Anti-KLK6 antibodies and methods of use

Abstract

The present disclosure provides antibodies and polypeptides that specifically bind to kallikrein related peptidase 6 (KLK6). Also provided are compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Description

ANTI-KLK6 ANTIBODIES AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States ProvisionalApplication Serial Number 63 / 682,072, filed August 12, 2024, the contents of which are hereby incorporated by reference herein in their entirety. REFERENCE TO SEQUENCE LISTING

[0002] This application contains a sequence listing which has been submitted electronicallyin ST.26 format and is hereby incorporated by reference in its entirety. Said ST.26 copy, created on August 12, 2025, is named “220442_seqlist.xml” and is 226,309 bytes in size. FIELD

[0003] The present disclosure relates to antibodies that are specific for kallikrein relatedpeptidase 6 (KLK6), and methods of use thereof. BACKGROUND

[0004] Members of the kallikrein subfamily of the peptidase S1 family of serine proteasesare serine proteases involved in coordination of various physiological functions. Kallikreins have been implicated in carcinogenesis, and several are known cancer biomarkers (e.g., PSA, KLK3). Kallikrein related peptidase 6 (KLK6), also referred to as kallikrein-6, neurosin, protease M, hK6, or zyme, is a serine protease with extracellular substrates. It can degrade components of the extracellular matrix, and it can trigger intracellular signaling through protease-activated receptors (e.g., PAR1) that are involved in various biological processes including inflammatory responses and cancer progression. In vivo studies have shown that KLK6 inhibits T cell migration and potentially increases cancer cell invasion and metastasis. KLK6 overexpression is associated with poor prognosis in various cancers, including ovarian, breast, colon, pancreatic, and head and neck cancer. KLK6 has also been implicated as a biomarker for tau-related Alzheimer’s disease and as a target in multiple sclerosis and demyelination.

[0005] Thus, there is a need for therapies targeting KLK6.SUMMARY

[0006] The present disclosure provides antibodies and polypeptides that specifically bindto KLK6 (e.g., human KLK6). In some embodiments, the anti-KLK6 antibodies neutralize KLK6 enzymatic activity. Also provided are pharmaceutical compositions comprising these 1 BUSINESS.33373149.1antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies. The antibodies provided herein are particularly advantageous because they specifically bind KLK6 and inhibit KLK6 enzymatic function and therefore have utility in the treatment and diagnosis of cancer (e.g., KLK6-expressing cancer), Alzheimer’s disease (e.g., tau-related Alzheimer’s disease), and demyelinating diseases (e.g., multiple sclerosis).

[0007] Accordingly, in one aspect, provided herein is an antibody that specifically bindshuman KLK6, the antibody comprising a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in any one of SEQ ID NOs: 1- 37 and a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74.

[0008] In certain embodiments, the VH amino acid sequence and VL amino acid sequenceare as set forth in: SEQ ID NwOs: 1 and 38, 2 and 39, 3 and 40, 4 and 41, 5 and 42, 6 and 43, 7 and 44, 8 and 45, 9 and 46, 10 and 47, 11 and 48, 12 and 49, 13 and 50, 14 and 51, 15 and 52, 16 and 53, 17 and 54, 18 and 55, 19 and 56, 20 and 57, 21 and 58, 22 and 59, 23 and 60, 24 and 61, 25 and 62, 26 and 63, 27 and 64, 28 and 65, 29 and 66, 30 and 67, 31 and 68, 32 and 69, 33 and 70, 34 and 71, 35 and 72, 36 and 73, or 37 and 74, respectively.

[0009] In certain embodiments, the antibody comprises the CDRH1, CDRH2, and CDRH3amino acid sequences set forth in: SEQ ID NOs: 75, 99, and 132; 75, 100, and 133; 76, 101, and 134; 77, 102, and 135; 78, 103, and 136; 79, 104, and 137; 80, 105, and 138; 81, 106, and 139; 82, 107, and 140; 77, 108, and 141; 83, 109, and 142; 84, 110, and 143; 75, 111, and 144; 85, 112, and 145; 77, 113, and 146; 86, 114, and 147; 87, 115, and 148; 88, 116, and 149; 89, 104, and 150; 90, 117, and 151; 80, 105, and 152; 80, 118, and 153; 89, 119, and 154; 80, 101, and 155; 91, 120, and 156; 92, 121, and 157; 93, 122, and 158; 94, 123, and 159; 76, 124, and 160; 76, 101, and 161; 95, 125, and 162; 76, 126, and 163; 96, 127, and 164; 79, 128, and 165; 97, 129, and 166; 98, 130, and 167; or 91, 131, and 168, respectively.

[0010] In certain embodiments, the antibody comprises the CDRL1, CDRL2, and CDRL3amino acid sequences set forth in: SEQ ID NOs: 169, 194, and 215; 170, 195, and 216; 171, 196, and 217; 172, 197, and 218; 173, 198, and 219; 174, 196, and 220; 175, 199, and 221; 176, 195, and 222; 173, 195, and 223; 172, 197, and 224; 170, 195, and 225; 177, 200, and 226; 178, 195, and 227; 177, 201, and 228; 179, 202, and 229; 180, 203, and 230; 181, 196, and 231; 170, 195, and 232; 182, 204, and 233; 170, 205, and 234; 177, 206, and 221; 171, 196, and 231; 183, 196, and 220; 184, 207, and 235; 185, 208, and 236; 170, 209, and 237; 186, 206, and 238; 176, 210, and 239; 187, 196, and 231; 184, 211, and 240; 188, 212, and 2 BUSINESS.33373149.1241; 177, 199, and 242; 189, 213, and 243; 190, 196, and 220; 191, 195, and 244; 192, 195, and 245; or 193, 214, and 246, respectively.

[0011] In certain embodiments, the antibody comprises the CDRH1, CDRH2, CDRH3,CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in: SEQ ID NOs: 75, 99, 132, 169, 194, and 215; 75, 100, 133, 170, 195, and 216; 76, 101, 134, 171, 196, and 217; 77, 102, 135, 172, 197, and 218; 78, 103, 136, 173, 198, and 219; 79, 104, 137, 174, 196, and 220; 80, 105, 138, 175, 199, and 221; 81, 106, 139, 176, 195, and 222; 82, 107, 140, 173, 195, and 223; 77, 108, 141, 172, 197, and 224; 83, 109, 142, 170, 195, and 225; 84, 110, 143, 177, 200, and 226; 75, 111, 144, 178, 195, and 227; 85, 112, 145, 177, 201, and 228; 77, 113, 146, 179, 202, and 229; 86, 114, 147, 180, 203, and 230; 87, 115, 148, 181, 196, and 231; 88, 116, 149, 170, 195, and 232; 89, 104, 150, 182, 204, and 233; 90, 117, 151, 170, 205, and 234; 80, 105, 152, 177, 206, and 221; 80, 118, 153, 171, 196, and 231; 89, 119, 154, 183, 196, and 220; 80, 101, 155, 184, 207, and 235; 91, 120, 156, 185, 208, and 236; 92, 121, 157, 170, 209, and 237; 93, 122, 158, 186, 206, and 238; 94, 123, 159, 176, 210, and 239; 76, 124, 160, 187, 196, and 231; 76, 101, 161, 184, 211, and 240; 95, 125, 162, 188, 212, and 241; 76, 126, 163, 177, 199, and 242; 96, 127, 164, 189, 213, and 243; 79, 128, 165, 190, 196, and 220; 97, 129, 166, 191, 195, and 244; 98, 130, 167, 192, 195, and 245; 91, 131, 168, 193, 214, and 246, respectively.

[0012] In certain embodiments, the antibody comprises the VH amino acid sequence setforth in any one of SEQ ID NOs: 1-37. In certain embodiments, the antibody comprises a heavy chain constant region, optionally selected from the group consisting of human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In certain embodiments, the antibody comprises a heavy chain constant region that is a variant of a wild-type heavy chain constant region, wherein the variant heavy chain constant region binds to an FcγR with lower affinity than the wild-type heavy chain constant region binds to the FcγR. In certain embodiments, the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 247 or 248.

[0013] In certain embodiments, the antibody reduces or inhibits a function of KLK6.

[0014] In certain embodiments, the antibody comprises the VL amino acid sequence setforth in any one of SEQ ID NOs: 38-74. In certain embodiments, the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 249 or 250.

[0015] In certain embodiments, the VH and VL comprise the amino acid sequences setforth in: SEQ ID NOs: 1 and 38, 2 and 39, 3 and 40, 4 and 41, 5 and 42, 6 and 43, 7 and 44, 8 and 45, 9 and 46, 10 and 47, 11 and 48, 12 and 49, 13 and 50, 14 and 51, 15 and 52, 16 and 53, 17 and 54, 18 and 55, 19 and 56, 20 and 57, 21 and 58, 22 and 59, 23 and 60, 24 and 61, 25 3 BUSINESS.33373149.1and 62, 26 and 63, 27 and 64, 28 and 65, 29 and 66, 30 and 67, 31 and 68, 32 and 69, 33 and 70, 34 and 71, 35 and 72, 36 and 73, or 37 and 74, respectively.

[0016] In another aspect, provided herein is a polypeptide comprising a VH comprising theCDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in any one of SEQ ID NOs: 1-37. In certain embodiments, the VH comprises the CDRH1, CDRH2, and CDRH3 amino acid sequences set forth in SEQ ID NOs: 75, 99, and 132; 75, 100, and 133; 76, 101, and 134; 77, 102, and 135; 78, 103, and 136; 79, 104, and 137; 80, 105, and 138; 81, 106, and 139; 82, 107, and 140; 77, 108, and 141; 83, 109, and 142; 84, 110, and 143; 75, 111, and 144; 85, 112, and 145; 77, 113, and 146; 86, 114, and 147; 87, 115, and 148; 88, 116, and 149; 89, 104, and 150; 90, 117, and 151; 80, 105, and 152; 80, 118, and 153; 89, 119, and 154; 80, 101, and 155; 91, 120, and 156; 92, 121, and 157; 93, 122, and 158; 94, 123, and 159; 76, 124, and 160; 76, 101, and 161; 95, 125, and 162; 76, 126, and 163; 96, 127, and 164; 79, 128, and 165; 97, 129, and 166; 98, 130, and 167; or 91, 131, and 168, respectively.

[0017] Also provided herein is a polypeptide comprising a VL comprising the CDRL1,CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74. In certain embodiments, the VL comprises the CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 169, 194, and 215; 170, 195, and 216; 171, 196, and 217; 172, 197, and 218; 173, 198, and 219; 174, 196, and 220; 175, 199, and 221; 176, 195, and 222; 173, 195, and 223; 172, 197, and 224; 170, 195, and 225; 177, 200, and 226; 178, 195, and 227; 177, 201, and 228; 179, 202, and 229; 180, 203, and 230; 181, 196, and 231; 170, 195, and 232; 182, 204, and 233; 170, 205, and 234; 177, 206, and 221; 171, 196, and 231; 183, 196, and 220; 184, 207, and 235; 185, 208, and 236; 170, 209, and 237; 186, 206, and 238; 176, 210, and 239; 187, 196, and 231; 184, 211, and 240; 188, 212, and 241; 177, 199, and 242; 189, 213, and 243; 190, 196, and 220; 191, 195, and 244; 192, 195, and 245; or 193, 214, and 246, respectively.

[0018] Also provided herein is a polypeptide comprising the amino acid sequence set forthin any one of SEQ ID NOs: 1-74.

[0019] In certain embodiments, an antibody or polypeptide provided herein is conjugatedto a cytotoxic agent, cytostatic agent, toxin, radionuclide, or detectable label.

[0020] In another aspect, provided herein is a polynucleotide encoding: a VH, a VL, aheavy chain, and / or a light chain of an antibody or a polypeptide described herein. Also provided is a vector comprising a polynucleotide described herein. Also provided is a recombinant host cell comprising a polynucleotide described herein; a vector described herein; a polynucleotide encoding a heavy chain variable region or a heavy chain of an antibody 4 BUSINESS.33373149.1described herein and a second polynucleotide encoding a light chain variable region or a light chain of an antibody described herein; and / or a first vector comprising a first polynucleotide encoding a heavy chain variable region or a heavy chain of an antibody described herein and a second vector comprising a second polynucleotide encoding a light chain variable region or a light chain of an antibody described herein.

[0021] In another aspect provided herein is a composition comprising an antibody, apolypeptide, a polynucleotide, a vector, and / or a host cell described herein and a pharmaceutically acceptable carrier or excipient.

[0022] In another aspect, provided herein is a method of producing an antibody, the methodcomprising culturing a host cell described herein under suitable conditions such that a polynucleotide is expressed, and the antibody is produced.

[0023] In another aspect, provided herein is a method of treating a KLK6-associateddisease or disorder in a subject, the method comprising administering to the subject an effective amount of: an antibody described herein; a polypeptide described herein; a polynucleotide described herein; a vector described herein; a host cell described herein; and / or a composition described herein. In some embodiments, administering the antibody, polypeptide, polynucleotide, vector, host cell, or composition results in a reduction or inhibition of a KLK6 function in the subject. In some embodiments, the KLK6-associated disease or disorder is cancer. In some embodiments, the KLK6-associated disease or disorder is Alzheimer’s disease. In some embodiments, the KLK6-associated disease or disorder is a demyelinating disease. In some embodiments, the KLK6-associated disease or disorder is multiple sclerosis. In some embodiments, the method further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a chemotherapeutic, a radiotherapeutic, or a checkpoint targeting agent. In some embodiments, the checkpoint targeting agent is selected from the group consisting of an antagonist anti-PD-1 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, an antagonist anti-CTLA- 4 antibody, an antagonist anti-TIM-3 antibody, an antagonist anti-LAG-3 antibody, an antagonist anti-VISTA antibody, an antagonist anti-TIGIT antibody, an antagonist anti-CD96 antibody, an antagonist anti-CEACAM1 antibody, an agonist anti-CD137 antibody, an agonist anti-GITR antibody, and an agonist anti-OX40 antibody.

[0024] In another aspect, provided herein is a use of an antibody described herein; apolypeptide described herein; a polynucleotide described herein; a vector described herein; a host cell described herein; and / or a composition described herein for the manufacture of a 5 BUSINESS.33373149.1medicament for treating cancer, Alzheimer’s disease, a demyelinating disease, or multiple sclerosis.

[0025] In another aspect, provided herein is an antibody described herein; a polypeptidedescribed herein; a polynucleotide described herein; a vector described herein; a host cell described herein; and / or a composition described herein for use in medicine.

[0026] In another aspect, provided herein is an antibody described herein; a polypeptidedescribed herein; a polynucleotide described herein; a vector described herein; a host cell described herein; and / or a composition described herein for use in treating cancer, Alzheimer’s disease, a demyelinating disease, or multiple sclerosis in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 is a graph of KLK6 enzymatic activity over time following incubation of 20nM activated KLK6 protein with the indicated concentrations of an anti-KLK6 polyclonal antibody (pAb) or control immunoglobulin (Ig). Data represent mean ± SD (n=2).

[0028] FIG. 2 is a plot of KLK6 enzymatic activity following incubation of 20 nMactivated KLK6 with 80 nM of the indicated anti-KLK6 antibodies, negative control IgG, or positive control goat pAb. Dashed lines indicate the level of background signal, maximum signal (KLK6 enzymatic activity following incubation with negative control IgG), and positive control signal (KLK6 enzymatic activity following incubation with positive control goat pAb). Arrows indicate anti-KLK6 antibodies displaying ≥ 75% inhibition of KLK6 enzymatic activity. Data represent mean ± SD (n=2).

[0029] FIG. 3 is a plot of KLK6 enzymatic activity following incubation of 20 nMactivated KLK6 with increasing concentrations of the indicated anti-KLK6 antibodies, negative control IgG1, or positive control pAb. Dashed lines indicate maximum signal (KLK6 enzymatic activity with no antibody treatment) and minimum signal (substrate alone). DETAILED DESCRIPTION

[0030] The instant disclosure provides anti-KLK6 antibodies and polypeptides. Alsoprovided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies. The antibodies disclosed herein are particularly useful for diagnosing and / or treating cancer, Alzheimer’s disease, demyelinating diseases, and / or multiple sclerosis in a subject. 6 BUSINESS.33373149.1Definitions

[0031] As used herein, the term “KLK6” refers to the serine protease kallikrein relatedpeptidase 6. As used herein, the term “human KLK6” refers to a protein encoded by a wild- type human KLK6 gene (e.g., the gene set forth in RefSeq NM_002774.4). The amino acid sequence of an exemplary human KLK6 protein is set forth in RefSeq NP_002765.1.

