. Pat. No. 5,565,332), and, for example, U.S. Pat. No. 6,407,213, U.S. Pat. No. 5,766,886, International Publication No. WO93 / 17105; Tan P et al., (2002) J Immunol 169: 1119-25; Caldas C et al., (2000) Protein Eng. 13(5): 353-60; Morea V et al., (2000) Methods 20(3): 267-79; Baca M et al., (1997) J Biol Chem 272(16): 10678-84; Roguska MA et al., (1996) Protein Eng 9(10): 895 904;Couto JR et al., (1995) Cancer Res. 55 (23 Supp): 5973s-5977s;Couto JR et al., (1995) Cancer Res 55(8): 1717-22;Sandhu JS (1994) Gene 150(2): 409-10 and Pedersen JT et al., (1994) J Mol Biol 235(3): 959-73. They can be produced using a variety of techniques known in the art, see also U.S. Application Publication No. US2005 / 0042664(A1) (February 24, 2005), which is incorporated herein by reference in its entirety.

[0275] In a specific embodiment, the humanized antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK) comprises the VH and VL of antibody z10 (see Table 11), the VH and VL of antibody z11 (see Table 12), or the VH and VL of antibody z13 (see Table 13). Methods for making multispecific (e.g., bispecific) antibodies have been described, see, e.g., U.S. Patent Nos. 7,951,917; 7,183,076; 8,227,577; 5,837,242; 5,989,830; 5,869,620; 6,132,992 and 8,586,713.

[0276] Single domain antibodies, e.g., antibodies lacking light chains, can be produced by methods well known in the art. Riechmann L & Muyldermans S (1999) J Immunol 231: 25-38; Nuttall SD et al., (2000) Curr Pharm Biotechnol 1(3): 253-263; Muyldermans S, (2001) J Biotechnol 74(4): 277-302; U.S. Patent No. 6,005,005. ,079; and International Publication Nos. WO94 / 04678, WO94 / 25591, and WO01 / 44301.

[0277] Furthermore, antibodies that immunospecifically bind to a MERTK (e.g., human MERTK) antigen can then be utilized to generate anti-idiotypic antibodies that "mimic" the antigen using techniques well known to those skilled in the art. (See, e.g., Greenspan NS & Bona CA (1989) FASEB J 7(5): 437-444; and Nissinoff A (1991) J Immunol 147(8): 2429-2438).

[0278] In certain embodiments, the anti-MERTK antibody or antigen-binding fragment thereof described herein binds to the same or overlapping epitope of MERTK (e.g., human MERTK) as the anti-MERTK antibody or antigen-binding fragment thereof described herein. In certain embodiments, an antibody described herein that competitively blocks (e.g., in a dose-dependent manner) any one of the antibodies described herein (e.g., z10, z11, or z13, or xAb) from binding to MERTK (e.g., human MERTK) is a human anti-MERTK antibody or antigen-binding fragment thereof. Human antibodies can be produced using any method known in the art. For example, transgenic mice that cannot express functional endogenous immunoglobulins but can express human immunoglobulin genes can be used. In particular, human heavy and light chain immunoglobulin gene complexes can be introduced into mouse embryonic stem cells by random or homologous recombination. Alternatively, human variable regions, constant regions, and diversity regions can be introduced into mouse embryonic stem cells in addition to human heavy and light chain genes. The mouse heavy and light chain immunoglobulin genes can be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. HHomozygous deletion of the region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring that express human antibodies. The transgenic mice are immunized in the usual manner with a selected antigen, such as all or part of an antigen (e.g., MERTK). Monoclonal antibodies against the antigen can be obtained from the immunized transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes carried by the transgenic mice rearrange during B-cell differentiation and subsequently undergo class switching and somatic mutation. Therefore, such techniques can be used to produce therapeutically useful IgG, IgA, IgM, and IgE antibodies. For an overview of this technology for producing human antibodies, see, for example, Lonberg N & Huszar D (1995) Int Rev Immunol 13:65-93. Producing Human Antibodies and Human Monoclonal Antibodies For a detailed discussion of this technology for, as well as protocols for producing such antibodies, see, e.g., International Publication Nos. WO 98 / 24893, WO 96 / 34096, and WO 96 / 33735; and U.S. Pat. Nos. 5,413,923, 5,625,126, 5,633,425, 5,569,825, 5,661,016, 5,545,806, 5,814,318, and 5,939,598. Examples of mice capable of producing human antibodies include the Xenomouse™ (Abgenix, Inc.; U.S. Patent Nos. 6,075,181 and 6,150,184), HuAb-Mouse™ (Mederex, Inc. / Gen Pharm; U.S. Patent Nos. 5,545,806 and 5,569,825), Trans Chromo Mouse™ (Kirin), and KM Mouse™ (Medarex / Kirin).

[0279] The human antibody that specifically binds to MERTK (for example, human MERTK) can be produced by various methods known in the art, including the phage display method described above, using an antibody library derived from human immunoglobulin sequence.See also U.S. Patent Nos. 4,444,887, 4,716,111 and 5,885,793; and International Publication Nos. WO98 / 46645, WO98 / 50433, WO98 / 24893, WO98 / 16654, WO96 / 34096, WO96 / 33735 and WO91 / 10741.

[0280] In some embodiments, human antibodies can be produced using mouse-human hybridomas. For example, Epstein-Barr virus (EBV)-transformed human peripheral blood lymphocytes can be fused with mouse myeloma cells to produce mouse-human hybridomas that secrete human monoclonal antibodies, and these mouse-human hybridomas can be screened to determine those that secrete human monoclonal antibodies that immunospecifically bind to a target antigen (e.g., human MERTK). Such methods are known and described in the art, see, for example, Shinmoto H et al., (2004) Cytotechnology 46: 19-23; Naganawa Y et al., (2005) Human Antibodies 14: 27-31.

[0281] In a specific embodiment, methods for screening and selecting antibodies or antigen-binding fragments thereof described herein that specifically bind to MERTK (e.g., human MERTK) are as described in Example 1 below.

[0282] Once an anti-MERTK antibody or antigen-binding fragment thereof described herein is produced, it can be purified by any method known in the art for the purification of immunoglobulin molecules, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for specific antigens following Protein A, and sizing column chromatography), centrifugation, differential solubility, or any other standard technique for the purification of proteins. Additionally, the antibodies described herein can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.

[0283] In specific embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof described herein are isolated or purified. Generally, an isolated antibody is one that is substantially free of other antibodies having antigenic specificities different from that of the isolated antibody. For example, in certain embodiments, preparations of antibodies described herein are substantially free of cellular material and / or chemical precursors. The phrase "substantially free of cellular material" includes preparations of antibodies separated from cellular components of isolated or recombinantly produced cells. Thus, antibodies that are substantially free of cellular material include preparations of antibodies having less than about 30%, 20%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (by dry weight) of heterologous proteins (also referred to herein as "contaminating proteins") and / or antibody variants, e.g., different post-translationally modified forms of antibodies or other different versions of antibodies (e.g., antibody fragments). When an antibody is recombinantly produced, it is also generally substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, 2%, 1%, 0.5%, or 0.1% of the volume of the protein preparation. When an antibody is produced by chemical synthesis, it is generally substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals involved in the synthesis of the protein. Thus, such preparations of antibodies have less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. In specific embodiments, the antibodies described herein are isolated or purified. Polynucleotides

[0284] In certain aspects, provided herein are polynucleotides comprising nucleotide sequences encoding the anti-MERTK antibodies or antigen-binding fragments thereof described herein that specifically bind to MERTK (e.g., human MERTK) antigen, and vectors, e.g., vectors comprising such polynucleotides for their efficient expression in host cells (e.g., E. coli and mammalian cells). In some embodiments, the polynucleotides are isolated or purified.

[0285] As used herein, an "isolated" polynucleotide or nucleic acid molecule is one that is separated from other nucleic acid molecules that are present in the nucleic acid molecule's natural source (e.g., mouse or human). Also, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular materials or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. For example, the phrase "substantially free" includes preparations of polynucleotides or nucleic acid molecules that have less than about 15%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% of other materials, such as cellular materials, culture medium, other nucleic acid molecules, chemical precursors, and / or other chemicals.

[0286] In certain aspects, provided herein are polynucleotides comprising nucleotide sequences encoding the anti-MERTK antibodies or antigen-binding fragments thereof described herein, which specifically bind to MERTK (e.g., human MERTK) polynucleotides and comprise the amino acid sequences described herein, and antibodies that compete with such antibodies for binding to MERTK (e.g., human MERTK) polypeptides (e.g., in a dose-dependent manner) or bind to the same or overlapping epitope as such antibodies.

[0287] In certain aspects, provided herein is a polynucleotide comprising a nucleotide sequence encoding the light chain or the heavy chain of an antibody described herein.

[0288] In certain embodiments, the polynucleotide described herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence described herein (SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 108, or SEQ ID NO: 109). In certain embodiments, the polynucleotide described herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK), wherein the anti-MERTK antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence described herein (SEQ ID NO: 106 or SEQ ID NO: 111). In certain embodiments, the polynucleotide described herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106. In certain embodiments, the polynucleotides described herein comprise a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106. In certain embodiments, the polynucleotides described herein comprise a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106.In certain embodiments, the polynucleotides described herein comprise a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 111. In certain embodiments, the polynucleotides described herein comprise a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106.

[0289] In certain embodiments, the polynucleotides described herein encode a VH, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 119, SEQ ID NO: 121, SEQ ID NO: 122, or SEQ ID NO: 123. In certain embodiments, the polynucleotides described herein encode a VL, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 120 or SEQ ID NO: 124. In a specific embodiment, the polynucleotides described herein encode a VH and a VL, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 119, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 120. In another specific embodiment, the polynucleotides described herein encode a VH and a VL, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 121, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 120. In another specific embodiment, the polynucleotides described herein encode a VH and a VL, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 122, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 120. In another embodiment, a polynucleotide described herein encodes a VH and a VL, wherein the polynucleotide comprises the nucleic acid sequence of SEQ ID NO:123, and the polynucleotide comprises the nucleic acid sequence of SEQ ID NO:124.

[0290] In specific aspects, provided herein are polynucleotides comprising nucleotide sequences encoding antibodies comprising a light chain and a heavy chain, e.g., separate light and heavy chains. With respect to the light chain, in specific embodiments, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein comprising a human kappa light chain or a human lambda light chain.

[0291] In a specific aspect, a polynucleotide provided herein comprises a nucleotide sequence encoding the light chain of an antibody, wherein the nucleotide sequence comprises the variable light chain region of SEQ ID NO: 106 and the nucleotide sequence of a human light chain constant region of a human kappa or lambda light chain. In another aspect, a polynucleotide provided herein comprises a nucleotide sequence encoding the light chain of an antibody, wherein the light chain comprises the variable light chain region of SEQ ID NO: 111 and the human light chain constant region of a human kappa or lambda light chain.

[0292] In certain embodiments, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises a light chain, wherein the amino acid sequence of the variable region of the light chain may comprise any of the amino acid sequences of SEQ ID NO: 106 or SEQ ID NO: 111, and wherein the constant region of the light chain comprises the amino acid sequence of a human kappa light chain constant region. In another specific embodiment, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises a light chain, wherein the amino acid sequence of the variable region of the light chain may comprise any of the amino acid sequences of SEQ ID NO: 106 or SEQ ID NO: 111, and wherein the constant region of the light chain comprises the amino acid sequence of a human lambda light chain constant region. In another aspect, the polynucleotides provided herein comprise a nucleotide sequence encoding the light chain of the antibody, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 113 or 118. In another aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding the light chain of an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the nucleotide sequence comprises SEQ ID NO: 126 or 130.

[0293] In certain embodiments, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises a heavy chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 105, and a heavy chain constant region. In another specific embodiment, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and comprises a heavy chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 107, and a heavy chain constant region. In another specific embodiment, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and comprises a heavy chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 108, and a heavy chain constant region. In another specific embodiment, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and comprises a heavy chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 109, and a heavy chain constant region. In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and comprises a heavy chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 110, and a heavy chain constant region.

[0294] In certain embodiments, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence of SEQ ID NO: 112. In certain embodiments, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence of SEQ ID NO: 114. In certain embodiments, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence of SEQ ID NO: 115. In certain embodiments, the polynucleotides provided herein comprise a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence of SEQ ID NO: 116. In certain embodiments, the polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence of SEQ ID NO: 117.

[0295] In a specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding a heavy chain of an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the nucleotide sequence comprises SEQ ID NO: 119, and the nucleotide sequence of a human heavy chain constant region. In another aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding a heavy chain of an antibody that specifically binds to MERTK, wherein the nucleotide sequence comprises SEQ ID NO: 125.

[0296] In a specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding a heavy chain of an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the nucleotide sequence comprises SEQ ID NO: 121 and a nucleotide sequence of a human heavy chain constant region. In another aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding a heavy chain of an antibody that specifically binds to MERTK, wherein the nucleotide comprises SEQ ID NO: 127.