[0032] As used herein, the terms “antibody” and “antibodies” include full-lengthantibodies, antigen-binding fragments of full-length antibodies, and molecules comprising antibody CDRs, VH regions, and / or VL regions. Examples of antibodies include, without limitation, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain 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, intrabodies, heteroconjugate antibodies, antibody-drug conjugates, bispecific T cell engagers (BiTEs), chimeric antigen receptors, single domain antibodies, monovalent antibodies, single-chain antibodies or single- chain Fvs (scFv), camelized antibodies, affibodies, Fab fragments, F(ab’)2fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), and antigen-binding fragments of any of the above. In certain embodiments, antibodies described herein refer to polyclonal antibody populations. Antibodies can 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., IgG2a or IgG2b) of immunoglobulin molecule. In certain embodiments, antibodies described herein are IgG antibodies, or a class (e.g., human IgG1or IgG4) or subclass thereof. In a specific embodiment, the antibody is a humanized monoclonal antibody. In another specific embodiment, the antibody is a human monoclonal antibody.

[0033] “Multispecific antibodies” are antibodies (e.g., bispecific antibodies) thatspecifically bind to two or more different antigens or two or more different regions of the same antigen. Multispecific antibodies include bispecific antibodies that contain two different antigen-binding sites (exclusive of the Fc region). Multispecific antibodies can include, for example, recombinantly produced antibodies, human antibodies, humanized antibodies, resurfaced antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, heteroconjugate antibodies, linked single-chain antibodies or linked-single-chain Fvs (scFv), camelized antibodies, affybodies, linked Fab fragments, F(ab’)2fragments, 7 BUSINESS.33373149.1chemically-linked Fvs, and disulfide-linked Fvs (sdFv). Multispecific antibodies can 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., IgG2a or IgG2b) of immunoglobulin molecule. In certain embodiments, multispecific antibodies described herein are IgG antibodies, or a class (e.g., human IgG1, IgG2, or IgG4) or subclass thereof.

[0034] As used herein, the term “CDR” or “complementarity determining region” meansthe noncontiguous antigen combining sites found within the variable regions of heavy and light chain polypeptides. These particular regions have been described by, for example, Kabat et al., J. Biol. Chem.252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991), by Chothia et al., J. Mol. Biol.196: 901-917 (1987), and by MacCallum et al., J. Mol. Biol. 262: 732-745 (1996), all of which are herein incorporated by reference in their entireties, where the definitions include overlapping or subsets of amino acid residues when compared against each other. In certain embodiments, the term “CDR” is a CDR as defined by MacCallum et al., J. Mol. Biol. 262:732-745 (1996) and Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422-439, Springer-Verlag, Berlin (2001). In certain embodiments, the term “CDR” is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991). In certain embodiments, heavy chain CDRs and light chain CDRs of an antibody are defined using different conventions. In certain embodiments, heavy chain CDRs and / or light chain CDRs are defined by performing structural analysis of an antibody and identifying residues in the variable region(s) predicted to make contact with an epitope region of a target molecule (e.g., human KLK6). CDRH1, CDRH2, and CDRH3 denote the heavy chain CDRs, and CDRL1, CDRL2, and CDRL3 denote the light chain CDRs.

[0035] As used herein, the terms “variable region” and “variable domain” are usedinterchangeably and are common in the art. The variable region typically refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids or 110 to 125 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable region are called framework regions (FRs). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible 8 BUSINESS.33373149.1for the interaction and specificity of the antibody with antigen. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In certain embodiments, the variable region is a primate (e.g., non-human primate) variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).

[0036] As used herein, the terms “VH” and “VL” refer to antibody heavy and light chainvariable regions, respectively, as described in Kabat et al., (1991) Sequences of Proteins of Immunological Interest (NIH Publication No. 91-3242, Bethesda), which is herein incorporated by reference in its entirety.

[0037] As used herein, the term “constant region” is common in the art. The constant regionis an antibody portion, e.g., a carboxyl terminal portion of a light and / or heavy chain, which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with an Fc receptor (e.g., Fc gamma receptor).

[0038] As used herein, the term “heavy chain” when used in reference to an antibody canrefer to any distinct type, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (µ), based on the amino acid sequence of the constant region, which give rise to IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3, and IgG4.

[0039] As used herein, the term “light chain” when used in reference to an antibody canrefer to any distinct type, e.g., kappa (κ) or lambda (λ), based on the amino acid sequence of the constant region. Light chain amino acid sequences are well known in the art. In specific embodiments, the light chain is a human light chain.

[0040] As used herein, the term “specifically binds” refers to the specificity of a bindingmolecule (e.g., an antibody) for an antigen, as is understood by one skilled in the art. Binding molecules that specifically bind to an antigen typically bind to the antigen with an equilibrium dissociation constant (KD) of less than 1×10−6M, as measured by, e.g., ELISA assay, surface plasmon resonance, or other suitable assays known in the art. The skilled worker will appreciate that, in certain embodiments, a binding molecule can specifically bind to different antigens, e.g., different antigens that share a common epitope that is recognized by the binding molecule.

[0041] As used herein, the term “affinity” refers to the strength of the sum total ofnoncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a 9 BUSINESS.33373149.1binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein.

[0042] As used herein, the term “EU numbering system” refers to the EU numberingconvention for the constant regions of an antibody, as described in Edelman, G.M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Kabat et al, Sequences of Proteins of Immunological Interest, U.S. Dept. Health and Human Services, 5th edition, 1991, each of which is herein incorporated by reference in its entirety.

[0043] As used herein, the term “treat,” “treating,” and “treatment” refer to therapeutic orpreventative measures described herein. The methods of “treatment” employ administration of an antibody to a subject having a disease or disorder, or predisposed to having such a disease or disorder, in order to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or recurring disease or disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.

[0044] As used herein, the term “pharmaceutically active substance” refers to a moleculeor moiety that is used to achieve a beneficial outcome in a subject. Beneficial outcomes include, but are not limited to, diagnosis, prognosis, treatment, cure and prevention (prophylaxis) of diseases and / or symptoms and / or health problems.

[0045] As used herein, the term “effective amount” in the context of the administration ofa therapy to a subject refers to the amount of a therapy that achieves a desired prophylactic or therapeutic effect.

[0046] As used herein, the term “subject” includes any human or non-human animal. Incertain embodiments, the subject is a human or non-human mammal. In certain embodiments, the subject is a human.

[0047] As used herein with respect to an antibody, polypeptide, or polynucleotide, the term“isolated” refers to an antibody, polypeptide, or polynucleotide that is separated from one or more contaminants (e.g., polypeptides, polynucleotides, lipids, or carbohydrates, etc.) which are present in a natural source (e.g., in a mouse or a human) of the antibody, polypeptide, or polynucleotide. Moreover, an “isolated” antibody, polypeptide, or polynucleotide can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. For example, the language “substantially free” includes preparations of antibody, polypeptide, or polynucleotide having less than about 15%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (in particular less than about 10%) of other material, e.g., cellular material, culture medium, 10 BUSINESS.33373149.1other nucleic acid molecules, chemical precursors, and / or other chemicals. All instances of “isolated antibodies” described herein are additionally contemplated as antibodies that may be, but need not be, isolated. All instances of “isolated polypeptides” described herein are additionally contemplated as polypeptides that may be, but need not be, isolated. All instances of “isolated polynucleotides” described herein are additionally contemplated as polynucleotides that may be, but need not be, isolated. All instances of “antibodies” described herein are additionally contemplated as antibodies that may be, but need not be, isolated. All instances of “polypeptides” described herein are additionally contemplated as polypeptides that may be, but need not be, isolated. All instances of “polynucleotides” described herein are additionally contemplated as polynucleotides that may be, but need not be, isolated.

[0048] The determination of “percent identity” between two sequences (e.g., amino acidsequences or nucleic acid sequences) can 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, modified as in Karlin S & Altschul SF (1993) PNAS 90: 5873-5877, each of which is herein incorporated by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215: 403, which is herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., ofXBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information(NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 11-17, which is herein incorporated by reference in its entirety. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for 11 BUSINESS.33373149.1comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0049] The percent identity between two sequences can be determined using techniquessimilar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted. Anti-KLK6 Antibodies

[0050] In one aspect, the instant disclosure provides antibodies that specifically bind toKLK6 (e.g., human KLK6). The VH, VL, CDRH and CDRL amino acid sequences of exemplary antibodies are set forth in Tables 1-4, respectively. Table 1. VH amino acid sequences of exemplary anti-KLK6 antibodies. Ab VH Amino Acid Sequence SEQ ID12 BUSINESS.33373149.17708EVQLVESGGNVVRPGGSLRLSCAASGFTFDDYGMTWVRQVPGKGLEWVSGINWNGG 12 STGYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCARVAAAIYYYYYMDVW GKGTTVTVSS13 BUSINESS.33373149.18679EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYAMSWVRQAPGKGLEWVSGINWNGG 30 STGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCARALGAVYYYYYMDVW GKGTTVTVSSAb VL Amino Acid Sequence SEQ ID14 BUSINESS.33373149.18542DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLEI 51 GVPSRFSGSGSGTEFTLTISSLQPYDFATYYCLHYNSYSRTFGQGTKVEIK 8549DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYDASTLQS 5215 BUSINESS.33373149.1Table 3. CDRH amino acid sequences of exemplary anti-KLK6 antibodies. Ab CDRH1 SEQ CDRH2 amino acid SEQ CDRH3 amino acid SEQ amino ID sequence ID sequence ID acid16 BUSINESS.33373149.1Table 4. CDRL amino acid sequences of exemplary anti-KLK6 antibodies. Ab CDRL1 amino acid SEQ CDRL2 amino SEQ CDRL3 amino SEQ sequence ID acid sequence ID acid sequence ID 7671RAS SVSSYLN169AASSL R194NYSIP21517 BUSINESS.33373149.19967RASQIIYNNLA190GASTRAT196QQYNNWPPT2209999RASQFISIYLN191AASSLQS195QQGYTTPYT244to any CDR numbering scheme known in the art.

[0052] In certain embodiments, one or more of the CDRs of an antibody disclosed hereincan be determined according to Kabat et al., J. Biol. Chem.252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest (1991), each of which is herein incorporated by reference in its entirety.

[0053] In certain embodiments, an antibody provided herein comprises the CDRH1,CDRH2, and / or CDRH3 of a VH amino acid sequence set forth in any of SEQ ID NOs: 1-37 as determined by the Kabat numbering scheme. In certain embodiments, an antibody provided herein comprises the CDRL1, CDRL2, and / or CDRL3 of a VL amino acid sequence set forth in any of SEQ ID NOs: 38-74 as determined by the Kabat numbering scheme.

[0054] In certain embodiments, one or more of the CDRs of an antibody disclosed hereincan be determined according to the Chothia numbering scheme, which refers to the location of immunoglobulin structural loops (see, e.g., Chothia C & Lesk AM, (1987), J Mol Biol 196: 901-917; Al-Lazikani B et al., (1997) J Mol Biol 273: 927-948; Chothia C et al., (1992) J Mol Biol 227: 799-817; Tramontano A et al., (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No.7,709,226, all of which are herein incorporated by reference in their entireties).

[0055] In certain embodiments, an antibody provided herein comprises the CDRH1,CDRH2, and / or CDRH3 of a VH amino acid sequence set forth in any of SEQ ID NOs: 1-37 as determined by the Chothia numbering system. In certain embodiments, an antibody provided herein comprises the CDRL1, CDRL2, and / or CDRL3 of a VL amino acid sequence set forth in any of SEQ ID NOs: 38-74 as determined by the Chothia numbering system.

[0056] In certain embodiments, one or more of the CDRs of an antibody disclosed hereincan be determined according to MacCallum RM et al., (1996) J Mol Biol 262: 732-745, herein incorporated by reference in its entirety. See also, e.g., Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001), herein incorporated by reference in its entirety. 18 BUSINESS.33373149.1

[0057] In certain embodiments, an antibody provided herein comprises the CDRH1,CDRH2, and / or CDRH3 of a VH amino acid sequence set forth in any of SEQ ID NOs: 1-37 as determined by the MacCallum numbering system. In certain embodiments, an antibody provided herein comprises the CDRL1, CDRL2, and / or CDRL3 of a VL amino acid sequence set forth in any of SEQ ID NOs: 38-74 as determined by the MacCallum numbering system.

[0058] In certain embodiments, the CDRs of an antibody disclosed herein can bedetermined according to the IMGT numbering system as described in: Lefranc M-P, (1999) The Immunologist 7: 132-136; Lefranc M-P et al., (1999) Nucleic Acids Res 27: 209-212, each of which is herein incorporated by reference in its entirety; and Lefranc M-P et al., (2009) Nucleic Acids Res 37: D1006-D1012.

[0059] In certain embodiments, an antibody provided herein comprises the CDRH1,CDRH2, and / or CDRH3 of a VH amino acid sequence set forth in any of SEQ ID NOs: 1-37 as determined by the IMGT numbering system. In certain embodiments, an antibody provided herein comprises the CDRL1, CDRL2, and / or CDRL3 of a VL amino acid sequence set forth in any of SEQ ID NOs: 38-74 as determined by the IMGT numbering system.

[0060] In certain embodiments, the CDRs of an antibody disclosed herein can bedetermined according to the AbM numbering scheme, which refers to AbM hypervariable regions, which represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (Oxford Molecular Group, Inc.), herein incorporated by reference in its entirety.

[0061] In certain embodiments, an antibody provided herein comprises the CDRH1,CDRH2, and / or CDRH3 of a VH amino acid sequence set forth in any of SEQ ID NOs: 1-37 as determined by the AbM numbering scheme. In certain embodiments, an antibody provided herein comprises the CDRL1, CDRL2, and / or CDRL3 of a VL amino acid sequence set forth in any of SEQ ID NOs: 38-74 as determined by the AbM numbering scheme.

[0062] In certain embodiments, the CDRs of an antibody disclosed herein can bedetermined according to the AHo numbering system, as described in Honegger and Plückthun, A., J. Mol. Biol.309:657-670 (2001), herein incorporated by reference in its entirety.

[0063] In certain embodiments, an antibody provided herein comprises the CDRH1,CDRH2, and / or CDRH3 of a VH amino acid sequence set forth in any of SEQ ID NOs: 1-37 as determined by the AHo numbering system. In certain embodiments, an antibody provided herein comprises the CDRL1, CDRL2, and / or CDRL3 of a VL amino acid sequence set forth in any of SEQ ID NOs: 38-74 as determined by the AHo numbering system. 19 BUSINESS.33373149.1

[0064] In certain embodiments, the individual CDRs of an antibody disclosed herein areeach independently determined according to one of the Kabat, Chothia, MacCallum, IMGT, AHo, or AbM numbering schemes, or by structural analysis of the multispecific molecule, wherein the structural analysis identifies residues in the variable region(s) predicted to make contact with an epitope region of KLK6.

[0065] In certain embodiments, the instant disclosure provides an antibody that specificallybinds KLK6 (e.g., human KLK6) comprising a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of a VH amino acid sequence set forth in any one of SEQ ID NOs: 1-37, and a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of a VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74, wherein each CDR is independently determined according to one of the Kabat, Chothia, MacCallum, IMGT, AHo, or AbM numbering schemes, or by structural analysis of the multispecific molecule, wherein the structural analysis identifies residues in the variable region(s) predicted to make contact with an epitope region of KLK6 (e.g., human KLK6).

[0066] In certain embodiments, the instant disclosure provides an antibody that specificallybinds KLK6 (e.g., human KLK6) comprising a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of a VH amino acid sequence set forth in any one of SEQ ID NOs: 1-37, and a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of a VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74, wherein the VH amino acid sequence and the VL amino acid sequence are from the same antibody (i.e., as shown in Tables 1 and 2), and wherein each CDR is independently determined according to one of the Kabat, Chothia, MacCallum, IMGT, AHo, or AbM numbering schemes, or by structural analysis of the multispecific molecule, wherein the structural analysis identifies residues in the variable region(s) predicted to make contact with an epitope region of KLK6 (e.g., human KLK6).