[0297] In a specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding a heavy chain of an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the nucleotide sequence comprises SEQ ID NO: 122, and the nucleotide sequence of a human heavy chain constant region. In another aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding a heavy chain of an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the nucleotide sequence comprises SEQ ID NO: 128.

[0298] In a specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding a heavy chain of an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the nucleotide sequence comprises SEQ ID NO: 123, and the nucleotide sequence of a human heavy chain constant region. In another aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding a heavy chain of an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the nucleotide comprises SEQ ID NO: 129.

[0299] In a specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and a nucleotide sequence encoding the heavy chain of the antibody, wherein the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 119 and the nucleotide sequence of a human heavy chain constant region, and the nucleotide sequence encoding the light chain comprises SEQ ID NO: 120 and the nucleotide sequence of a human heavy chain constant region. In another specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and a nucleotide sequence encoding the heavy chain of the antibody, wherein the nucleotide sequence encoding the light chain comprises SEQ ID NO: 120 and the nucleotide sequence of a human light chain constant region, and the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 121 and the nucleotide sequence of a human heavy chain constant region. In another specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and a nucleotide sequence encoding the heavy chain of the antibody, wherein the nucleotide sequence encoding the light chain comprises SEQ ID NO: 120 and the nucleotide sequence of a human light chain constant region, and the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 122 and the nucleotide sequence of a human heavy chain constant region. In another specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and a nucleotide sequence encoding the heavy chain of the antibody, wherein the nucleotide sequence encoding the light chain comprises SEQ ID NO: 124 and the nucleotide sequence of a human light chain constant region, and the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 123 and the nucleotide sequence of a human heavy chain constant region.

[0300] In a specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises (1) a variable heavy chain region and a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 105, and (2) a variable light chain region and a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 106. In another specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises (1) a variable heavy chain region and a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 107, and (2) a variable light chain region and a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 106. In another specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises (1) a variable heavy chain region and a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 108, and (2) a variable light chain region and a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 106. In another specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises (1) a variable heavy chain region and a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 110, and (2) a variable light chain region and a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 111.

[0301] In another specific aspect, the polynucleotide provided herein comprises a nucleotide sequence encoding an antibody that specifically binds to MERTK (e.g., human MERTK), wherein the antibody comprises (1) a variable heavy chain region and a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 109, and (2) a variable light chain region and a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 106.

[0302] In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other nucleotide sequence encodes the light chain of the antibody, the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 125, and the nucleotide sequence encoding the light chain comprises SEQ ID NO: 126. In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other nucleotide sequence encodes the light chain of the antibody, the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 127, and the nucleotide sequence encoding the light chain comprises SEQ ID NO: 126. In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other nucleotide sequence encodes the light chain of the antibody, the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 128, and the nucleotide sequence encoding the light chain comprises SEQ ID NO: 126. In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other nucleotide sequence encodes the light chain of the antibody, the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 129, and the nucleotide sequence encoding the light chain comprises SEQ ID NO: 130.

[0303] In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other encodes the light chain of the antibody, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 112 and the light chain comprises the amino acid sequence of SEQ ID NO: 113. In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other encodes the light chain of the antibody, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 114 and the light chain comprises the amino acid sequence of SEQ ID NO: 113. In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other encodes the light chain of the antibody, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 115 and the light chain comprises the amino acid sequence of SEQ ID NO: 113. In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other encodes the light chain of the antibody, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 116 and the light chain comprises the amino acid sequence of SEQ ID NO: 113. In another specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof that specifically binds to MERTK (e.g., human MERTK), wherein one nucleotide sequence encodes the heavy chain of the antibody and the other encodes the light chain of the antibody, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 117 and the light chain comprises the amino acid sequence of SEQ ID NO: 118.

[0304] In certain embodiments, polynucleotide, nucleic acid or nucleotide comprises deoxyribonucleic acid, ribonucleic acid, ribonucleotide and their polymeric forms.In some embodiments, polynucleotide, nucleic acid or nucleotide is single-stranded or double-stranded.In specific embodiments, the sequence of polynucleotide, nucleic acid or nucleotide is cDNA sequence.

[0305] In some embodiments, the polynucleotide sequences (e.g., nucleic acid sequences) described herein encoding the anti-MERTK antibodies or antigen-binding fragments thereof are codon-optimized using methodologies known to those skilled in the art. In certain embodiments, the optimized polynucleotide sequences encoding the anti-MERTK antibodies or antigen-binding fragments thereof described herein, or antigen-binding fragments thereof (e.g., VH domain and / or VL domain) can hybridize to antisense (e.g., complementary) polynucleotides of non-optimized polynucleotide sequences encoding the anti-MERTK antibodies or antigen-binding fragments thereof described herein (e.g., VH domain and / or VL domain). In specific embodiments, the optimized nucleotide sequences encoding the anti-MERTK antibodies or antigen-binding fragments thereof described herein hybridize to antisense polynucleotides of non-optimized polynucleotide sequences encoding the anti-MERTK antibodies or antigen-binding fragments thereof described herein under high stringency conditions. In a specific embodiment, an optimized nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof hybridizes to an antisense polynucleotide of a non-optimized nucleotide sequence encoding an anti-MERTK antibody or antigen-binding fragment thereof described herein under high stringency, medium stringency, or low stringency hybridization conditions. Information regarding hybridization conditions is described, for example, in U.S. Patent Application Publication No. US2005 / 0048549 (e.g., paragraphs 72-73), which is incorporated herein by reference.

[0306] Polynucleotides can be obtained and the nucleotide sequence of the polynucleotides can be determined by any method known in the art. The nucleotide sequences encoding the antibodies and modified versions of these antibodies described herein can be determined using methods well known in the art, i.e., nucleotide codons known to encode specific amino acids are assembled in such a way to generate a nucleic acid sequence encoding the antibody. Such polynucleotides encoding antibodies can be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier G et al., (1994), BioTechniques 17: 242-6), which can be briefly described as follows: This involves the synthesis of overlapping oligonucleotides containing portions of the nucleotide sequence, annealing and ligating the oligonucleotides, and then amplifying the ligated oligonucleotides by PCR.

[0307] Alternatively, polynucleotides encoding the antibodies described herein can be generated from nucleic acid from a suitable source (e.g., a hybridoma) using methods well known in the art (e.g., PCR and other molecular cloning methods). For example, PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of a known sequence can be performed using genomic DNA obtained from hybridoma cells producing the antibody of interest. Such PCR amplification methods can be used to obtain nucleic acids containing sequences encoding the antibody light and / or heavy chains. Such PCR amplification methods can be used to obtain nucleic acids containing sequences encoding the antibody variable light and / or variable heavy chain regions. The amplified nucleic acids can be cloned into vectors for expression in host cells and further cloning, e.g., to generate humanized antibodies.

[0308] If a clone containing a nucleic acid sequence encoding a particular antibody is not available but the sequence of the antibody molecule is known, nucleic acids encoding the immunoglobulin can be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library, or a cDNA library generated from any tissue or cell that expresses the antibody, such as hybridoma cells selected to express an antibody described herein, or nucleic acid isolated therefrom, preferably polyA+ RNA) by PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of the sequence, or by cloning using oligonucleotide probes specific for the particular gene sequence to identify, for example, a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by PCR can then be cloned into replicable cloning vectors using any method well known in the art.

[0309] DNA encoding the anti-MERTK antibody described herein can be easily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the anti-MERTK antibody). Hybridoma cells can serve as a source of such DNA. Once isolated, the DNA can be placed into an expression vector, which can then be transfected into host cells that do not otherwise produce immunoglobulin proteins, such as E. coli cells, monkey COS cells, Chinese hamster ovary (CHO) cells (e.g., CHO cells from CHO GS System™ (Lonza)), 293F cells, HEK293 cells, or myeloma cells, to obtain the synthesis of MERTK agonist antibodies in the recombinant host cells.

[0310] To generate whole antibodies, the VH or VL sequence can be amplified in an scFv clone using PCR primers containing the VH or VL nucleotide sequence, a restriction site, and a flanking sequence that protects the restriction site. Using cloning techniques known to those skilled in the art, the PCR-amplified VH domain can be cloned into a vector expressing a heavy chain constant region, such as the human gamma 4 constant region, and the PCR-amplified VL domain can be cloned into a vector expressing a light chain constant region, such as the human kappa or lambda constant region. In certain embodiments, the vector for expressing the VH or VL domain contains a promoter, a secretion signal, a cloning site for the variable domain, a constant domain, and a selection marker. The VH and VL domains can also be cloned into a single vector expressing the necessary constant regions. The heavy chain conversion vector and the light chain conversion vector are then co-transfected into a cell line using techniques known to those skilled in the art to generate stable or transient cell lines expressing full-length antibodies, such as IgG.

[0311] The DNA can also be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains for the murine sequences, or by covalently joining all or part of the coding sequence for a non-immunoglobulin polypeptide to the immunoglobulin coding sequence.

[0312] Also provided are polynucleotides that hybridize to polynucleotides encoding the antibodies or antigen-binding fragments thereof described herein under high, medium, or low stringency hybridization conditions. In specific embodiments, the polynucleotides described herein hybridize to polynucleotides encoding the VH (SEQ ID NO: 119, 121, 122, or 123) and / or VL (SEQ ID NO: 120 or 124) provided herein under high, medium, or low stringency hybridization conditions.

[0313] Hybridization conditions are described in the art and are known to those skilled in the art. For example, hybridization under stringent conditions can include hybridization to filter-bound DNA in 6× sodium chloride / sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC / 0.1% SDS at about 50-65° C.; hybridization under highly stringent conditions can include hybridization to filter-bound nucleic acid in 6×SSC at about 45° C., followed by one or more washes in 0.1×SSC / 0.2% SDS at about 68° C. Hybridization under other stringent hybridization conditions is known and described to those skilled in the art, for example, in Ausubel et al. FM et al., eds., (1989) Current Protocols in Molecular Biology, Vol. I, Green Publishing Associates, Inc. and John Wiley & Sons, Inc., New York at pages 6.3.1-6.3.6 and 2.10.3. 5.3.3. Cells and Vectors

[0314] In certain aspects, provided herein is a vector (e.g., an expression vector) comprising a polynucleotide comprising a nucleotide sequence encoding the anti-MERTK antibody or antigen-binding fragment thereof described herein for recombinant expression in a host cell, preferably a mammalian cell. The expression vector may be, for example, a plasmid or a viral vector (e.g., Newcastle disease virus, adenovirus, adeno-associated virus, vaccinia, etc.). Also provided herein is a host cell comprising such a vector for recombinantly expressing the anti-MERTK antibody or antigen-binding fragment thereof described herein.

[0315] Recombinant expression of an antibody described herein (e.g., a full-length antibody, a heavy and / or light chain of the antibody, or a single-chain antibody described herein) that specifically binds to MERTK (e.g., human MERTK) involves construction of an expression vector containing a polynucleotide encoding the antibody. Once a polynucleotide encoding an antibody molecule described herein, the heavy and / or light chain of the antibody, or an antigen-binding fragment thereof (e.g., a heavy and / or light chain variable region) is obtained, vectors for the production of the antibody molecule can be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing proteins by expressing polynucleotides containing antibody or antibody fragment (e.g., light or heavy chain, or both) encoding nucleotide sequences are described herein. Methods well known to those skilled in the art can be used to construct expression vectors containing the coding sequence for an antibody or antibody fragment (e.g., light or heavy chain, or both) and appropriate transcriptional and translational control signals. These methods include, for example, in These include recombinant DNA techniques in vitro, synthetic techniques, and in vivo genetic recombination. Also provided are replicable vectors containing a nucleotide sequence encoding the antibody molecule described herein, the heavy or light chain of the antibody, or the heavy or light chain variable domain of the anti-MERTK antibody or its antigen-binding fragment, operably linked to a promoter. Such vectors can contain, for example, nucleotide sequences encoding the constant region of the antibody molecule (see, for example, International Publication Nos. WO86 / 05807 and WO89 / 01036; and U.S. Patent No. 5,122,464), and the variable domain of the antibody can be cloned into such vectors for expression of the entire heavy chain, the entire light chain, or both the entire heavy and light chains.

[0316] The expression vector can be transferred into cells (e.g., host cells) by conventional techniques, and the resulting cells can then be cultured by conventional techniques to produce the anti-MERTK antibody or antigen-binding fragment thereof described herein. Thus, provided herein are host cells containing a polynucleotide encoding an antibody or antigen-binding fragment thereof described herein, or a heavy or light chain thereof, or a fragment thereof, or a single-chain antibody described herein, operably linked to a promoter for expression of such a sequence in the host cell. As used herein, the term "host cell" can be any type of cell, e.g., a primary cell, a cell in culture, or a cell derived from a cell line. In specific embodiments, the term "host cell" refers to a cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. The progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due, for example, to mutations or environmental influences that may occur in subsequent generations or upon integration of the nucleic acid molecule into the host cell genome.