[0067] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), wherein the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of the VH and VL amino acid sequences set forth in SEQ ID NOs: 1 and 38; SEQ ID NOs: 2 and 39; SEQ ID NOs: 3 and 40; SEQ ID NOs: 4 and 41; SEQ ID NOs: 5 and 42; SEQ ID NOs: 6 and 43; SEQ ID NOs: 7 and 44; SEQ ID NOs: 8 and 45; SEQ ID NOs: 9 and 46; SEQ ID NOs: 10 and 47; SEQ ID NOs: 11 and 48; SEQ ID NOs: 12 and 49; SEQ ID NOs: 13 and 50; SEQ ID NOs: 14 and 51; SEQ ID NOs: 15 and 52; SEQ ID NOs: 16 and 53; SEQ ID NOs: 17 and 54; SEQ ID NOs: 18 and 55; SEQ ID NOs: 19 and 56; SEQ ID NOs: 20 and 57; SEQ ID NOs: 21 and 58; SEQ ID NOs: 20 BUSINESS.33373149.122 and 59; SEQ ID NOs: 23 and 60; SEQ ID NOs: 24 and 61; SEQ ID NOs: 25 and 62; SEQ ID NOs: 26 and 63; SEQ ID NOs: 27 and 64; SEQ ID NOs: 28 and 65; SEQ ID NOs: 29 and 66; SEQ ID NOs: 30 and 67; SEQ ID NOs: 31 and 68; SEQ ID NOs: 32 and 69; SEQ ID NOs: 33 and 70; SEQ ID NOs: 34 and 71; SEQ ID NOs: 35 and 72; SEQ ID NOs: 36 and 73; or SEQ ID NOs: 37 and 74, respectively.

[0068] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), wherein the antibody comprises a VH comprising a CDRH1, CDRH2, and / or CDRH3 amino acid sequence set forth in Table 3. In certain embodiments, the antibody comprises a VH comprising a CDRH1 amino acid sequence set forth in any one of SEQ ID NOs: 75-98. In certain embodiments, the antibody comprises a VH comprising a CDRH2 amino acid sequence set forth in any one of SEQ ID NOs: 99-131. In certain embodiments, the antibody comprises a VH comprising a CDRH3 amino acid sequence set forth in any one of SEQ ID NOs: 132-168.

[0069] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), wherein the antibody comprises a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of any of the antibodies in Table 3. In certain embodiments, the antibody comprises a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences set forth in SEQ ID NOs: 75, 99, and 132; SEQ ID NOs: 75, 100, and 133; SEQ ID NOs: 76, 101, and 134; SEQ ID NOs: 77, 102, and 135; SEQ ID NOs: 78, 103, and 136; SEQ ID NOs: 79, 104, and 137; SEQ ID NOs: 80, 105, and 138; SEQ ID NOs: 81, 106, and 139; SEQ ID NOs: 82, 107, and 140; SEQ ID NOs: 77, 108, and 141; SEQ ID NOs: 83, 109, and 142; SEQ ID NOs: 84, 110, and 143; SEQ ID NOs: 75, 111, and 144; SEQ ID NOs: 85, 112, and 145; SEQ ID NOs: 77, 113, and 146; SEQ ID NOs: 86, 114, and 147; SEQ ID NOs: 87, 115, and 148; SEQ ID NOs: 88, 116, and 149; SEQ ID NOs: 89, 104, and 150; SEQ ID NOs: 90, 117, and 151; SEQ ID NOs: 80, 105, and 152; SEQ ID NOs: 80, 118, and 153; SEQ ID NOs: 89, 119, and 154; SEQ ID NOs: 80, 101, and 155; SEQ ID NOs: 91, 120, and 156; SEQ ID NOs: 92, 121, and 157; SEQ ID NOs: 93, 122, and 158; SEQ ID NOs: 94, 123, and 159; SEQ ID NOs: 76, 124, and 160; SEQ ID NOs: 76, 101, and 161; SEQ ID NOs: 95, 125, and 162; SEQ ID NOs: 76, 126, and 163; SEQ ID NOs: 96, 127, and 164; SEQ ID NOs: 79, 128, and 165; SEQ ID NOs: 97, 129, and 166; SEQ ID NOs: 98, 130, and 167; or SEQ ID NOs: 91, 131, and 168, respectively.

[0070] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), wherein the antibody comprises a VL comprising a CDRL1, CDRL2, and / or CDRL3 amino acid sequence set forth in Table 4. In certain 21 BUSINESS.33373149.1embodiments, the antibody comprises a VL comprising a CDRL1 amino acid sequence set forth in any one of SEQ ID NOs: 169-193. In certain embodiments, the antibody comprises a VL comprising a CDRL2 amino acid sequence set forth in any one of SEQ ID NOs: 194-214. In certain embodiments, the antibody comprises a VL comprising a CDRL3 amino acid sequence set forth in any one of SEQ ID NOs: 215-246.

[0071] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), wherein the antibody comprises a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of any of the antibodies in Table 4. In certain embodiments, the antibody comprises a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 169, 194, and 215; SEQ ID NOs: 170, 195, and 216; SEQ ID NOs: 171, 196, and 217; SEQ ID NOs: 172, 197, and 218; SEQ ID NOs: 173, 198, and 219; SEQ ID NOs: 174, 196, and 220; SEQ ID NOs: 175, 199, and 221; SEQ ID NOs: 176, 195, and 222; SEQ ID NOs: 173, 195, and 223; SEQ ID NOs: 172, 197, and 224; SEQ ID NOs: 170, 195, and 225; SEQ ID NOs: 177, 200, and 226; SEQ ID NOs: 178, 195, and 227; SEQ ID NOs: 177, 201, and 228; SEQ ID NOs: 179, 202, and 229; SEQ ID NOs: 180, 203, and 230; SEQ ID NOs: 181, 196, and 231; SEQ ID NOs: 170, 195, and 232; SEQ ID NOs: 182, 204, and 233; SEQ ID NOs: 170, 205, and 234; SEQ ID NOs: 177, 206, and 221; SEQ ID NOs: 171, 196, and 231; SEQ ID NOs: 183, 196, and 220; SEQ ID NOs: 184, 207, and 235; SEQ ID NOs: 185, 208, and 236; SEQ ID NOs: 170, 209, and 237; SEQ ID NOs: 186, 206, and 238; SEQ ID NOs: 176, 210, and 239; SEQ ID NOs: 187, 196, and 231; SEQ ID NOs: 184, 211, and 240; SEQ ID NOs: 188, 212, and 241; SEQ ID NOs: 177, 199, and 242; SEQ ID NOs: 189, 213, and 243; SEQ ID NOs: 190, 196, and 220; SEQ ID NOs: 191, 195, and 244; SEQ ID NOs: 192, 195, and 245; or SEQ ID NOs: 193, 214, and 246, respectively.

[0072] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), wherein the antibody comprises a VH comprising a CDRH1, CDRH2, and / or CDRH3 amino acid sequence set forth in Table 3 and a VL comprising a CDRL1, CDRL2, and / or CDRL3 amino acid sequence set forth in Table 4, wherein 2, 3, 4, 5, or 6 of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences are from the same antibody (i.e., as shown in Tables 3 and 4). In certain embodiments, the antibody comprises a VH comprising CDRH1, CDRH2, and CDRH3 regions, and a VL comprising CDRL1, CDRL2, and CDRL3 regions, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 regions comprise the amino acid sequences set forth in SEQ ID NOs: 75, 99, 132, 169, 194, and 215; SEQ ID NOs: 75, 100, 133, 170, 195, and 216; SEQ ID NOs: 76, 101, 134, 171, 196, and 217; SEQ ID NOs: 77, 102, 135, 172, 197, 22 BUSINESS.33373149.1and 218; SEQ ID NOs: 78, 103, 136, 173, 198, and 219; SEQ ID NOs: 79, 104, 137, 174, 196, and 220; SEQ ID NOs: 80, 105, 138, 175, 199, and 221; SEQ ID NOs: 81, 106, 139, 176, 195, and 222; SEQ ID NOs: 82, 107, 140, 173, 195, and 223; SEQ ID NOs: 77, 108, 141, 172, 197, and 224; SEQ ID NOs: 83, 109, 142, 170, 195, and 225; SEQ ID NOs: 84, 110, 143, 177, 200, and 226; SEQ ID NOs: 75, 111, 144, 178, 195, and 227; SEQ ID NOs: 85, 112, 145, 177, 201, and 228; SEQ ID NOs: 77, 113, 146, 179, 202, and 229; SEQ ID NOs: 86, 114, 147, 180, 203, and 230; SEQ ID NOs: 87, 115, 148, 181, 196, and 231; SEQ ID NOs: 88, 116, 149, 170, 195, and 232; SEQ ID NOs: 89, 104, 150, 182, 204, and 233; SEQ ID NOs: 90, 117, 151, 170, 205, and 234; SEQ ID NOs: 80, 105, 152, 177, 206, and 221; SEQ ID NOs: 80, 118, 153, 171, 196, and 231; SEQ ID NOs: 89, 119, 154, 183, 196, and 220; SEQ ID NOs: 80, 101, 155, 184, 207, and 235; SEQ ID NOs: 91, 120, 156, 185, 208, and 236; SEQ ID NOs: 92, 121, 157, 170, 209, and 237; SEQ ID NOs: 93, 122, 158, 186, 206, and 238; SEQ ID NOs: 94, 123, 159, 176, 210, and 239; SEQ ID NOs: 76, 124, 160, 187, 196, and 231; SEQ ID NOs: 76, 101, 161, 184, 211, and 240; SEQ ID NOs: 95, 125, 162, 188, 212, and 241; SEQ ID NOs: 76, 126, 163, 177, 199, and 242; SEQ ID NOs: 96, 127, 164, 189, 213, and 243; SEQ ID NOs: 79, 128, 165, 190, 196, and 220; SEQ ID NOs: 97, 129, 166, 191, 195, and 244; SEQ ID NOs: 98, 130, 167, 192, 195, and 245; or SEQ ID NOs: 91, 131, 168, 193, 214, and 246, respectively.

[0073] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6) comprising a VH comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 100% (e.g., at least 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) identical to the amino acid sequence set forth in any one of SEQ ID NOs: 1-37. In certain embodiments, the instant disclosure provides an antibody that specifically binds to KLK6 (e.g., human KLK6), comprising a VH comprising an amino acid sequence set forth in any one of SEQ ID NOs: 1-37. In certain embodiments, the amino acid sequence of the VH consists of the amino acid sequence set forth in any one of SEQ ID NOs: 1-37.

[0074] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), comprising a VL comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 100% (e.g., at least 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) identical to the amino acid sequence set forth in any one of SEQ ID NOs: 38-74. In certain embodiments, the instant disclosure provides an antibody that specifically binds to KLK6 (e.g., human KLK6), comprising a VL comprising an amino acid sequence set forth in any one of SEQ ID NOs: 38-74. In certain embodiments, the amino acid sequence of the VL consists of the amino acid sequence set forth in any one of SEQ ID NOs: 38-74. 23 BUSINESS.33373149.1

[0075] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), comprising a VH comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 100% (e.g., at least 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99%) identical to the amino acid sequence set forth in any one of SEQ ID NOs: 1-37, and a VL comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 100% (e.g., at least 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) identical to the amino acid sequence set forth in any one of SEQ ID NOs: 38-74. In certain embodiments, the instant disclosure provides an antibody that specifically binds to KLK6 (e.g., human KLK6), comprising a VH comprising an amino acid sequence of any one of SEQ ID NOs: 1- 37, and a VL comprising an amino acid sequence of any one of SEQ ID NOs: 38-74. In certain embodiments, the amino acid sequence of the VH consists of the amino acid sequence set forth in any one of SEQ ID NOs: 1-37, and the amino acid sequence of the VL consists of the amino acid sequence set forth in any one of SEQ ID NOs: 38-74.

[0076] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), comprising a VH comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 100% (e.g., at least 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99%) identical to an amino acid sequence set forth in any one of SEQ ID NOs: 1-37, and a VL comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 100% (e.g., at least 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) identical to an amino acid sequence set forth in any one of SEQ ID NOs: 38-74, wherein the amino acid sequences set forth in any one of SEQ ID NOs: 1-37 and any one of SEQ ID NOs: 38-74 are from the same antibody (i.e., as shown in Tables 1 and 2). In certain embodiments, the instant disclosure provides an antibody that specifically binds to KLK6 (e.g., human KLK6), comprising a VH comprising an amino acid sequence of any one of SEQ ID NOs: 1-37, and a VL comprising an amino acid sequence of any one of SEQ ID NOs: 38-74, wherein the amino acid sequences set forth in any one of SEQ ID NOs: 1-37 and any one of SEQ ID NOs: 38-74 are from the same antibody (i.e., as shown in Tables 1 and 2). In certain embodiments, the amino acid sequence of the VH consists of the amino acid sequence set forth in any one of SEQ ID NOs: 1-37, and the amino acid sequence of the VL consists of the amino acid sequence set forth in any one of SEQ ID NOs: 38-74, wherein the amino acid sequences set forth in any one of SEQ ID NOs: 1-37 and any one of SEQ ID NOs: 38-74 are from the same antibody (i.e., as shown in Tables 1 and 2).

[0077] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), wherein the antibody comprises a VH and VL comprising 24 BUSINESS.33373149.1the amino acid sequences set forth in SEQ ID NOs: 1 and 38; SEQ ID NOs: 2 and 39; SEQ ID NOs: 3 and 40; SEQ ID NOs: 4 and 41; SEQ ID NOs: 5 and 42; SEQ ID NOs: 6 and 43; SEQ ID NOs: 7 and 44; SEQ ID NOs: 8 and 45; SEQ ID NOs: 9 and 46; SEQ ID NOs: 10 and 47; SEQ ID NOs: 11 and 48; SEQ ID NOs: 12 and 49; SEQ ID NOs: 13 and 50; SEQ ID NOs: 14 and 51; SEQ ID NOs: 15 and 52; SEQ ID NOs: 16 and 53; SEQ ID NOs: 17 and 54; SEQ ID NOs: 18 and 55; SEQ ID NOs: 19 and 56; SEQ ID NOs: 20 and 57; SEQ ID NOs: 21 and 58; SEQ ID NOs: 22 and 59; SEQ ID NOs: 23 and 60; SEQ ID NOs: 24 and 61; SEQ ID NOs: 25 and 62; SEQ ID NOs: 26 and 63; SEQ ID NOs: 27 and 64; SEQ ID NOs: 28 and 65; SEQ ID NOs: 29 and 66; SEQ ID NOs: 30 and 67; SEQ ID NOs: 31 and 68; SEQ ID NOs: 32 and 69; SEQ ID NOs: 33 and 70; SEQ ID NOs: 34 and 71; SEQ ID NOs: 35 and 72; SEQ ID NOs: 36 and 73; or SEQ ID NOs: 37 and 74, respectively.

[0078] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), wherein the antibody comprises a VH and VL consisting of the amino acid sequences set forth in SEQ ID NOs: 1 and 38; SEQ ID NOs: 2 and 39; SEQ ID NOs: 3 and 40; SEQ ID NOs: 4 and 41; SEQ ID NOs: 5 and 42; SEQ ID NOs: 6 and 43; SEQ ID NOs: 7 and 44; SEQ ID NOs: 8 and 45; SEQ ID NOs: 9 and 46; SEQ ID NOs: 10 and 47; SEQ ID NOs: 11 and 48; SEQ ID NOs: 12 and 49; SEQ ID NOs: 13 and 50; SEQ ID NOs: 14 and 51; SEQ ID NOs: 15 and 52; SEQ ID NOs: 16 and 53; SEQ ID NOs: 17 and 54; SEQ ID NOs: 18 and 55; SEQ ID NOs: 19 and 56; SEQ ID NOs: 20 and 57; SEQ ID NOs: 21 and 58; SEQ ID NOs: 22 and 59; SEQ ID NOs: 23 and 60; SEQ ID NOs: 24 and 61; SEQ ID NOs: 25 and 62; SEQ ID NOs: 26 and 63; SEQ ID NOs: 27 and 64; SEQ ID NOs: 28 and 65; SEQ ID NOs: 29 and 66; SEQ ID NOs: 30 and 67; SEQ ID NOs: 31 and 68; SEQ ID NOs: 32 and 69; SEQ ID NOs: 33 and 70; SEQ ID NOs: 34 and 71; SEQ ID NOs: 35 and 72; SEQ ID NOs: 36 and 73; SEQ ID NOs: 37 and 74, respectively.

[0079] In certain embodiments, the instant disclosure provides an antibody that cross-competes for binding to KLK6 (e.g., human KLK6) with any of the antibodies described above. In certain embodiments, the instant disclosure provides an antibody that binds to the same or an overlapping epitope of KLK6 (e.g., an epitope of human KLK6) as an antibody described above.

[0080] In certain embodiments, the epitope of an antibody can be determined by, e.g.,NMR spectroscopy, surface plasmon resonance (BIAcore®), X-ray diffraction crystallography studies, ELISA assays, hydrogen / deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography electrospray mass spectrometry), array-based oligo-peptide scanning assays, and / or mutagenesis mapping (e.g., site-directed mutagenesis mapping). For X-ray 25 BUSINESS.33373149.1crystallography, crystallization may be accomplished using any of the known methods in the art (e.g., Giegé 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, all of which are herein incorporated by reference in their entireties). Antibody:antigen crystals may be studied using well known X- ray diffraction techniques and may be refined using computer software such as X-PLOR (YaleUniversity, 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, all of which are herein incorporated by reference in their entireties). Mutagenesis mapping studies may be accomplished using anymethod known to one of skill in the art. See, e.g., Champe M et al., (1995) supra andCunningham BC & Wells JA (1989) supra for a description of mutagenesis techniques, including alanine scanning mutagenesis techniques. In a specific embodiment, the epitope of an antibody is determined using alanine scanning mutagenesis studies. In addition, or antibodies that recognize and bind to the same or overlapping epitopes of KLK6 (e.g., human KLK6) can be identified using routine techniques such as an immunoassay, for example, by showing the ability of one antibody to block the binding of another antibody to a target antigen, i.e., a competitive binding assay. Competition binding assays also can be used to determine whether two antibodies have similar binding specificity for an epitope. Competitive binding can be determined in an assay in which the immunoglobulin under test inhibits specific binding of a reference antibody to a common antigen, such as KLK6 (e.g., human KLK6). Numerous types of competitive binding assays are known, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see Stahli C et al., (1983) Methods Enzymol 9: 242-253); solid phase direct biotin-avidin EIA (see Kirkland TN et al., (1986) J Immunol 137: 3614-9); solid phase direct labeled assay, solid phase direct labeled sandwich assay (see Harlow E & Lane D, (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using I-125 label (see Morel GA et al., (1988) Mol Immunol 25(1): 7-15); solid phase direct biotin-avidin EIA (see Cheung RC et al., (1990) Virology 176: 546-52); and direct labeled RIA (see Moldenhauer G et al., (1990) Scand J Immunol 32: 77-82), all of which are herein incorporated by reference in their entireties. Typically, such an assay involves the use of purified antigen (e.g., KLK6, such as human KLK6) bound to a solid surface or cells bearing 26 BUSINESS.33373149.1either of these, 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. Usually, the test immunoglobulin is present in excess. Usually, when a competing antibody is present in excess, it will inhibit specific binding of a reference or antibody to a common antigen by at least 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, or more. A competition binding assay can be configured in a large 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 labeled antibodies to the antigen is then measured usingradioactive or enzyme labels. For further details see, e.g., Wagener C et al., (1983) J Immunol130: 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, all of which are herein incorporated by reference in their entireties.

[0081] The anti-KLK6 antigen-binding molecules of the present disclosure can be linkedto or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association, or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bispecific or a multispecific antibody (e.g., a bispecific T cell engager [BiTE] or a dual-affinity re-targeting antibody [DART]) with a second or additional binding specificity. In some embodiments, the bispecific or multispecific antibody has binding specificity for a molecule on an effector cell (e.g., CD3, CD16, CD137). In some embodiments, an antibody provided herein is a multispecific antibody. In some embodiments, a multispecific antibody provided herein comprises a CD3-binding region. In some embodiments, the CD3-binding region comprises a sequence from an antibody known to bind CD3 (e.g., OKT3, UTCH1, L2K, TR66, etc.). In some embodiments, the CD3-binding region comprises a single-chain fragment variable (scFv) that specifically binds to CD3. In some embodiments, a multispecific antibody provided herein specifically binds to human CD3.

[0082] In certain embodiments, an antibody disclosed herein is conjugated to apharmaceutically active substance. Pharmaceutically active substances include, but are not limited to, cytotoxic agents, cytostatic agents, toxins, radionuclides (e.g., radioisotopes), polypeptides, polynucleoctides, detectable labels, and combinations thereof. In certain 27 BUSINESS.33373149.1embodiments, pharmaceutically active substance is a cytotoxic agent. In certain embodiments, the cytotoxic agent is able to induce death or destruction of a cell in contact therewith. In certain embodiments, the pharmaceutically active substance is a cytostatic agent. In certain embodiments, the cytostatic agent is able to prevent or substantially reduce proliferation and / or inhibits the activity or function of a cell in contact therewith. In certain embodiments, the cytotoxic agent or cytostatic agent is a chemotherapeutic agent.

[0083] In certain embodiments, the pharmaceutically active substance is a radionuclide.Suitable radionuclides include, but are not limited to, beta emitters, auger emitters, converted electron emitters, alpha emitters, and low photon energy emitters. In certain embodiments, the radionuclide is selected from3H,14C,32P,35S,36Cl,45Ca,51Cr,57Co,58Co,59Fe,67Cu,67Ga,76As,77As,89Sr,90Y,99Tc,99mTc,105Rh,111In,114mIn,117Lu,121I,123I,124I,125I,131I,149Tb,153Sm,161Tb,166Ho,177Lu,198Au,201Tl,211At,212Pb,213Bi,225Ac,186Re,188Re,212Bi,213Bi,221At,223Ac,223Ra,225Ac,255Fm, and combinations thereof.

[0084] In certain embodiments, the pharmaceutically active substance is a detectable label.In certain embodiments, the detectable label comprises a fluorescent moiety, a click chemistry handle, or a combination thereof.

[0085] In certain embodiments, the pharmaceutically active substance is a drug. Suitabledrugs include, but are not limited to, anti-cancer agents, anti-inflammatory agents, and anti- infective (e.g., anti-fungal, antibacterial, anti-parasitic, antiviral) agents. Suitable anti-cancer agents include, but are not limited to, alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, kinase inhibitors, anti-hormonal agents, aromatase inhibitors, anti-androgens, protein kinase inhibitors, lipid kinase inhibitors, antisense oligonucleotides (e.g., those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation), ribozymes, (e.g., VEGF expression inhibitors and HER2 expression inhibitors), vaccines (e.g., gene therapy vaccines), topoisomerase 1 inhibitors, anti-angiogenic agents, pharmaceutically acceptable salts, acids, solvates and derivatives of any of the above, and any combination thereof.

[0086] In certain embodiments, the pharmaceutically active substance is a toxin. Suitabletoxins include, but are not limited to, proteinaceous toxins (e.g., bacterial-derived toxins, and plant-derived toxins), toxins targeting tubulin filaments, toxins targeting DNA, toxins targeting RNA. Examples of proteinaceous toxins include saporin, dianthin, ricin, modeccin, abrin, volkensin, viscumin, shiga toxin, shiga-like toxin, pseudomonas exotoxin (PE, also known as exotoxin A), diphtheria toxin (DT), and cholera toxin. Examples of toxins targeting tubulin 28 BUSINESS.33373149.1filaments include maytansinoids (e.g. DM1 and DM4), auristatins (e.g., Monomethyl auristatin E (MMAE) and Monomethyl auristatin F (MMAF)), toxoids, tubulysins, cryptophycins, rhizoxin. Examples of DNA-targeting toxins include calicheamicins: N-Acetyl- y- calicheamicin, CC-1065 analogs, duocarmycins, doxorubicin, methotrexate, benzodiazepines, camptothecin analogues, and anthracyclines. Examples of RNA-targeting toxins are amanitins, spliceostatins, and thailanstatins.

[0087] In certain embodiments, the pharmaceutically active substance is a polypeptide.Suitable polypeptides include, but are not limited to, Cas9; toxins (e.g., saporin, dianthin, gelonin, (de)bouganin, agrostin, ricin (toxin A chain); pokeweed antiviral protein, apoptin, diphtheria toxin, pseudomonas exotoxin); metabolic enzymes (e.g., argininosuccinate lyase, argininosuccinate synthetase); enzymes of the coagulation cascade; repairing enzymes; enzymes for cell signaling; cell cycle regulation factors; gene regulating factors (e.g., ranscription factors such as NF-KB or gene repressors such as methionine repressor).

[0088] In certain embodiments, the pharmaceutically active substance is a polynucleotide.In certain embodiments, the polynucleotide comprises coding information. In certain embodiments, the polynucleotide is a gene or an open reading frame encoding a protein. In certain embodiments, the polynucleotide comprises regulatory information. In certain embodiments, the polynucleotide is a promoter, a regulatory element binding region, or a sequence encoding a micro RNA. Suitable polynucleotides include natural and artificial nucleic acids. Artificial nucleic acids include, but are not limited to, peptide nucleic acids (PNA), Morpholinos and locked nucleic acids (LNA), glycol nucleic acids (GNA), and threose nucleic acids (TNA). Each of these is distinguished from naturally occurring DNA or RNA by changes to the backbone of the molecule. Suitable polynucleotides include, but are not limited to, a vector; a gene (e.g., a cell suicide-inducing transgene); single stranded DNA; linear double stranded DNA; circular double stranded DNA (e.g., a plasmid); mini-circle DNA; a DNA aptamer; single stranded RNA; linear double stranded RNA; mRNA; tRNA; rRNA; short interfering RNA (siRNA); microRNA (miRNA); antisense RNA; anti-sense oligonucleotides; peptide nucleic acid (PNA); phosphoramidate morpholino oligomer (PMO); locked nucleic acid (LNA); bridged nucleic acid (BNA); 2’-deoxy-2’-fluoroarabino nucleic acid (FANA); 2’- O-methoxyethyl-RNA (MOE); 2'-0,4'-aminoethylene bridged nucleic acid; 3’-fluoro hexitol nucleic acid (FHNA); an RNA aptamer; and combinations thereof.

[0089] In certain embodiments, the antibodies provided herein specifically bind to KLK6(e.g., human KLK6) and reduce or inhibit a function of KLK6 by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 29 BUSINESS.33373149.1or 99% as assessed by methods described herein and / or known to one of skill in the art, relative to the KLK6 function without any antibody or with an unrelated antibody (e.g., an antibody that does not specifically bind to KLK6). In certain embodiments, the antibodies provided herein specifically bind to KLK6 (e.g., human KLK6) and reduce or inhibit a function of KLK6 by at least about 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein and / or known to one of skill in the art, relative to the KLK6 function without any antibody or with an unrelated antibody (e.g., an antibody that does not specifically bind to KLK6). Non-limiting examples of KLK6 functions include KLK6 signaling (e.g., through PAR1), KLK6 binding to a substrate, and KLK6 enzymatic activity (e.g., peptide cleavage). In certain embodiments, reduction or inhibition of a function of KLK6 is assessed as described in the Examples herein.

[0090] Any immunoglobulin (Ig) constant region can be used in the antibodies disclosedherein. In certain embodiments, the Ig region is a human IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule.

[0091] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), the antibody comprising a heavy chain constant region, optionally selected from the group consisting of human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0092] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), the antibody comprising a heavy chain constant region that is a variant of a wild-type heavy chain constant region, wherein the variant heavy chain constant region binds to an FcγR with lower affinity than the wild-type heavy chain constant region binds to the FcγR.

[0093] In certain embodiments, the instant disclosure provides an antibody that specificallybinds to KLK6 (e.g., human KLK6), the antibody comprising a heavy chain constant region comprising an amino acid sequence shown in Table 5. In certain embodiments, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 247 or 248. In certain embodiments, the heavy chain constant region consists of the amino acid sequence of SEQ ID NO: 247 or 248. Table 5. Heavy chain constant region amino acid sequences of exemplary anti-KLK6 30 BUSINESS.33373149.1antibodies. Description Amino Acid Sequence SEQ ID WT IgG1 heavy ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV 247,binds to KLK6 (e.g., human KLK6), the antibody comprising a light chain constant region comprising an amino acid sequence shown in Table 6. In certain embodiments, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 249 or 250. In certain embodiments, the heavy chain constant region consists of the amino acid sequence of SEQ ID NO: 249 or 250. Table 6. Light chain constant region amino acid sequences of exemplary anti-KLK6 antibodies. Description Amino Acid Sequence SEQ ID

[0095] In certain embodiments, one, two, or more mutations (e.g., amino acidsubstitutions) are introduced into an Fc region (e.g., a CH2 domain (residues 231-340 of human IgG1)) and / or a CH3 domain (residues 341-447 of human IgG1, numbered according to the EU numbering system) and / or a hinge region (residues 216-230, numbered according to the EU numbering system) of an antibody described herein, to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or antigen-dependent cellular cytotoxicity. 31 BUSINESS.33373149.1

[0096] In certain embodiments, one, two, or more mutations (e.g., amino acidsubstitutions) are introduced into the hinge region of an antibody described herein, such that the number of cysteine residues in the hinge region is altered (e.g., increased or decreased) as described in, e.g., U.S. Patent No. 5,677,425, herein incorporated by reference in its entirety. The number of cysteine residues in the hinge region may be altered to, e.g., facilitate assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody.

[0097] In a specific embodiment, one, two, or more amino acid mutations (e.g.,substitutions, insertions, or deletions) are introduced into an IgG constant region, or FcRn- binding fragment thereof (preferably an Fc or hinge-Fc fragment) to alter (e.g., decrease or increase) half-life of the antibody in vivo. See, e.g., International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U.S. Patent Nos. 5,869,046, 6,121,022, 6,277,375, and 6,165,745, all of which are herein incorporated by reference in their entireties, for examples of mutations that will alter (e.g., decrease or increase) the half-life of an antibody in vivo. In certain embodiments, one, two or more amino acid mutations (e.g., substitutions, insertions, or deletions) are introduced into an IgG constant region, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc fragment) to decrease the half-life of the antibody in vivo. In other embodiments, one, two or more amino acid mutations (e.g., substitutions, insertions, or deletions) are introduced into an IgG constant region, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc fragment) to increase the half-life of the antibody in vivo. In a specific embodiment, the antibodies may have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgG1) and / or the third constant (CH3) domain (residues 341-447 of human IgG1), numbered according to the EU numbering system. In a specific embodiment, the constant region of the IgG1of antibody described herein comprises a methionine (M) to tyrosine (Y) substitution in position 252, a serine (S) to threonine (T) substitution in position 254, and a threonine (T) to glutamic acid (E) substitution in position 256, numbered according to the EU numbering system. See U.S. Patent No.7,658,921, which is herein incorporated by reference in its entirety. This type of mutant IgG, referred to as “YTE mutant” has been shown to display fourfold increased half- life as compared to wild-type versions of the same antibody (see Dall’Acqua WF et al., (2006) J Biol Chem 281: 23514-24, which is herein incorporated by reference in its entirety). In certain embodiments, an antibody comprises an IgG constant region comprising one, two, three, or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, numbered according to the EU numbering system. 32 BUSINESS.33373149.1

[0098] In certain embodiments, one, two, or more mutations (e.g., amino acidsubstitutions) are introduced into an Fc region (e.g., a CH2 domain (residues 231-340 of human IgG1)) and / or a CH3 domain (residues 341-447 of human IgG1, numbered according to the EU numbering system) and / or a hinge region (residues 216-230, numbered according to the EU numbering system) of an antibody described herein, to increase or decrease the affinity of the antibody for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that decrease or increase the affinity of an antibody for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fc receptor of an antibody that can be made to alter the affinity of the antibody for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109: 6181-6186, U.S. Patent No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, all of which are herein incorporated by reference in their entireties.

[0099] In certain embodiments, the antibody comprises a heavy chain constant region thatis a variant of a wild-type heavy chain constant region, wherein the variant heavy chain constant region binds to FcγRIIB with higher affinity than the wild-type heavy chain constant region binds to FcγRIIB. In certain embodiments, the variant heavy chain constant region is a variant human heavy chain constant region, e.g., a variant human IgG1, a variant human IgG2, or a variant human IgG4heavy chain constant region. In certain embodiments, the variant human IgG heavy chain constant region comprises one or more of the following amino acid mutations, according to the EU numbering system: G236D, P238D, S239D, S267E, L328F, and L328E. In certain embodiments, the variant human IgG heavy chain constant region comprises a set of amino acid mutations selected from the group consisting of: S267E and L328F; P238D and L328E; P238D and one or more substitutions selected from the group consisting of E233D, G237D, H268D, P271G, and A330R; P238D, E233D, G237D, H268D, P271G, and A330R; G236D and S267E; S239D and S267E; V262E, S267E, and L328F; and V264E, S267E, and L328F, according to the EU numbering system. In certain embodiments, the FcγRIIB is expressed on a cell selected from the group consisting of macrophages, monocytes, B cells, dendritic cells, endothelial cells, and activated T cells.