[0317] A variety of host-expression vector systems can be utilized to express the antibody molecules described herein. Such host-expression systems represent vehicles by which a coding sequence of interest can be produced and subsequently purified, but also represent cells which, when transformed or transfected with the appropriate nucleotide coding sequence, are capable of expressing the antibody molecules described herein in situ. These include, but are not limited to, bacteria (e.g., E. coli and B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA, or cosmid DNA expression vectors containing the antibody coding sequence; yeast (e.g., Saccharomyces Pichia) transformed with recombinant yeast expression vectors containing the antibody coding sequence; insect cell systems infected with recombinant viral expression vectors (e.g., baculovirus) containing the antibody coding sequence; and plant cell systems (e.g., Chlamydomonas spp.) infected with recombinant viral expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing the antibody coding sequence. reinhardtii); or mammalian cell lines (e.g., COS (e.g., COS1 or COS), CHO, BHK, MDCK, HEK293, NS0, PER.C6, VERO, CRL7030, HsS78Bst, HeLa, and NIH3T3, HEK-293T, 293F, HepG2, SP210, R1.1, BW, LM, BSC1, BSC40, YB / 20, and BMT10 cells) harboring a recombinant expression construct containing a promoter derived from the genome of a mammalian cell (e.g., a metallothionein promoter) or a promoter derived from a mammalian virus (e.g., an adenovirus late promoter; a vaccinia virus 7.5K promoter). In a specific embodiment, the cells for expressing the antibodies or antigen-binding fragments thereof described herein are CHO cells, e.g., CHO cells from the CHO GS System™ (Lonza). In certain embodiments, cells for expressing the antibodies described herein are human cells, e.g., human cell lines.In specific embodiments, the mammalian expression vector is pOptiVEC™ or pcDNA3.3. In certain embodiments, bacterial cells such as Escherichia coli or eukaryotic cells (e.g., mammalian cells) are used for the expression of a recombinant antibody molecule, particularly for the expression of whole recombinant antibody molecules. For example, mammalian cells such as Chinese hamster ovary (CHO) cells, in conjunction with vectors such as the major intermediate-early gene promoter element from human cytomegalovirus, are effective expression systems for antibodies (Foecking MK). & Hofstetter H (1986) Gene 45: 101-5; and Cockett MI et al., (1990) Biotechnology 8(7): 662-7). In certain embodiments, the antibodies described herein are produced by CHO cells or NS0 cells. In specific embodiments, expression of the nucleotide sequence encoding the antibodies described herein that immunospecifically bind MERTK (e.g., human MERTK) is regulated by a constitutive promoter, an inducible promoter, or a tissue-specific promoter.

[0318] In bacterial systems, several expression vectors may be advantageously selected depending on the use intended for the expressed antibody molecule. For example, when producing large quantities of such antibodies, for the generation of pharmaceutical compositions of the antibody molecule, vectors which direct the expression of high levels of fusion protein products that are easily purified may be desirable. Such vectors include, but are not limited to, the E. coli expression vector pUR278 (Ruether U & Mueller-Hill B (1983) EMBO J 2: 1791-1794), in which the antibody coding sequence can be individually ligated into the vector in frame with the lac Z coding region to produce the fusion protein; the pIN vector (Inouye S & Inouye M (1985) Nuc Acids Res 13: 3101-3109; Van Heeke G & Schuster SM (1989) J Biol Chem 24: 5503-5509). For example, pGEX vectors can be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST). Generally, such fusion proteins are soluble and can be easily purified from lysed cells by adsorption and binding to matrix glutathione agarose beads, followed by elution in the presence of free glutathione. pGEX vectors are designed to contain thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

[0319] In an insect system, for example, Autographa californica nuclear polyhedrosis virus (AcNPV) can be used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The antibody coding sequence can be cloned individually into non-essential regions (e.g., the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (e.g., the polyhedrin promoter).

[0320] Several viral-based expression systems are available for mammalian host cells. When adenovirus is used as an expression vector, the coding sequence of the antibody of interest can be ligated into an adenovirus transcription / translation control complex, such as the late promoter and tripartite leader sequence. This chimeric gene can then be inserted into the adenovirus genome by in vitro or in vivo recombination. Insertion into a non-essential region of the viral genome (e.g., region E1 or E3) generates recombinant virus that is viable and capable of expressing antibody molecules in infected hosts (see, e.g., Logan J & Shenk T (1984) PNAS 81(12):3655-9). Specific initiation signals may also be required for efficient translation of the inserted antibody coding sequence. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in line with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, eg, Bitter G et al., (1987) Methods Enzymol. 153: 516-544).

[0321] In addition, a host cell strain can be selected that modulates the expression of the inserted sequence or modifies and processes the gene product in the specific manner desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products can be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. An appropriate cell line or host system can be selected to ensure the correct modification and processing of the expressed foreign protein. To this end, eukaryotic host cells that possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product can be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, Hela, MDCK, HEK293, NIH3T3, W138, 293F, BT483, Hs578T, HTB2, BT2O and T47D, NS0 (a murine myeloma cell line that does not endogenously produce any immunoglobulin chains), CRL7O3O, COS (e.g., COS1 or COS), PER.C6, VERO, HsS78Bst, HEK-293T, HEK293, HepG2, SP210, R1.1, BW, LM, BSC1, BSC40, YB / 20, BMT10 and HsS78Bst cells. In certain embodiments, the anti-MERTK antibodies described herein are produced in mammalian cells, such as CHO cells.

[0322] In specific embodiments, the antibodies or antigen-binding fragments thereof described herein have reduced or no fucose content. Such antibodies can be produced using techniques known to those skilled in the art. For example, the antibodies can be expressed in cells that have insufficient or no fucosylation ability. In a specific example, a cell line with knockout of both alleles of α1,6-fucosyltransferase can be used to produce antibodies or antigen-binding fragments thereof with reduced fucose content. The Potelligent® system (Lonza) is an example of such a system that can be used to produce antibodies or antigen-binding fragments thereof with reduced fucose content.

[0323] For long-term, high-yield production of recombinant proteins, stable expressing cells can be generated. For example, cell lines that stably express the anti-MERTK antibodies or antigen-binding fragments thereof described herein, or chimeric anti-MERTK antibodies or antigen-binding fragments thereof described herein can be engineered. In a specific embodiment, the cells provided herein stably express the light chain / light chain variable domain and heavy chain / heavy chain variable domain that associate to form the antibody or antigen-binding fragment thereof described herein.