[0100] In a further embodiment, one, two, or more amino acid substitutions are introducedinto an IgG constant region Fc region to alter the effector function(s) of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 239, 243, 267, 292, 297, 300, 318, 320, 322, 328, 330, 332, and 396, numbered according to the EU numbering system, can be replaced with a different amino acid residue such that the antibody 33 BUSINESS.33373149.1has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Patent Nos.5,624,821 and 5,648,260, each of which is herein incorporated by reference in its entirety. In certain embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain may reduce Fc receptor binding of the circulating antibody therebyincreasing tumor localization. See, e.g., U.S. Patent Nos. 5,585,097 and 8,591,886, each ofwhich is herein incorporated by reference in its entirety, for a description of mutations that delete or inactivate the constant region and thereby increase tumor localization. In certain embodiments, one or more amino acid substitutions may be introduced into the Fc region of an antibody described herein to remove potential glycosylation sites on the Fc region, which mayreduce Fc receptor binding (see, e.g., Shields RL et al., (2001) J Biol Chem 276: 6591-604,which is herein incorporated by reference in its entirety). In various embodiments, one or more of the following mutations in the constant region of an antibody described herein may be made: an N297A substitution; an N297Q substitution; an L234A substitution; an L234F substitution; an L235A substitution; an L235F substitution; an L235V substitution; an L237A substitution; an S239D substitution; an E233P substitution; an L234V substitution; a C236 deletion; a P238A substitution; an F243L substitution; a D265A substitution; an S267E substitution; an L328F substitution; an R292P substitution; a Y300L substitution; an A327Q substitution; a P329A substitution; an A330L substitution; an I332E substitution; or a P396L substitution, numbered according to the EU numbering system.

[0101] In certain embodiments, a mutation selected from the group consisting of D265A,P329A, and a combination thereof, numbered according to the EU numbering system, may be made in the constant region of an antibody described herein. In certain embodiments, a mutation selected from the group consisting of L235A, L237A, and a combination thereof, numbered according to the EU numbering system, may be made in the constant region of an antibody described herein. In certain embodiments, a mutation selected from the group consisting of S267E, L328F, and a combination thereof, numbered according to the EU numbering system, may be made in the constant region of an antibody described herein. In certain embodiments, a mutation selected from the group consisting of S239D, I332E, optionally A330L, and a combination thereof, numbered according to the EU numbering system, may be made in the constant region of an antibody described herein. In certain embodiments, a mutation selected from the group consisting of L235V, F243L, R292P, Y300L, P396L, and a combination thereof, numbered according to the EU numbering system, may be 34 BUSINESS.33373149.1made in the constant region of an antibody described herein. In certain embodiments, a mutation selected from the group consisting of S267E, L328F, and a combination thereof, numbered according to the EU numbering system, may be made in the constant region of an antibody described herein.

[0102] In a specific embodiment, an antibody described herein comprises the constantregion of an IgG1with an N297Q or N297A amino acid substitution, numbered according to the EU numbering system. In certain embodiments, an antibody described herein comprises the constant region of an IgG1with a mutation selected from the group consisting of D265A, P329A, and a combination thereof, numbered according to the EU numbering system. In another embodiment, an antibody described herein comprises the constant region of an IgG1with a mutation selected from the group consisting of L234A, L235A, and a combination thereof, numbered according to the EU numbering system. In another embodiment, an antibody described herein comprises the constant region of an IgG1 with a mutation selected from the group consisting of L234F, L235F, N297A, and a combination thereof, numbered according to the EU numbering system. In certain embodiments, amino acid residues in the constant region of an antibody described herein in the positions corresponding to positions L234, L235, and D265 in a human IgG1heavy chain, numbered according to the EU numbering system, are not L, L, and D, respectively. This approach is described in detail in International Publication No. WO 14 / 108483, which is herein incorporated by reference in its entirety. In certain embodiments, the amino acids corresponding to positions L234, L235, and D265 in a human IgG1heavy chain are F, E, and A; or A, A, and A, respectively, numbered according to the EU numbering system.

[0103] In certain embodiments, one or more amino acids selected from amino acid residues329, 331, and 322 in the constant region of an antibody described herein, numbered according to the EU numbering system, can be replaced with a different amino acid residue such that the antibody has altered C1q binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent No.6,194,551 (Idusogie et al.), which is herein incorporated by reference in its entirety. In certain embodiments, one or more amino acid residues within amino acid positions 231 to 238 in the N-terminal region of the CH2 domain of an antibody described herein are altered to thereby alter the ability of the antibody to fix complement, numbered according to the EU numbering system. This approach is described further in International Publication No. WO 94 / 29351, which is herein incorporated by reference in its entirety. In certain embodiments, the Fc region of an antibody described herein is modified to increase the ability of the antibody to mediate 35 BUSINESS.33373149.1antibody dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the antibody for an Fc^ receptor by mutating one or more amino acids (e.g., introducing amino acid substitutions) at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 328, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438, or 439, numbered according to the EU numbering system. This approach is described further in International Publication No. WO 00 / 42072, which is herein incorporated by reference in its entirety.

[0104] In certain embodiments, an antibody described herein comprises a modifiedconstant region of an IgG1, wherein the modification increases the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC). In certain embodiments, 0.1, 1, or 10 µg / ml of the antibody is capable of inducing cell death of at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of KLK6-expressing cells within 1, 2, or 3 hours, as assessed by methods described herein and / or known to a person of skill in the art. In certain embodiments, the modified constant region of an IgG1comprises S239D and I332E substitutions, numbered according to the EU numbering system. In certain embodiments, the modified constant region of an IgG1comprises S239D, A330L, and I332E substitutions, numbered according to the EU numbering system. In certain embodiments, the modified constant region of an IgG1comprises L235V, F243L, R292P, Y300L, and P396L substitutions, numbered according to the EU numbering system. In certain embodiments, the antibody is capable of inducing cell death in effector T cells and Tregs, wherein the percentage of Tregs that undergo cell death is higher than the percentage of effector T cells that undergo cell death by at least 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 1.6 fold, 1.7 fold, 1.8 fold, 1.9 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, or 5 fold.

[0105] In certain embodiments, an antibody described herein comprises the constant regionof an IgG4antibody and the serine at amino acid residue 228 of the heavy chain, numbered according to the EU numbering system, is substituted for proline.

[0106] In certain embodiments, any of the constant region mutations or modificationsdescribed herein can be introduced into one or both heavy chain constant regions of an antibody described herein having two heavy chain constant regions. 36 BUSINESS.33373149.1Polypeptides

[0107] In another aspect, provided herein are polypeptides comprising one or moresequences set forth in Tables 1-4, above. In certain embodiments, the polypeptide comprises the CDRH1, CDRH2, and / or CDRH3 of a VH amino acid sequence set forth in any one of SEQ ID NOs: 1-37, as determined by any of the methods discussed above. In certain embodiments, the polypeptide comprises a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in any one of SEQ ID NOs: 1- 37. In certain embodiments, the polypeptide comprises the CDRH1, CDRH2, and CDRH3 amino acid sequences set forth in SEQ ID NOs: 75, 99, and 132; 75, 100, and 133; 76, 101, and 134; 77, 102, and 135; 78, 103, and 136; 79, 104, and 137; 80, 105, and 138; 81, 106, and 139; 82, 107, and 140; 77, 108, and 141; 83, 109, and 142; 84, 110, and 143; 75, 111, and 144; 85, 112, and 145; 77, 113, and 146; 86, 114, and 147; 87, 115, and 148; 88, 116, and 149; 89, 104, and 150; 90, 117, and 151; 80, 105, and 152; 80, 118, and 153; 89, 119, and 154; 80, 101, and 155; 91, 120, and 156; 92, 121, and 157; 93, 122, and 158; 94, 123, and 159; 76, 124, and 160; 76, 101, and 161; 95, 125, and 162; 76, 126, and 163; 96, 127, and 164; 79, 128, and 165; 97, 129, and 166; 98, 130, and 167; or 91, 131, and 168, respectively.

[0108] In certain embodiments, the polypeptide comprises the CDRL1, CDRL2, and / orCDRL3 of a VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74, as determined by any of the methods discussed above. In certain embodiments, the polypeptide comprises a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74. In certain embodiments, the polypeptide comprises the CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 169, 194, and 215; 170, 195, and 216; 171, 196, and 217; 172, 197, and 218; 173, 198, and 219; 174, 196, and 220; 175, 199, and 221; 176, 195, and 222; 173, 195, and 223; 172, 197, and 224; 170, 195, and 225; 177, 200, and 226; 178, 195, and 227; 177, 201, and 228; 179, 202, and 229; 180, 203, and 230; 181, 196, and 231; 170, 195, and 232; 182, 204, and 233; 170, 205, and 234; 177, 206, and 221; 171, 196, and 231; 183, 196, and 220; 184, 207, and 235; 185, 208, and 236; 170, 209, and 237; 186, 206, and 238; 176, 210, and 239; 187, 196, and 231; 184, 211, and 240; 188, 212, and 241; 177, 199, and 242; 189, 213, and 243; 190, 196, and 220; 191, 195, and 244; 192, 195, and 245; or 193, 214, and 246, respectively.

[0109] In certain embodiments, the polypeptide comprises a VH comprising the CDRH1,CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in any one of SEQ ID NOs: 1-37; and a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74. In certain 37 BUSINESS.33373149.1embodiments, the polypeptide comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of the VH and VL amino acid sequences set forth in SEQ ID NOs: 1 and 38, 2 and 39, 3 and 40, 4 and 41, 5 and 42, 6 and 43, 7 and 44, 8 and 45, 9 and 46, 10 and 47, 11 and 48, 12 and 49, 13 and 50, 14 and 51, 15 and 52, 16 and 53, 17 and 54, 18 and 55, 19 and 56, 20 and 57, 21 and 58, 22 and 59, 23 and 60, 24 and 61, 25 and 62, 26 and 63, 27 and 64, 28 and 65, 29 and 66, 30 and 67, 31 and 68, 32 and 69, 33 and 70, 34 and 71, 35 and 72, 36 and 73, or 37 and 74, respectively.

[0110] In certain embodiments, a polypeptide provided herein comprises the CDRH1,CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in: SEQ ID NOs: 75, 99, 132, 169, 194, and 215; 75, 100, 133, 170, 195, and 216; 76, 101, 134, 171, 196, and 217; 77, 102, 135, 172, 197, and 218; 78, 103, 136, 173, 198, and 219; 79, 104, 137, 174, 196, and 220; 80, 105, 138, 175, 199, and 221; 81, 106, 139, 176, 195, and 222; 82, 107, 140, 173, 195, and 223; 77, 108, 141, 172, 197, and 224; 83, 109, 142, 170, 195, and 225; 84, 110, 143, 177, 200, and 226; 75, 111, 144, 178, 195, and 227; 85, 112, 145, 177, 201, and 228; 77, 113, 146, 179, 202, and 229; 86, 114, 147, 180, 203, and 230; 87, 115, 148, 181, 196, and 231; 88, 116, 149, 170, 195, and 232; 89, 104, 150, 182, 204, and 233; 90, 117, 151, 170, 205, and 234; 80, 105, 152, 177, 206, and 221; 80, 118, 153, 171, 196, and 231; 89, 119, 154, 183, 196, and 220; 80, 101, 155, 184, 207, and 235; 91, 120, 156, 185, 208, and 236; 92, 121, 157, 170, 209, and 237; 93, 122, 158, 186, 206, and 238; 94, 123, 159, 176, 210, and 239; 76, 124, 160, 187, 196, and 231; 76, 101, 161, 184, 211, and 240; 95, 125, 162, 188, 212, and 241; 76, 126, 163, 177, 199, and 242; 96, 127, 164, 189, 213, and 243; 79, 128, 165, 190, 196, and 220; 97, 129, 166, 191, 195, and 244; 98, 130, 167, 192, 195, and 245; or 91, 131, 168, 193, 214, and 246, respectively. Pharmaceutical Compositions

[0111] Provided herein are compositions comprising an anti-KLK6 antibody disclosedherein having the desired degree of purity in a physiologically acceptable carrier, excipient, orstabilizer (see, e.g., Remington’s Pharmaceutical Sciences (1990) Mack Publishing Co.,Easton, PA). Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low 38 BUSINESS.33373149.1molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0112] In a specific embodiment, pharmaceutical compositions comprise an anti-KLK6antibody disclosed herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. In a specific embodiment, pharmaceutical compositions comprise an anti-KLK6 antibody disclosed herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. In certain embodiments, the antibody is the only active ingredient included in the pharmaceutical composition. Pharmaceutical compositions described herein can be useful in decreasing or blocking KLK6 (e.g., human KLK6) activity and treating a condition, such as cancer, Alzheimer’s disease, a demyelinating disease, and / or multiple sclerosis. In certain embodiments, the present disclosure relates to a pharmaceutical composition of the present disclosure comprising an anti-KLK6 antibody of the present disclosure for use as a medicament. In another embodiment, the present disclosure relates to a pharmaceutical composition of the present disclosure for use in a method for the treatment of cancer, Alzheimer’s disease, a demyelinating disease, and / or multiple sclerosis.

[0113] Pharmaceutically acceptable carriers used in parenteral preparations includeaqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous vehicles include Sodium Chloride Injection, Ringer’s Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringer’s Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations can be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing 39 BUSINESS.33373149.1agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN®80). A sequestering or chelating agent of metal ions includes EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0114] A pharmaceutical composition can be formulated for any route of administration toa subject. Specific examples of routes of administration include intranasal, oral, pulmonary, transdermal, intradermal, and parenteral. Parenteral administration, characterized by either subcutaneous, intramuscular, or intravenous injection, is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if desired, the pharmaceutical compositions to be administered can also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0115] Preparations for parenteral administration of antibody include sterile solutionsready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use, and sterile emulsions. The solutions may be either aqueous or nonaqueous.

[0116] If administered intravenously, suitable carriers include physiological saline orphosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0117] Topical mixtures comprising an antibody are prepared as described for the local andsystemic administration. The resulting mixture can be a solution, suspension, emulsions, or the like and can be formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches, or any other formulations suitable for topical administration.

[0118] An anti-KLK6 antibody disclosed herein can be formulated as an aerosol for topicalapplication, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,126, 4,414,209, and4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma and are herein incorporated by reference in their 40 BUSINESS.33373149.1entireties). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflations, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will, in certain embodiments, have diameters of less than 50 microns, in certain embodiments, less than 10 microns.

[0119] An anti-KLK6 antibody disclosed herein can be formulated for local or topicalapplication, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the antibody alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[0120] Transdermal patches, including iontophoretic and electrophoretic devices, are wellknown to those of skill in the art, and can be used to administer an antibody. For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957, all of which are herein incorporated by reference in their entireties.

[0121] In certain embodiments, a pharmaceutical composition comprising an antibodydescribed herein is a lyophilized powder, which can be reconstituted for administration as solutions, emulsions, and other mixtures. It may also be reconstituted and formulated as solids or gels. The lyophilized powder is prepared by dissolving an antibody described herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. In certain embodiments, the lyophilized powder is sterile. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate, or other such buffer known to those of skill in the art, at, in certain embodiments, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In certain embodiments, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature. Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For 41 BUSINESS.33373149.1reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such an amount can be empirically determined.

[0122] The anti-KLK6 antibodies disclosed herein and other compositions provided hereincan also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions.For non-limiting examples of targeting methods, see, e.g., U.S. Patent Nos. 6,316,652,6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874, all of which are herein incorporated by reference in their entireties. In a specific embodiment, an antibody described herein is targeted to a tumor.

[0123] The compositions to be used for in vivo administration can be sterile. This is readilyaccomplished by filtration through, e.g., sterile filtration membranes. Methods of Use and Uses

[0124] In another aspect, the instant disclosure provides a method of treating a subjectusing the anti-KLK6 antibodies disclosed herein. In certain embodiments, the subject has or is suspected of having a KLK6-associated disease or disorder. In certain embodiments, the KLK6-associated disease or disorder is characterized by overexpression of KLK6 (e.g., human KLK6). In certain embodiments, the KLK6-associated disease or disorder is characterized by dysregulation of one or more KLK6 functions. In certain embodiments, the disease or disorder is resistant to a checkpoint targeting agent (e.g., an antagonist anti-CTLA-4 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, or an antagonist anti-PD- 1 antibody). In certain embodiments, the disease or disorder is recurrent after treatment with a checkpoint targeting agent (e.g., an antagonist anti-CTLA-4 antibody, an antagonist anti-PD- L1 antibody, an antagonist anti-PD-L2 antibody, or an antagonist anti-PD-1 antibody).

[0125] In certain embodiments, the instant disclosure provides a method of treating aKLK6-associated disease or disorder in a subject, the method comprising administering to the subject an effective amount of the antibody or pharmaceutical composition, as disclosed herein. In certain embodiments, the KLK6-associated disease or disorder is cancer. In certain embodiments, the KLK6-associated disease or disorder is Alzheimer’s disease. In certain embodiments, the KLK6-associated disease or disorder is a demyelinating disease. In certain embodiments, the KLK6-associated disease or disorder is multiple sclerosis. 42 BUSINESS.33373149.1

[0126] Cancers that can be treated with the anti-KLK6 antibodies or pharmaceuticalcompositions disclosed herein include, without limitation, a solid tumor, a hematological cancer (e.g., leukemia, lymphoma, myeloma, e.g., multiple myeloma), and a metastatic lesion. In certain embodiments, the cancer is a solid tumor. Examples of solid tumors include malignancies, e.g., sarcomas and carcinomas, e.g., adenocarcinomas of the various organ systems, such as those affecting the lung, breast, ovarian, lymphoid, gastrointestinal (e.g., colon), anal, genitals and genitourinary tract (e.g., renal, urothelial, bladder cells, prostate), pharynx, CNS (e.g., brain, neural or glial cells), head and neck, skin (e.g., melanoma), and pancreas, as well as adenocarcinomas which include malignancies such as colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), cancer of the small intestine, and cancer of the esophagus. The cancer may be at an early, intermediate, late stage, or metastatic cancer. In certain embodiments, the cancer is resistant to a checkpoint targeting agent (e.g., an antagonist anti-CTLA-4 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, or an antagonist anti-PD- 1 antibody). In certain embodiments, the cancer is recurrent after treatment with a checkpoint targeting agent (e.g., an antagonist anti-CTLA-4 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, or an antagonist anti-PD-1 antibody).

[0127] In certain embodiments, the cancer is chosen from lung cancer (e.g., lungadenocarcinoma or non-small cell lung cancer (NSCLC) (e.g., NSCLC with squamous and / or non-squamous histology, or NSCLC adenocarcinoma)), melanoma (e.g., an advanced melanoma), renal cancer (e.g., a renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), myeloma (e.g., a multiple myeloma), a prostate cancer, a breast cancer (e.g., a breast cancer that does not express one, two or all of estrogen receptor, progesterone receptor, or Her2 / neu, e.g., a triple negative breast cancer), an ovarian cancer, a colorectal cancer, a pancreatic cancer, a head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), anal cancer, gastro-esophageal cancer (e.g., esophageal squamous cell carcinoma), mesothelioma, nasopharyngeal cancer, thyroid cancer, cervical cancer, epithelial cancer, peritoneal cancer, or a lymphoproliferative disease (e.g., a post-transplant lymphoproliferative disease).

[0128] In certain embodiments, the cancer is a hematological cancer, for example, aleukemia, a lymphoma, or a myeloma. In certain embodiments, the cancer is a leukemia, for example, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute myeloblastic leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia 43 BUSINESS.33373149.1(CMML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia. In certain embodiments, the cancer is a lymphoma, for example, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B-cell like (ABC) diffuse large B cell lymphoma, germinal center B cell (GCB) diffuse large B cell lymphoma, mantle cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, relapsed non-Hodgkin lymphoma, refractory non- Hodgkin lymphoma, recurrent follicular non-Hodgkin lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, or extranodal marginal zone lymphoma. In certain embodiments the cancer is a myeloma, for example, multiple myeloma.

[0129] In another embodiment, the cancer is chosen from a carcinoma (e.g., advanced ormetastatic carcinoma), melanoma or a lung carcinoma, e.g., a non-small cell lung carcinoma.

[0130] In certain embodiments, the cancer is a lung cancer, e.g., a lung adenocarcinoma,non-small cell lung cancer, or small cell lung cancer.

[0131] In certain embodiments, the cancer is a melanoma, e.g., an advanced melanoma. Incertain embodiments, the cancer is an advanced or unresectable melanoma that does not respond to other therapies. In other embodiments, the cancer is a melanoma with a BRAF mutation (e.g., a BRAF V600 mutation). In yet other embodiments, the anti-KLK6 antibodies or pharmaceutical composition disclosed herein is administered after treatment with an anti- CTLA-4 antibody (e.g., ipilimumab) with or without a BRAF inhibitor (e.g., vemurafenib or dabrafenib).

[0132] In another embodiment, the cancer is a hepatocarcinoma, e.g., an advancedhepatocarcinoma, with or without a viral infection, e.g., a chronic viral hepatitis.

[0133] In another embodiment, the cancer is a prostate cancer, e.g., an advanced prostatecancer.

[0134] In yet another embodiment, the cancer is a myeloma, e.g., multiple myeloma.

[0135] In yet another embodiment, the cancer is a renal cancer, e.g., a renal cell carcinoma(RCC) (e.g., a metastatic RCC, clear cell renal cell carcinoma (CCRCC) or kidney papillary cell carcinoma).

[0136] In yet another embodiment, the cancer is chosen from a lung cancer, a melanoma,a renal cancer, a breast cancer, a colorectal cancer, a leukemia, or a metastatic lesion of the cancer.

[0137] Demyelinating diseases that can be treated with the anti-KLK6 antibodies orpharmaceutical compositions disclosed herein include any condition in which the myelin sheath is degraded or impaired. Demyelinating diseases include, but are not limited to, multiple 44 BUSINESS.33373149.1sclerosis, optic neuritis, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), transverse myelitis, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, central pontine myelinolysis, Guillain-Barré syndrome (GBS), Charco-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, Balo’s disease (concentric sclerosis), HTLV-1 associated myelopathy (HAM), and Schilder’s disease.

[0138] In certain embodiments, administration of an antibody disclosed herein to a subjectresults in a reduction or inhibition of a KLK6 function in the subject. In certain embodiments, the KLK6 function is reduced or inhibited by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein and / or known to one of skill in the art, relative to the KLK6 function in a subject to which the antibody has not been administered. In certain embodiments, the KLK6 function is reduced or inhibited by at least about 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein and / or known to one of skill in the art, relative to the KLK6 function in a subject to which the antibody has not been administered. Non-limiting examples of KLK6 functions include KLK6 signaling (e.g., through PAR1), KLK6 binding to a substrate, and KLK6 enzymatic activity (e.g., peptide cleavage). In certain embodiments, reduction or inhibition of a function of KLK6 is assessed as described in the Examples herein.

[0139] In certain embodiments, these methods further comprise administering anadditional therapeutic agent to the subject. In certain embodiments, the additional therapeutic agent is a chemotherapeutic, a radiotherapeutic, or a checkpoint targeting agent. In certain embodiments, the chemotherapeutic agent is a hypomethylating agent (e.g., azacitidine). In certain embodiments, the chemotherapeutic agent is a DNA damage-inducing agent (e.g., gemcitabine). In certain embodiments, the checkpoint targeting agent is selected from the group consisting of an antagonist anti-CTLA-4 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, an antagonist anti-PD-1 antibody, an antagonist anti-TIM- 3 antibody, an antagonist anti-LAG-3 antibody, an antagonist anti-VISTA antibody, an antagonist anti-CD96 antibody, an antagonist anti-CEACAM1 antibody, an agonist anti- CD137 antibody, an agonist anti-GITR antibody, and an agonist anti-OX40 antibody. In certain embodiments, the checkpoint targeting agent is selected from the group consisting of an antagonist anti-CTLA-4 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD- L2 antibody, and an antagonist anti-PD-1 antibody, wherein the KLK6 (e.g., human KLK6) 45 BUSINESS.33373149.1antibodies or pharmaceutical compositions disclosed herein synergize with the checkpoint targeting agent.

[0140] In certain embodiments, the present disclosure relates to an antibody and / orpharmaceutical composition of the present disclosure for use in a method of the present disclosure, wherein the method further comprises administering an additional therapeutic agent to the subject. In certain embodiments, the present disclosure relates to (a) an antibody and / or pharmaceutical composition of the present disclosure and (b) an additional therapeutic agent for use as a medicament. In certain embodiments, the present disclosure relates to (a) an antibody and / or pharmaceutical composition of the present disclosure and (b) an additional therapeutic agent for use in a method for the treatment of cancer, Alzheimer’s disease, a demyelinating disease, and / or multiple sclerosis. In a further embodiment, the present disclosure relates to a pharmaceutical composition, kit or kit-of-parts comprising (a) an antibody and / or pharmaceutical composition of the present disclosure and (b) an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is a chemotherapeutic, a radiotherapeutic, or a checkpoint targeting agent.

[0141] In certain embodiments, an anti-PD-1 antibody is used in methods disclosed herein.In certain embodiments, the anti-PD-1 antibody is nivolumab, also known as BMS-936558 or MDX1106, developed by Bristol-Myers Squibb. In certain embodiments, the anti-PD-1 antibody is pembrolizumab, also known as lambrolizumab or MK-3475, developed by Merck & Co. In certain embodiments, the anti-PD-1 antibody is pidilizumab, also known as CT-011, developed by CureTech. In certain embodiments, the anti-PD-1 antibody is MEDI0680, also known as AMP-514, developed by MedImmune. In certain embodiments, the anti-PD-1 antibody is PDR001 developed by Novartis Pharmaceuticals. In certain embodiments, the anti- PD-1 antibody is REGN2810 developed by Regeneron Pharmaceuticals. In certain embodiments, the anti-PD-1 antibody is PF-06801591 developed by Pfizer. In certain embodiments, the anti-PD-1 antibody is BGB-A317 developed by BeiGene. In certain embodiments, the anti-PD-1 antibody is TSR-042 developed by AnaptysBio and Tesaro. In certain embodiments, the anti-PD-1 antibody is SHR-1210 developed by Hengrui.

[0142] Further non-limiting examples of anti-PD-1 antibodies that may be used intreatment methods disclosed herein are disclosed in the following patents and patent applications, all of which are herein incorporated by reference in their entireties for all purposes: U.S. Patent No. 6,808,710; U.S. Patent No. 7,332,582; U.S. Patent No. 7,488,802; U.S. Patent No.8,008,449; U.S. Patent No.8,114,845; U.S. Patent No.8,168,757; U.S. Patent No. 8,354,509; U.S. Patent No. 8,686,119; U.S. Patent No. 8,735,553; U.S. Patent No. 46 BUSINESS.33373149.18,747,847; U.S. Patent No. 8,779,105; U.S. Patent No.8,927,697; U.S. Patent No.8,993,731; U.S. Patent No.9,102,727; U.S. Patent No.9,205,148; U.S. Publication No. US 2013 / 0202623 A1; U.S. Publication No. US 2013 / 0291136 A1; U.S. Publication No. US 2014 / 0044738 A1; U.S. Publication No. US 2014 / 0356363 A1; U.S. Publication No. US 2016 / 0075783 A1; PCT Publication No. WO 2013 / 033091 A1; PCT Publication No. WO 2015 / 036394 A1; PCT Publication No. WO 2014 / 179664 A2; PCT Publication No. WO 2014 / 209804 A1; PCT Publication No. WO 2014 / 206107 A1; PCT Publication No. WO 2015 / 058573 A1; PCT Publication No. WO 2015 / 085847 A1; PCT Publication No. WO 2015 / 200119 A1; PCT Publication No. WO 2016 / 015685 A1; and PCT Publication No. WO 2016 / 020856 A1.

[0143] In certain embodiments, an anti-PD-L1 antibody is used in methods disclosedherein. In certain embodiments, the anti-PD-L1 antibody is atezolizumab developed by Genentech. In certain embodiments, the anti-PD-L1 antibody is durvalumab developed by AstraZeneca, Celgene, and MedImmune. In certain embodiments, the anti-PD-L1 antibody is avelumab, also known as MSB0010718C, developed by Merck Serono and Pfizer. In certain embodiments, the anti-PD-L1 antibody is MDX-1105 developed by Bristol-Myers Squibb. In certain embodiments, the anti-PD-L1 antibody is AMP-224 developed by Amplimmune and GSK.

[0144] Non-limiting examples of anti-PD-L1 antibodies that may be used in treatmentmethods disclosed herein are disclosed in the following patents and patent applications, all of which are herein incorporated by reference in their entireties for all purposes: U.S. Patent No. 7,943,743; U.S. Patent No. 8,168,179; U.S. Patent No.8,217,149; U.S. Patent No.8,552,154; U.S. Patent No. 8,779,108; U.S. Patent No. 8,981,063; U.S. Patent No. 9,175,082; U.S. Publication No. US 2010 / 0203056 A1; U.S. Publication No. US 2003 / 0232323 A1; U.S. Publication No. US 2013 / 0323249 A1; U.S. Publication No. US 2014 / 0341917 A1; U.S. Publication No. US 2014 / 0044738 A1; U.S. Publication No. US 2015 / 0203580 A1; U.S. Publication No. US 2015 / 0225483 A1; U.S. Publication No. US 2015 / 0346208 A1; U.S. Publication No. US 2015 / 0355184 A1; PCT Publication No. WO 2014 / 100079 A1; PCT Publication No. WO 2014 / 022758 A1; PCT Publication No. WO 2014 / 055897 A2; PCT Publication No. WO 2015 / 061668 A1; PCT Publication No. WO 2015 / 109124 A1; PCT Publication No. WO 2015 / 195163 A1; PCT Publication No. WO 2016 / 000619 A1; and PCT Publication No. WO 2016 / 030350 A1.

[0145] In certain embodiments, an anti-CTLA-4 antibody is used in methods disclosedherein. In certain embodiments, the anti-CTLA-4 antibody is ipilimumab developed by Bristol- Myers Squibb. 47 BUSINESS.33373149.1

[0146] In certain embodiments, an anti-KLK6 antibody disclosed herein is administered toa subject in combination with a compound that targets an immunomodulatory enzyme(s) such as IDO (indoleamine-(2,3)-dioxygenase) and / or TDO (tryptophan 2,3-dioxygenase). Therefore, in certain embodiments, the additional therapeutic agent is a compound that targets an immunomodulatory enzyme(s), such as an inhibitor of indoleamine-(2,3)-dioxygenase (IDO). In certain embodiments, such compound is selected from the group consisting ofepacadostat (Incyte Corp; see, e.g., WO 2010 / 005958 which is herein incorporated by referencein its entirety), F001287 (Flexus Biosciences / Bristol-Myers Squibb), indoximod (NewLink Genetics), and NLG919 (NewLink Genetics). In certain embodiments, the compound is epacadostat. In another embodiment, the compound is F001287. In another embodiment, the compound is indoximod. In another embodiment, the compound is NLG919. In a specific embodiment, an anti-KLK6 antibody disclosed herein is administered to a subject in combination with an IDO inhibitor for treating cancer. The IDO inhibitor as described herein for use in treating cancer is present in a solid dosage form of a pharmaceutical composition such as a tablet, a pill, or a capsule, wherein the pharmaceutical composition includes an IDO inhibitor and a pharmaceutically acceptable excipient. As such, the antibody as described herein and the IDO inhibitor as described herein can be administered separately, sequentially, or concurrently as separate dosage forms. In certain embodiments, the antibody is administered parenterally, and the IDO inhibitor is administered orally. In certain embodiments, the inhibitor is selected from the group consisting of epacadostat (Incyte Corporation), F001287 (Flexus Biosciences / Bristol-Myers Squibb), indoximod (NewLink Genetics), and NLG919 (NewLink Genetics). Epacadostat has been described in PCT Publication No. WO 2010 / 005958, which is herein incorporated by reference in its entirety for all purposes. In certain embodiments, the inhibitor is epacadostat. In another embodiment, the inhibitor is F001287. In another embodiment, the inhibitor is indoximod. In another embodiment, the inhibitor is NLG919.

[0147] In certain embodiments, an anti-KLK6 antibody disclosed herein is administered toa subject in combination with a vaccine. The vaccine can be, e.g., a peptide vaccine, a DNA vaccine, or an RNA vaccine.