[0324] In certain embodiments, rather than using expression vectors containing viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoters, enhancers, sequences, transcription terminators, polyadenylation sites, etc.) and a selectable marker. After introduction of the foreign DNA / polynucleotide, engineered cells can be grown in an enriched medium for 1-2 days and then switched to a selective medium. The selectable marker on the recombinant plasmid confers resistance to selection, allowing the cells to stably integrate the plasmid into their chromosomes and grow to form foci that can then be cloned and expanded into cell lines. This method can be advantageously used to engineer cell lines that express the humanized anti-MERTK antibodies or antigen-binding fragments thereof described herein, or the chimeric anti-MERTK antibodies or antigen-binding fragments thereof described herein. Such engineered cell lines can be particularly useful in screening and evaluating compositions that interact directly or indirectly with antibody molecules.

[0325] Several selection systems can be used, including but not limited to herpes simplex virus thymidine kinase (Wigler M et al., (1977) Cell 11(1): 223-32), herpes simplex virus thymidine kinase (HKK) ... These include the genes for poxanthine guanine phosphoribosyltransferase (Szybalska EH & Szybalski W (1962) PNAS 48(12): 2026-2034) and adenine phosphoribosyltransferase (Lowy I et al., (1980) Cell 22(3): 817-23). These can be used in tk, hgprt, or aprt cells, respectively. Antimetabolite resistance can also be used as the basis for selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler M et al., (1980) PNAS 77(6): 3567-70; O'Hare K et al., (1981) PNAS 78: 1527-31); Micoff gpt (Mulligan RC & Berg P (1981) PNAS 78(4): 2072-6), which confers resistance to phenolic acids; neo (Wu GY), which confers resistance to the aminoglycoside G-418; & Wu CH (1991) Biotherapy 3: 87-95;Tolstoshev P (1993) Ann Rev Pharmacol Toxicol 32: 573-596;Mulligan RC (1993) Science 260: 926-932; and Morgan RA & Anderson WF (1993) Ann Rev Biochem 62: 191-217; Nabel GJ & Felgner PL (1993) Trends Biotechnol 11(5): 211-5); and Haig hygro (Santerre RF et al., (1984) Gene 30(1-3): 147-56). Methods generally known in the field of recombinant DNA technology can be routinely applied to select the desired recombinant clones, and such methods are described, for example, in Ausubel FM et al., (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); Kriegler M, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and Chapters 12 and 13, Dracopoli NC et al., (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993), which are incorporated herein by reference in their entireties. (eds.), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colbere-Garapin F et al., (1981) J Mol Biol 150: 1-14.

[0326] Expression levels of antibody molecules can be increased by vector amplification (for a review, see Bebbington CR & Hentschel CCG, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells). in DNA cloning, Vol. 3 (Academic Press, New York, 1987) If the marker in the antibody expression vector system is amplifiable, increasing the level of inhibitor present in the host cell culture will increase the number of copies of the marker gene. Since the amplified region is associated with the antibody gene, antibody production will also increase (Crouse GF et al., (1983) Mol Cell Biol 3: 257-66).

[0327] Host cells can be co-transfected with two or more expression vectors described herein: a first vector encoding a heavy chain-derived polypeptide and a second vector encoding a light chain-derived polypeptide. The two vectors can contain the same selectable marker that allows for equal expression of heavy and light chain polypeptides. Host cells can be co-transfected with different amounts of two or more expression vectors. For example, host cells can be transfected with any one of the following ratios of the first expression vector to the second expression vector: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, or 1:50.

[0328] In a specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the variable light chain region (VL) of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and a nucleotide sequence encoding the variable heavy chain region (VH) of the antibody, wherein the VL comprises the amino acid sequence of SEQ ID NO: 106 and the VH comprises the amino acid sequence of SEQ ID NO: 105. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and a nucleotide sequence encoding the heavy chain of the antibody, wherein the light chain comprises a variable light chain region comprising the amino acid sequence of SEQ ID NO: 106 and a human light chain constant region, and the heavy chain comprises a variable heavy chain region comprising the amino acid sequence of SEQ ID NO: 105 and a human heavy chain constant region.

[0329] In a specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the variable light chain region (VL) of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and a nucleotide sequence encoding the variable heavy chain region (VH) of the antibody, wherein the VL comprises the amino acid sequence of SEQ ID NO: 106 and the VH comprises the amino acid sequence of SEQ ID NO: 109. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and a nucleotide sequence encoding the heavy chain of the antibody, wherein the light chain comprises a variable light chain region comprising the amino acid sequence of SEQ ID NO: 106 and a human light chain constant region, and the heavy chain comprises a variable heavy chain region comprising the amino acid sequence of SEQ ID NO: 109 and a human heavy chain constant region.

[0330] In a specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the VL of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the VH of the antibody, wherein the VL comprises the amino acid sequence of SEQ ID NO: 106 and the VH comprises the amino acid sequence of SEQ ID NO: 107. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the heavy chain of the antibody, wherein the light chain comprises a VL comprising the amino acid sequence of SEQ ID NO: 106 and a human light chain constant region, and the heavy chain comprises a VH comprising the amino acid sequence of SEQ ID NO: 107 and a human heavy chain constant region.

[0331] In a specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the VL of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the VH of the antibody, wherein the VL comprises the amino acid sequence of SEQ ID NO: 106 and the VH comprises the amino acid sequence of SEQ ID NO: 108. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the heavy chain of the antibody, wherein the light chain comprises the variable light chain region of SEQ ID NO: 108 and a human light chain constant region, and the heavy chain comprises the nucleotide sequence of the variable heavy chain region of SEQ ID NO: 105 and a human heavy chain constant region.

[0332] In a specific aspect, the host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the VL of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the VH of the antibody, wherein the VL comprises the amino acid sequence of SEQ ID NO: 111 and the VH comprises the amino acid sequence of SEQ ID NO: 110.

[0333] In another specific aspect, the host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the heavy chain of the antibody, wherein the nucleotide sequence encoding the light chain comprises SEQ ID NO: 120 and the nucleotide sequence of a human light chain constant region, and the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 119 and the nucleotide sequence of a human heavy chain constant region.