[0148] In certain embodiments, an anti-KLK6 antibody disclosed herein is administered toa subject in combination with an adjuvant. Various adjuvants can be used depending on the treatment context. Non-limiting examples of appropriate adjuvants include, but not limited to, Complete Freund’s Adjuvant (CFA), Incomplete Freund’s Adjuvant (IFA), montanide ISA (incomplete Seppic adjuvant), the Ribi adjuvant system (RAS), Titer Max, muramyl peptides, Syntex Adjuvant Formulation (SAF), alum (aluminum hydroxide and / or aluminum phosphate), 48 BUSINESS.33373149.1aluminum salt adjuvants, Gerbu®adjuvants, nitrocellulose absorbed antigen, encapsulated or entrapped antigen, 3 De-O-acylated monophosphoryl lipid A (3 D-MPL), immunostimulatory oligonucleotides, toll-like receptor (TLR) ligands, mannan-binding lectin (MBL) ligands, STING agonists, immuno-stimulating complexes such as saponins, Quil A, QS-21, QS-7, ISCOMATRIX, and others. Other adjuvants include CpG oligonucleotides and double stranded RNA molecules, such as poly(A) and poly(U). Combinations of the above adjuvants may alsobe used. See, e.g., U.S. Patent Nos. 6,645,495; 7,029,678; and 7,858,589, all of which areincorporated herein by reference in their entireties. In certain embodiments, the adjuvant used herein is QS-21 STIMULON.

[0149] In certain embodiments, an anti-KLK6 antibody disclosed herein is administered toa subject in combination with an additional therapeutic agent comprising a TCR. In certain embodiments, the additional therapeutic agent is a soluble TCR. In certain embodiments, the additional therapeutic agent is a cell expressing a TCR. Therefore, in certain embodiments, the present disclosure relates to an antibody and / or pharmaceutical composition of the present disclosure in combination with an additional therapeutic agent comprising a TCR for use as a medicament and / or for use in a method for the treatment of cancer.

[0150] In certain embodiments, an anti-KLK6 antibody disclosed herein is administered toa subject in combination with a cell expressing a chimeric antigen receptor (CAR). In certain embodiments, the cell is a T cell.

[0151] In certain embodiments, an anti-KLK6 antibody disclosed herein is administered toa subject in combination with a TCR mimic antibody. In certain embodiments, the TCR mimic antibody is an antibody that specifically binds to a peptide-MHC complex. For non-limitingexamples of TCR mimic antibodies, see, e.g., U.S. Patent No. 9,074,000 and U.S. PublicationNos. US 2009 / 0304679 A1 and US 2014 / 0134191 A1, all of which are incorporated herein by reference in their entireties.

[0152] In certain embodiments, an anti-KLK6 antibody disclosed herein is administered toa subject in combination with a bispecific T-cell engager (BiTE) (e.g., as described in WO2005061547A2, which is incorporated by reference herein in its entirety) and / or a dual- affinity re-targeting antibody (DART) (e.g., as described in WO2012162067A2, which is incorporated by reference herein in its entirety). In certain embodiments, the BiTE and / or DART specifically binds to a tumor-associated antigen (e.g., a polypeptide overexpressed in a tumor, a polypeptide derived from an oncovirus, a polypeptide comprising a post-translational modification specific to a tumor, a polypeptide specifically mutated in a tumor) and a molecule on an effector cell (e.g., CD3 or CD16). In certain embodiments, the tumor-associated antigen 49 BUSINESS.33373149.1is EGFR (e.g., human EGFR), optionally wherein the BiTE and / or DART comprises the VH and VL sequences of cetuximab. In certain embodiments, the tumor-associated antigen is Her2 (e.g., human Her2), optionally wherein the BiTE and / or DART comprises the VH and VL sequences of trastuzumab. In certain embodiments, the tumor-associated antigen is CD20 (e.g., human CD20).

[0153] The anti-KLK6 antibody and the additional therapeutic agent (e.g.,chemotherapeutic, radiotherapeutic, checkpoint targeting agent, IDO inhibitor, vaccine, adjuvant, a soluble TCR, a cell expressing a TCR, a cell expressing a chimeric antigen receptor, and / or a TCR mimic antibody) can be administered separately, sequentially, or concurrently as separate dosage forms. In certain embodiments, an anti-KLK6 antibody is administered parenterally, and an IDO inhibitor is administered orally.

[0154] An antibody or pharmaceutical composition described herein may be delivered to asubject by a variety of routes. These include, but are not limited to, parenteral, intranasal, intratracheal, oral, intradermal, topical, intramuscular, intraperitoneal, transdermal, intravenous, intratumoral, conjunctival, intra-arterial, and subcutaneous routes. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent for use as a spray. In certain embodiments, the antibody or pharmaceutical composition described herein is delivered subcutaneously or intravenously. In certain embodiments, the antibody or pharmaceutical composition described herein is delivered intra-arterially. In certain embodiments, the antibody or pharmaceutical composition described herein is delivered intratumorally. In certain embodiments, the antibody or pharmaceutical composition described herein is delivered into a tumor draining lymph node.

[0155] The amount of an antibody or composition which will be effective in the treatmentand / or prevention of a condition will depend on the nature of the disease and can be determined by standard clinical techniques.

[0156] The precise dose to be employed in a composition will also depend on the route ofadministration, and the seriousness of the infection or disease caused by it and should be decided according to the judgment of the practitioner and each subject’s circumstances. For example, effective doses may also vary depending upon means of administration, target site, physiological state of the patient (including age, body weight, and health), whether the patient is human or an animal, other medications administered, or whether treatment is prophylactic or therapeutic. Usually, the patient is a human, but non-human mammals, including transgenic mammals, can also be treated. Treatment dosages are optimally titrated to optimize safety and efficacy. 50 BUSINESS.33373149.1

[0157] An anti-KLK6 antibody described herein can also be used to assay KLK6 (e.g.,human KLK6) protein levels in a biological sample using classical immunohistological methods known to those of skill in the art, including immunoassays, such as the enzyme linked immunosorbent assay (ELISA), immunoprecipitation, or Western blotting. Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (125I,121I), carbon (14C), sulfur (35S), tritium (3H), indium (121In), and technetium (99Tc); luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin. Such labels can be used to label an antibody described herein. Alternatively, a second antibody that recognizes an anti-KLK6 antibody described herein can be labeled and used in combination with an anti-KLK6 antibody to detect KLK6 (e.g., human KLK6) protein levels. Therefore, in certain embodiments, the present disclosure relates to the use of an anti-KLK6 antibody of the present disclosure for in vitro detection of KLK6 (e.g., human KLK6) protein in a biological sample. In a further embodiment, the present disclosure relates to the use of an anti-KLK6 antibody of the disclosure, for assaying and / or detecting KLK6 (e.g., human KLK6) protein levels in a biological sample in vitro, optionally wherein the anti-KLK6 antibody is conjugated to a radionuclide or detectable label, and / or carries a label described herein, and / or wherein an immunohistological method is used.

[0158] Assaying for the expression level of KLK6 (e.g., human KLK6) protein is intendedto include qualitatively or quantitatively measuring or estimating the level of KLK6 (e.g., human KLK6) protein in a first biological sample either directly (e.g., by determining or estimating absolute protein level) or relatively (e.g., by comparing to the disease associated protein level in a second biological sample). KLK6 (e.g., human KLK6) polypeptide expression level in the first biological sample can be measured or estimated and compared to a standard KLK6 (e.g., human KLK6) protein level, the standard being taken, for example, from a second biological sample obtained from an individual not having the disorder or being determined by averaging levels from a population of individuals not having the disorder. As will be appreciated in the art, once the “standard” KLK6 (e.g., human KLK6) polypeptide level is known, it can be used repeatedly as a standard for comparison. Therefore, in a further embodiment, the present disclosure relates to an in vitro method for assaying and / or detecting KLK6 protein levels, for example human KLK6 protein levels, in a biological sample, comprising qualitatively or quantitatively measuring or estimating the level of KLK6 protein, for example of human KLK6 protein, in a biological sample, by an immunohistological method. 51 BUSINESS.33373149.1

[0159] As used herein, the term “biological sample” refers to any biological sampleobtained from a subject, cell line, tissue, or other source of cells potentially expressing KLK6 (e.g., human KLK6). Methods for obtaining tissue biopsies and body fluids from animals (e.g., humans or cynomolgus monkeys) are well known in theart. Biological samplesinclude peripheral blood mononuclear cells (PBMCs).

[0160] An anti-KLK6 antibody described herein can be used for prognostic, diagnostic,monitoring, and screening applications, including in vitro and in vivo applications well known and standard to the skilled artisan and based on the present description. Prognostic, diagnostic,monitoring, and screening assays and kits for in vitro assessment and evaluation of immunesystem status, immune response, cancer (e.g., tumorigenesis), Alzheimer’s disease, demyelinating diseases, and / or multiple sclerosis may be utilized to predict, diagnose, andmonitor to evaluate patient samples, including those known to have or suspected of having animmune system-dysfunction or a KLK6-associated disease or disorder, or with regard to an anticipated or desired immune system response, antigen response, or vaccine response. The assessment and evaluation of immune system status, immune response, and / or KLK6- associated diseases or disorders are also useful in determining the suitability of a patient for a clinical trial of a drug or for the administration of a particular chemotherapeutic agent, a radiotherapeutic agent, or an antibody, including combinations thereof, versus a different agent or antibody. This type of prognostic and diagnostic monitoring and assessment is already in practice utilizing antibodies against the HER2 protein in breast cancer (HercepTestTM, Dako) where the assay is also used to evaluate patients for antibody therapy using Herceptin®. In vivo applications include directed cell therapy and immune system modulation and radio imaging of immune responses. Therefore, in certain embodiments, the present disclosure relates to an anti-KLK6 antibody and / or pharmaceutical composition of the present disclosure for use as a diagnostic. In certain embodiments, the present disclosure relates to an anti-KLK6 antibody and / or pharmaceutical composition of the present disclosure for use in a method for the prediction, diagnosis, and / or monitoring of a subject having or suspected to have an immune system-dysfunction or KLK66-associated disease or disorder (e.g., cancer, Alzheimer’s disease, demyelinating diseases, or multiple sclerosis) and / or with regard to an anticipated or desired immune system response, antigen response, or vaccine response. In another embodiment, the present disclosure relates to the use of an anti-KLK6 antibody of the disclosure, for predicting, diagnosing, and / or monitoring of a subject having or suspected to have an immune system-dysfunction, KLK6-associated disease or disorder (e.g., cancer, Alzheimer’s disease, demyelinating diseases, or multiple sclerosis), and / or with regard to an 52 BUSINESS.33373149.1anticipated or desired immune system response, antigen response, or vaccine response by assaying and / or detecting human KLK6 protein levels in a biological sample of the subject in vitro.

[0161] In certain embodiments, an anti-KLK6 antibody can be used inimmunohistochemistry of biopsy samples. In certain embodiments, the method is an in vitro method. In another embodiment, an anti-KLK6 antibody can be used to detect levels of KLK6 (e.g., human KLK6), or levels of cells which contain KLK6 (e.g., human KLK6), the levels of which can then be linked to certain disease symptoms. Anti-KLK6 antibodies described herein may carry a detectable or functional label and / or may be conjugated to a radionuclide or detectable label. When fluorescence labels are used, currently available microscopy and fluorescence-activated cell sorter analysis (FACS) or combination of both methods procedures known in the art may be utilized to identify and to quantitate the specific binding members. Anti-KLK6 antibodies described herein may carry or may be conjugated to a fluorescence label. Exemplary fluorescence labels include, for example, reactive and conjugated probes, e.g., Aminocoumarin, Fluorescein and Texas red, Alexa Fluor dyes, Cy dyes, and DyLight dyes. An anti-KLK6 antibody may carry or may be conjugated to a radioactive label or radionuclide, such as the isotopes3H,14C,32P,35S,36Cl,51Cr,57Co,58Co,59Fe,67Cu,90Y,99Tc,111In,117Lu,121I,124I,125I,131I,198Au,211At,213Bi,225Ac, and186Re. When radioactive labels are used, currently available counting procedures known in the art may be utilized to identify and quantitate the specific binding of an anti-KLK6 antibody to KLK6 (e.g., human KLK6). In the instance where the label is an enzyme, detection may be accomplished by any of the presently utilized colorimetric, spectrophotometric, fluorospectrophotometric, amperometric, or gasometric techniques as known in the art. This can be achieved by contacting a sample or a control sample with an anti-KLK6 antibody under conditions that allow for the formation of a complex between the anti-KLK6 antibody and KLK6 (e.g., human KLK6). Any complexes formed between the anti-KLK6 antibody and KLK6 (e.g., human KLK6), are detected and compared in the sample and the control. In light of the specific binding of the anti-KLK6 antibodies described herein for KLK6 (e.g., human KLK6), the anti-KLK6 antibodies can be used to specifically detect KLK6 (e.g., human KLK6). The anti-KLK6 antibodies described herein can also be used to purify KLK6 (e.g., human KLK6) via immunoaffinity purification. Also included herein is an assay system which may be prepared in the form of a test kit, kit, or kit-of-parts for the quantitative analysis of the extent of the presence of, for instance, KLK6 (e.g., human KLK6) / KLK6 (e.g., human KLK6) ligand complexes. The system, test kit, kit, or 53 BUSINESS.33373149.1kit-of-parts may comprise a labeled component, e.g., a labeled antibody, and one or more additional immunochemical reagents. Polynucleotides, Vectors, and Methods of Producing Antibodies

[0162] In another aspect, provided herein are polynucleotides comprising a nucleotidesequence encoding an antibody, or a portion thereof, described herein or a fragment thereof (e.g., a VL and / or VH; and a light chain and / or heavy chain) that specifically binds to a KLK6 (e.g., human KLK6) antigen, and vectors, e.g., vectors comprising such polynucleotides for recombinant expression in host cells (e.g., E. coli and mammalian cells). Provided herein are polynucleotides comprising nucleotide sequences encoding a heavy and / or light chain of any of the antibodies provided herein, as well as vectors comprising such polynucleotide sequences, e.g., expression vectors for their efficient expression in host cells, e.g., mammalian cells. In certain embodiments, a nucleic acid molecule(s) encoding an antibody described herein is isolated or purified.

[0163] In particular aspects, provided herein are polynucleotides comprising nucleotidesequences encoding antibodies, which specifically bind to a KLK6 (e.g., human KLK6) polypeptide and comprise an amino acid sequence as described herein, as well as antibodies which compete with such antibodies for binding to a KLK6 (e.g., human KLK6) polypeptide (e.g., in a dose-dependent manner), or which binds to the same epitope as that of such antibodies.

[0164] In certain aspects, provided herein are polynucleotides comprising a nucleotidesequence encoding the light chain or heavy chain of an antibody described herein. The polynucleotides can comprise nucleotide sequences encoding a light chain comprising the VLFRs and CDRs of antibodies described herein (see, e.g., Tables 2 and 4) or nucleotidesequences encoding a heavy chain comprising the VH FRs and CDRs of antibodies describedherein (see, e.g., Tables 1 and 3). In certain embodiments, a polynucleotide encodes a VH, VL,heavy chain, and / or light chain of an antibody described herein. In another embodiment, a polynucleotide encodes the first VH and the first VL of an antibody described herein. In another embodiment, a polynucleotide encodes the second VH and the second VL of an antibody described herein. In another embodiment, a polynucleotide encodes the first heavy chain and the first light chain of an antibody described herein. In another embodiment, a polynucleotide encodes the second heavy chain and the second light chain of an antibody described herein. In another embodiment, a polynucleotide encodes the VH and / or the VL, or the heavy chain and / or the light chain, of an antibody described herein. 54 BUSINESS.33373149.1

[0165] Also provided herein are polynucleotides encoding an anti-KLK6 antibody that areoptimized, e.g., by codon / RNA optimization, replacement with heterologous signal sequences, and elimination of mRNA instability elements. Methods to generate optimized nucleic acids encoding an anti-KLK6 antibody or a fragment thereof (e.g., light chain, heavy chain, VH domain, or VL domain) for recombinant expression by introducing codon changes and / or eliminating inhibitory regions in the mRNA can be carried out by adapting the optimization methods described in, e.g., U.S. Patent Nos.5,965,726; 6,174,666; 6,291,664; 6,414,132; and 6,794,498, accordingly, all of which are herein incorporated by reference in their entireties. For example, potential splice sites and instability elements (e.g., A / T or A / U rich elements) within the RNA can be mutated without altering the amino acids encoded by the nucleic acid sequences to increase stability of the RNA for recombinant expression. The alterations utilize the degeneracy of the genetic code, e.g., using an alternative codon for an identical amino acid. In certain embodiments, it can be desirable to alter one or more codons to encode a conservative mutation, e.g., a similar amino acid with similar chemical structure and properties and / or function as the original amino acid. Such methods can increase expression of an anti-KLK6 antibody or fragment thereof by at least 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold or more relative to the expression of an anti-KLK6 antibody encoded by polynucleotides that have not been optimized.