[0334] In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the heavy chain of the antibody, wherein the nucleotide sequence encoding the light chain comprises SEQ ID NO: 120 and the nucleotide sequence of a human light chain constant region, and the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 121 and the nucleotide sequence of a human heavy chain constant region. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the heavy chain of the antibody, wherein the nucleotide sequence encoding the light chain comprises SEQ ID NO: 120 and the nucleotide sequence of a human light chain constant region, and the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 122 and the nucleotide sequence of a human heavy chain constant region. In another specific aspect, the host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the light chain of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and a nucleotide sequence encoding the heavy chain of the antibody, wherein the nucleotide sequence encoding the light chain comprises SEQ ID NO: 124 and the nucleotide sequence of a human light chain constant region, and the nucleotide sequence encoding the heavy chain comprises SEQ ID NO: 123 and the nucleotide sequence of a human heavy chain constant region.

[0335] In a specific aspect, a host cell provided herein comprises a first vector and a second vector, wherein the first vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and the second vector comprises the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 105 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 106. In another specific aspect, a host cell provided herein comprises a first vector and a second vector, wherein the first vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and the second vector comprises the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 107 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 106. In another specific aspect, a host cell provided herein comprises a first vector and a second vector, wherein the first vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and the second vector comprises the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 108 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 106. In another specific aspect, a host cell provided herein comprises a first vector and a second vector, wherein the first vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and the second vector comprises the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 109 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 106. In another specific aspect, the host cell provided herein comprises a first vector and a second vector, wherein the first vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and the second vector comprises the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 110 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 111.In some embodiments, the first vector comprises a heavy chain constant region and / or the second vector comprises a light chain constant region.

[0336] Alternatively, a single vector can be used that encodes and expresses both heavy and light chain polypeptides. In such an expression vector, transcription of both genes can be driven by a common promoter, but translation of mRNA from the first gene can be by a cap-dependent scanning mechanism and translation of mRNA from the second gene can be by a cap-independent mechanism, e.g., by an IRES.

[0337] In a specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and nucleotides encoding the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 105 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 106. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and nucleotides encoding the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 107 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 106. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and nucleotides encoding the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 108 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 106. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding the variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK) and nucleotides encoding the variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 109 and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 106. In another specific aspect, a host cell provided herein comprises a vector, wherein the vector comprises a nucleotide sequence encoding a variable heavy chain region of an antibody described herein that specifically binds to MERTK (e.g., human MERTK), and nucleotides encoding a variable light chain region of the antibody, wherein the variable heavy chain region comprises the amino acid sequence of SEQ ID NO: 110, and the variable light chain region comprises the amino acid sequence of SEQ ID NO: 111. In some embodiments, the vector comprises a heavy chain constant region and / or a light chain constant region.

[0338] In specific embodiments, the host cells described herein (e.g., ex vivo host cells) are cultured under conditions to produce the antibody or antigen-binding fragment thereof encoded by the polynucleotide sequence contained in the host cell, using techniques known in the art. In certain embodiments, the antibody or antigen-binding fragment thereof has been isolated or purified from the host cell, using techniques known in the art. 5.4. Production of Antibody-Drug Conjugates

[0339] In another aspect, provided herein is a method of producing an antibody-drug conjugate described herein, wherein a linker is absent, the method comprising the steps of (a) conjugating a cytotoxic agent directly to the antibody moiety to produce the antibody-drug conjugate, and (b) purifying the antibody-drug conjugate. Exemplary methods of producing antibody-drug conjugates are described in Section 6 (e.g., Example 4).

[0340] In another aspect, provided herein is a method of producing an antibody-drug conjugate described herein, wherein the antibody-drug conjugate comprises a linker, and the method comprises the following steps, in the order stated: (a) conjugating the linker directly to the antibody moiety to produce a linker-antibody moiety, (b) conjugating the linker of the linker-antibody moiety directly to a cytotoxic agent to produce the antibody-drug conjugate, and (c) purifying the antibody-drug conjugate.

[0341] In another aspect, provided herein is a method of producing an antibody-drug conjugate described herein, wherein the antibody-drug conjugate comprises a linker, and the method comprises the following steps, in the order stated: (a) conjugating the linker directly to a cytotoxic agent to produce a linker-cytotoxic agent moiety, (b) conjugating the linker of the linker-cytotoxic agent moiety directly to the antibody moiety to produce the antibody-drug conjugate, and (c) purifying the antibody-drug conjugate.

[0342] The conjugation and purification steps can be carried out using methods known in the art for producing antibody-drug conjugates, e.g., methods described in Beck A et al., (2017) Nat Rev Drug Discov 16: 315-337;Peters C and Brown S, (2015) Biosci Rep 35: art:e00225;McCombs JR and Owen SC (2015) The AAPS Journal 17: 339-351; Jackson DY (2016) Org Process Res Dev 20: 852-866; or Olivier KJ and Hurvitz SA ed., (2016) Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical, Wiley. In some embodiments, the drug moiety is conjugated to one chain of the antibody moiety (e.g., when the antibody moiety is an scFv or when the antibody moiety is a multi-chain antibody such as an immunoglobulin (which is a tetramer) or an antigen-binding fragment thereof). In other embodiments, the drug moiety is conjugated to two or more chains of the antibody moiety (when the antibody moiety is a multi-chain antibody such as an immunoglobulin or an antigen-binding fragment thereof). In a specific embodiment, the drug moiety is conjugated to two identical chains of the immunoglobulin, e.g., the heavy chain or the light chain. In other embodiments, the drug moiety is conjugated to all chains of the antibody moiety (when the antibody moiety is a multi-chain antibody such as an immunoglobulin or an antigen-binding fragment thereof). In a specific embodiment, the antibody-drug conjugates described herein are purified by chromatography. In another specific embodiment, the antibody-drug conjugates described herein are purified by centrifugation.By way of example and not limitation, conjugation chemistries that can be used to generate antibody-drug conjugates include thiols and maleimides, thiols and autohydrolyzing maleimides, thiols and phenyloxadiazole sulfones, oxime ligation, reaction of alkoxyamines with keto groups, strain-promoted azide-alkyne cycloaddition (SPAAC), copper-free click chemistry, cysteine ​​oxidized to formylglycine, hydrazino-iso-Picteh-Spengler (HIPS) ligation, ligation of γ-carboxyamide groups from glutamine residues and primary amines, ligation of LPETG and polyglycerol. These can be primary amines of lysine motifs, maleimides and 6-thiofucose, fucose-specific conjugation of hydrazides, periodate oxidation (aldehydes) and aminooxy payloads, strain-promoted alkyne-azide cycloaddition, C2-keto-gal oximation, site-selective aldehyde oxidation and oxime ligation, oxime ligation NH2 and indole-based 5-difluoro-2,4-dinitrobenzene derivatives, thiols and bissulfones, thiols and dibromomaleimides, thiols and maleimides followed by pH 9.2 treatment (45°C, 48 hours), or thiols and arylpropionitriles (Beck A et al., (2017) Nat Rev. See Drug Discov 16: 315-337).

[0343] The anti-MERTK antibodies or antigen-binding fragments thereof described herein can be produced as described in Section 5.3 below. In specific embodiments, the anti-MERTK antibodies or antigen-binding fragments thereof described herein can be conjugated to a drug moiety by methods known in the art, e.g., as described in Beck A et al., (2017) Nat Rev Drug, to facilitate conjugation with the drug moiety, particularly to promote site-specific conjugation with the drug moiety. Disov 16: 315-337; Peters C and Brown S, (2015) Biosci Rep 35: art:e00225; McCombs JR and Owen SC (2015) The AAPS Journal 17: 339-351; Jackson DY (2016) Org Process Res Dev 20: 852-866; or Olivier KJ and Hurvitz SA ed., (2016) Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical, Wiley. Non-limiting exemplary methods that can be used to engineer or modify an anti-MERTK antibody or antigen-binding fragment thereof to facilitate conjugation with a drug moiety (Beck A et al., (2017) Nat Rev Drug Discov 16: 315-337) These include the addition of one or more additional cysteines or selenocysteines, unnatural amino acid engineering, the addition of one or more amino acid tags recognizable by certain enzymes that can assist in conjugation, glycan remodeling, the addition of amino-terminal serine, and native cysteine ​​crosslinks.

[0344] The linker and cytotoxic agent can be produced by any method known in the art for producing linkers and cytotoxic agents, respectively. Pharmaceutical Compositions

[0345] Provided herein are pharmaceutical compositions comprising (a) an anti-MERTK antibody (e.g., a humanized antibody) or antigen-binding fragment thereof described herein, and (b) a pharmaceutically acceptable carrier. In specific embodiments, the antibody or antigen-binding fragment thereof is purified. In specific embodiments, the antibody or antigen-binding fragment thereof is present in the pharmaceutical composition in a therapeutically effective amount. In specific embodiments, the pharmaceutical composition comprises an anti-MERTK antibody or antigen-binding fragment thereof (e.g., antibody z10) comprising a VH comprising the amino acid sequence of SEQ ID NO: 105 and a VL comprising the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, the pharmaceutical composition comprises an anti-MERTK antibody or antigen-binding fragment thereof (e.g., antibody z11) comprising a VH comprising the amino acid sequence of SEQ ID NO: 107 and a VL comprising the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, the pharmaceutical composition comprises an anti-MERTK antibody or antigen-binding fragment thereof (e.g., antibody z13) comprising a VH comprising the amino acid sequence of SEQ ID NO: 108 and a VL comprising the amino acid sequence of SEQ ID NO: 106. In another specific embodiment, the pharmaceutical composition comprises an anti-MERTK antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:109 and a VL comprising the amino acid sequence of SEQ ID NO:106.

[0346] Also provided herein is a pharmaceutical composition comprising (a) a chimeric anti-MERTK antibody or antigen-binding fragment thereof described herein, and (b) a pharmaceutically acceptable carrier. In a specific embodiment, the antibody or antigen-binding fragment thereof is purified. In a specific embodiment, the antibody or antigen-binding fragment thereof is present in the pharmaceutical composition in a therapeutically effective amount. In a specific embodiment, the pharmaceutical composition comprises a chimeric antibody or antigen-binding fragment thereof (e.g., antibody xAb) comprising a VH comprising the amino acid sequence of SEQ ID NO: 110 and a VL comprising the amino acid sequence of SEQ ID NO: 111. Also provided herein is a pharmaceutical composition comprising a polynucleotide or vector described herein and a pharmaceutically acceptable carrier.

[0347] Also provided herein is a pharmaceutical composition comprising (a) an antibody-drug conjugate described herein, and (b) a pharmaceutically acceptable carrier. In a specific embodiment, the antibody-drug conjugate is present in the pharmaceutical composition in a therapeutically effective amount.

[0348] Also provided herein is a pharmaceutical composition comprising (a) a bispecific antibody (e.g., as described herein) that binds to MERTK (e.g., human MERTK) and another antigen of interest, and (b) a pharmaceutically acceptable carrier. In a specific embodiment, the bispecific antibody is purified. In a specific embodiment, the bispecific antibody is present in the pharmaceutical composition in a therapeutically effective amount.

[0349] In a specific embodiment, the population of antibody-drug conjugates contained in the pharmaceutical composition has a drug-to-antibody ratio (DAR) of 1 to 20. DAR is the average number of cytotoxic agents conjugated to an antibody. In another specific embodiment, the population of antibody-drug conjugates contained in the pharmaceutical composition has a DAR of 1 to 15. In another specific embodiment, the population of antibody-drug conjugates contained in the pharmaceutical composition has a DAR of 1 to 12. In another specific embodiment, the population of antibody-drug conjugates contained in the pharmaceutical composition has a DAR of 1 to 8. In another specific embodiment, the population of antibody-drug conjugates contained in the pharmaceutical composition has a DAR of 3 to 5. In another specific embodiment, the population of antibody-drug conjugates contained in the pharmaceutical composition has a DAR of 3.5 to 4.

[0350] Acceptable carriers, which may be excipients or stabilizers, are nontoxic to recipients at the dosages and concentrations employed and include, but are not limited to, buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (less than about 10 residues) polypeptides. proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0351] In a specific embodiment, the pharmaceutical composition comprises an anti-MERTK antibody or antigen-binding fragment thereof described herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. In a specific embodiment, the pharmaceutical composition comprises an effective amount of an anti-MERTK antibody or antigen-binding fragment thereof described herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. In a specific embodiment, the pharmaceutical composition and / or antibody or antigen-binding fragment thereof described herein can be combined with a therapeutically effective amount of any of the additional therapeutic agents described herein (see Section 5.4.2 below).

[0352] In specific embodiments, pharmaceutical compositions comprise an antibody-drug conjugate described herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. In specific embodiments, pharmaceutical compositions comprise an effective amount of an antibody-drug conjugate described herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. In specific embodiments, the pharmaceutical compositions and / or antibody-drug conjugates described herein can be combined with a therapeutically effective amount of any of the additional therapeutic agents described herein (see Section 5.4.2 below).

[0353] In some embodiments, the antibody-drug conjugate is the only active ingredient in the pharmaceutical composition.

[0354] In some embodiments, the anti-MERTK antibody is the only active in...

Claims

[Claim 1] The invention as depicted in the drawings.

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