[0166] In certain embodiments, an optimized polynucleotide sequence encoding an anti-KLK6 antibody described herein or a fragment thereof (e.g., VL domain and / or VH domain) can hybridize to an antisense (e.g., complementary) polynucleotide of an unoptimized polynucleotide sequence encoding an anti-KLK6 antibody described herein or a fragment thereof (e.g., VL domain and / or VH domain). In specific embodiments, an optimized nucleotide sequence encoding an anti-KLK6 antibody described herein or a fragment thereof hybridizes under high stringency conditions to antisense polynucleotide of an unoptimized polynucleotide sequence encoding an anti-KLK6 antibody described herein or a fragment thereof. In a specific embodiment, an optimized nucleotide sequence encoding an anti-KLK6 antibody described herein or a fragment thereof hybridizes under high stringency, intermediate or lower stringency hybridization conditions to an antisense polynucleotide of an unoptimized nucleotide sequence encoding an anti-KLK6 antibody described herein or a fragment thereof.Information regarding hybridization conditions has been described, see, e.g., U.S. PatentApplication Publication No. US 2005 / 0048549 (e.g., paragraphs 72-73), which is herein incorporated by reference in its entirety. 55 BUSINESS.33373149.1

[0167] The polynucleotides can be obtained, and the nucleotide sequence of thepolynucleotides determined, by any method known in the art. Nucleotide sequences encoding antibodies described herein, e.g., antibodies described in Tables 1-4, and modified versions of these antibodies can be determined using methods known in the art, i.e., nucleotide codons known to encode particular amino acids are assembled in such a way to generate a nucleic acid that encodes the antibody. Such a polynucleotide encoding the antibody can be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier G et al., (1994), BioTechniques 17: 242-6, herein incorporated by reference in its entirety), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.

[0168] Alternatively, a polynucleotide encoding an antigen-binding region of an antibodydescribed 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 comprising the sequence encoding the light chain and / or heavy chain of an antibody. Such PCR amplification methods can be used to obtain nucleic acids comprising the sequence encoding the variable light chain region and / or the variable heavy chain region of an antibody. The amplified nucleic acids can be cloned into vectors for expression in host cells and for further cloning.

[0169] If a clone containing a nucleic acid encoding a particular antigen-binding region orantibody is not available, but the sequence of the antigen-binding region or antibody molecule is known, a nucleic acid 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, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody described herein) by PCR amplification using synthetic primers hybridizable to the 3’ and 5’ ends of the sequence, or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., 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. 56 BUSINESS.33373149.1

[0170] DNA encoding anti-KLK6 (e.g., human KLK6) antibodies described herein can bereadily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the anti-KLK6 (e.g., human KLK6) antibodies). Hybridoma cells can serve as a source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells (e.g., CHO cells from the CHO GS System™ (Lonza)), or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of anti-KLK6 antibodies in the recombinant host cells.

[0171] To generate whole antibodies or antigen-binding regions, PCR primers includingVH or VL nucleotide sequences, a restriction site, and a flanking sequence to protect the restriction site can be used to amplify the VH or VL sequences in scFv clones. Utilizing cloning techniques known to those of skill in the art, the PCR amplified VH domains can be cloned into vectors expressing a heavy chain constant region, e.g., the human gamma 1 or human gamma 4 constant region, and the PCR amplified VL domains can be cloned into vectors expressing a light chain constant region, e.g., human kappa or lambda constant regions. In certain embodiments, the vectors for expressing the VH or VL domains comprise an EF-1α promoter, a secretion signal, a cloning site for the variable region, constant regions, and a selection marker such as neomycin. The VH and VL domains can also be cloned into one vector expressing the necessary constant regions. The heavy chain conversion vectors and light chain conversion vectors are then co-transfected into cell lines to generate stable or transient cell lines that express full-length antibodies, e.g., IgG, using techniques known to those of skill in the art.

[0172] The DNA also can be modified, for example, by substituting the coding sequencefor human heavy and light chain constant regions in place of the murine sequences, or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide.

[0173] Also provided are polynucleotides that hybridize under high stringency,intermediate or lower stringency hybridization conditions to polynucleotides that encode an antibody described herein. In specific embodiments, polynucleotides described herein hybridize under high stringency, intermediate or lower stringency hybridization conditions to polynucleotides encoding a VH domain and / or VL domain provided herein.

[0174] Hybridization conditions have been described in the art and are known to one ofskill in the art. For example, hybridization under stringent conditions can involve hybridization 57 BUSINESS.33373149.1to filter-bound DNA in 6x sodium chloride / sodium citrate (SSC) at about 45°C followed by one or more washes in 0.2xSSC / 0.1% SDS at about 50-65°C; hybridization under highly stringent conditions can involve hybridization to filter-bound nucleic acid in 6xSSC at about 45°C followed by one or more washes in 0.1xSSC / 0.2% SDS at about 68°C. Hybridization under other stringent hybridization conditions are known to those of skill in the art and havebeen described, see, e.g., Ausubel FM et al., eds., (1989) Current Protocols in MolecularBiology, 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, which is herein incorporated by reference in its entirety.

[0175] In certain aspects, provided herein are cells (e.g., host cells) expressing (e.g.,recombinantly) antibodies described herein which specifically bind to KLK6 (e.g., human KLK6), and related polynucleotides and expression vectors. Provided herein are vectors (e.g., expression vectors) comprising polynucleotides comprising nucleotide sequences encoding anti-KLK6 antibodies or a fragment for recombinant expression in host cells, preferably in mammalian cells (e.g., CHO cells). Also provided herein are host cells comprising such vectors for recombinantly expressing anti-KLK6 antibodies described herein (e.g., human or humanized antibody). In a particular aspect, provided herein are methods for producing an antibody described herein, comprising expressing the antibody from a host cell.

[0176] Recombinant expression of an antibody described herein (e.g., a full-length antigen-binding region or antibody or heavy and / or light chain of an antibody described herein) that specifically binds to KLK6 (e.g., human KLK6) generally involves construction of an expression vector containing a polynucleotide that encodes the antibody. Once a polynucleotide encoding an antibody molecule, heavy and / or light chain of an antibody, or a fragment thereof (e.g., heavy and / or light chain variable regions) described herein has been obtained, the vector 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 a protein by expressing a polynucleotide containing an antibody or antibody fragment (e.g., light chain or heavy chain) encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing an antibody or antibody fragment (e.g., light chain or heavy chain) coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Also provided are replicable vectors comprising a nucleotide sequence encoding containing an antibody molecule described herein, a heavy or light chain of an antibody, a heavy or light chain variable region of an antibody or a fragment thereof, or a heavy 58 BUSINESS.33373149.1or light chain CDR, operably linked to a promoter. Such vectors can, for example, include thenucleotide sequence encoding the constant region of the antibody molecule (see, e.g.,International Publication Nos. WO 86 / 05807 and WO 89 / 01036; and U.S. Patent No. 5,122,464, which are herein incorporated by reference in their entireties) and variable regions of the antibody can be cloned into such a vector for expression of the entire heavy, the entire light chain, or both the entire heavy and light chains.

[0177] In certain embodiments, a vector comprises a polynucleotide encoding a VH, VL,heavy chain, and / or light chain of an antibody described herein. In another embodiment, a vector comprises a polynucleotide encoding the VH and the VL of an antibody described herein. In another embodiment, a vector comprises a polynucleotide encoding the heavy chain and the light chain of an antibody described herein.

[0178] An expression vector can be transferred to a cell (e.g., host cell) by conventionaltechniques and the resulting cells can then be cultured by conventional techniques to produce cells containing an antibody described herein or a fragment thereof. Thus, provided herein are host cells containing a polynucleotide encoding containing an antibody described herein or fragments thereof, or a heavy or light chain thereof, or fragment thereof, or a single-chain antibody described herein, operably linked to a promoter for expression of such sequences in the host cell.

[0179] In certain embodiments, a host cell comprises a polynucleotide encoding the VHand VL of an antibody described herein. In another embodiment, a host cell comprises a vector comprising a polynucleotide encoding the VH and VL of an antibody described herein. In another embodiment, a host cell comprises a first polynucleotide encoding the VH of an antibody described herein, and a second polynucleotide encoding the VL of an antibody described herein. In another embodiment, a host cell comprises a first vector comprising a first polynucleotide encoding the VH of an antibody described herein, and a second vector comprising a second polynucleotide encoding the VL of an antibody described herein.

[0180] In specific embodiments, a heavy chain / heavy chain variable region expressed by afirst cell is associated with a light chain / light chain variable region of a second cell to form an anti-KLK6 (e.g., human KLK6) antibody described herein. In certain embodiments, provided herein is a population of host cells comprising such first host cell and such second host cell.

[0181] In certain embodiments, provided herein is a population of vectors comprising afirst vector comprising a polynucleotide encoding a light chain / light chain variable region of an anti-KLK6 (e.g., human KLK6) antibody described herein, and a second vector comprising 59 BUSINESS.33373149.1a polynucleotide encoding a heavy chain / heavy chain variable region of an anti-KLK6 (e.g., human KLK6) antibody described herein.

[0182] A variety of host-expression vector systems can be utilized to express antibodymolecules described herein (see, e.g., U.S. Patent No. 5,807,715, which is herein incorporatedby reference in its entirety). Such host-expression systems represent vehicles by which the coding sequences of interest can be produced and subsequently purified, but also represent cells which can, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule described herein in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli and B. subtilis) transformed with, e.g., recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containingantibody coding sequences; yeast (e.g., Saccharomyces and Pichia) transformed with, e.g.,recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with, e.g., recombinant virus expression vectors (e.g., baculovirus) containingantibody coding sequences; plant cell systems (e.g., green algae such as Chlamydomonasreinhardtii) infected with, e.g., recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with, e.g., recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS (e.g., COS1 or COS), CHO, BHK, MDCK, HEK 293, NS0, PER.C6, VERO, CRL7O3O, HsS78Bst, HeLa, and NIH 3T3, HEK-293T, HepG2, SP210, R1.1, B-W, L-M, BSC1, BSC40, YB / 20 and BMT10 cells) harboring, e.g., recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). In a specific embodiment, cells for expressing antibodies described herein are Chinese hamster ovary (CHO) cells, for example CHO cells from the CHO GS System™ (Lonza). In certain embodiments, the heavy chain and / or light chain of an antibody produced by a CHO cell may have an N-terminal glutamine or glutamate residue replaced by pyroglutamate. In certain embodiments, cells for expressing antibodies described herein are human cells, e.g., human cell lines. In a specific embodiment, a mammalian expression vector is pOptiVEC™ or pcDNA3.3. In certain embodiments, bacterial cells such as Escherichia coli, or eukaryotic cells (e.g., mammalian cells), especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule. For example, mammalian cells such as CHO cells, in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus, are an effective expression system for antibodies (Foecking MK & Hofstetter 60 BUSINESS.33373149.1H (1986) Gene 45: 101-5; and Cockett MI et al., (1990) Biotechnology 8(7): 662-7, each of which is herein incorporated by reference in its entirety). In certain embodiments, antibodies described herein are produced by CHO cells or NS0 cells. In a specific embodiment, the expression of nucleotide sequences encoding antibodies described herein which specifically bind to KLK6 (e.g., human KLK6) is regulated by a constitutive promoter, inducible promoter, or tissue specific promoter.

[0183] In bacterial systems, a number of expression vectors can be advantageously selecteddepending upon the use intended for the antibody molecule being expressed. For example, when a large quantity of such an antibody is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified can 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 coding sequence can be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye S & Inouye M (1985) Nuc Acids Res 13: 3101-3109; Van Heeke G & Schuster SM (1989) J Biol Chem 24: 5503-5509); and the like, all of which are herein incorporated by reference in their entireties. For example, pGEX vectors can also be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

[0184] In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV),for example, can be used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The coding sequence can be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).

[0185] In mammalian host cells, a number of viral-based expression systems can beutilized. In cases where an adenovirus is used as an expression vector, the coding sequence of interest can be ligated to an adenovirus transcription / translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene can then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region El or E3) will result in a recombinant virus that is viable andcapable of expressing the molecule in infected hosts (see, e.g., Logan J & Shenk T (1984)61 BUSINESS.33373149.1PNAS 81(12): 3655-9, which is herein incorporated by reference in its entirety). Specific initiation signals can also be required for efficient translation of inserted coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase 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 can be enhanced by the inclusion of appropriate transcription enhancer elements,transcription terminators, etc. (see, e.g., Bitter G et al., (1987) Methods Enzymol. 153: 516-544, which is herein incorporated by reference in its entirety).

[0186] In addition, a host cell strain can be chosen which modulates the expression of theinserted sequences or modifies and processes the gene product in the specific fashion 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. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which 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, HEK 293, NIH 3T3, W138, 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, HepG2, SP210, R1.1, B-W, L-M, BSC1, BSC40, YB / 20, BMT10, and HsS78Bst cells. In certain embodiments, anti-KLK6 (e.g., human KLK6) antibodies described herein are produced in mammalian cells, such as CHO cells.

[0187] In a specific embodiment, the antibodies described herein have reduced fucosecontent or no fucose content. Such antibodies can be produced using techniques known one skilled in the art. For example, the antibodies can be expressed in cells deficient or lacking the ability to fucosylate. In a specific example, cell lines with a knockout of both alleles of α1,6- fucosyltransferase can be used to produce antibodies with reduced fucose content. The Potelligent®system (Lonza) is an example of such a system that can be used to produce antibodies with reduced fucose content.

[0188] For long-term, high-yield production of recombinant proteins, stable expressioncells can be generated. For example, cell lines which stably express an anti-KLK6 (e.g., human KLK6) antibody described herein can be engineered. In specific embodiments, a cell provided 62 BUSINESS.33373149.1herein stably expresses a light chain / light chain variable region and a heavy chain / heavy chain variable region which associate to form an antigen-binding region or an antibody described herein.

[0189] In certain aspects, rather than using expression vectors which contain viral originsof replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA / polynucleotide, engineered cells can be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method can advantageously be used to engineer cell lines which express an anti- KLK6 (e.g., human KLK6) described herein or a fragment thereof. Such engineered cell lines can be particularly useful in screening and evaluation of compositions that interact directly or indirectly with the antibody molecule.

[0190] A number of selection systems can be used, including but not limited to the herpessimplex virus thymidine kinase (Wigler M et al., (1977) Cell 11(1): 223-32), hypoxanthineguanine phosphoribosyltransferase (Szybalska EH & Szybalski W (1962) PNAS 48(12): 2026-2034), and adenine phosphoribosyltransferase (Lowy I et al., (1980) Cell 22(3): 817-23) genes in tk-, hgprt- or aprt-cells, respectively, all of which are herein incorporated by reference in their entireties. Also, antimetabolite resistance can be used as the basis of 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); gpt, which confers resistance to mycophenolic acid (Mulligan RC & Berg P (1981) PNAS 78(4): 2072-6); neo, which confers resistance to the aminoglycoside G-418 (Wu GY & 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 hygro, which confers resistance to hygromycin (Santerre RF et al., (1984) Gene 30(1-3): 147-56), all of which are herein incorporated by reference in their entireties. Methods commonly known in the art of recombinant DNA technology can be routinely applied to select the desired recombinant clone 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 in Chapters 12 and 13, 63 BUSINESS.33373149.1Dracopoli NC et al., (eds.), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colbère-Garapin F et al., (1981) J Mol Biol 150: 1-14, all of which are herein incorporated by reference in their entireties.

[0191] The expression levels of an antibody molecule can be increased by vectoramplification (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), which is herein incorporated by reference in its entirety). When a marker in the vector system is amplifiable, an increase in the level of inhibitor present in culture of the host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the gene of interest, production of the protein will also increase (Crouse GF et al., (1983) Mol Cell Biol 3: 257-66, which is herein incorporated by reference in its entirety).

[0192] The host cell can be co-transfected with two or more expression vectors describedherein, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors can contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. The host cells can be co-transfected with different amounts of the two or more expression vectors. For example, host cells can be transfected with any one of the following ratios of a first expression vector and a second expression vector: about 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.

[0193] Alternatively, a single vector can be used which encodes, and is capable ofexpressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot NJ (1986) Nature 322: 562-565; and Köhler G (1980) PNAS 77: 2197-2199, each of which is herein incorporated by reference in its entirety). The coding sequences for the heavy and light chains can comprise cDNA or genomic DNA. The expression vector can be monocistronic or multicistronic. A multicistronic nucleic acid construct can encode 2, 3, 4, 5, 6, 7, 8, 9, 10, or more genes / nucleotide sequences, or in the range of 2-5, 5-10, or 10-20 genes / nucleotide sequences. For example, a bicistronic nucleic acid construct can comprise, in the following order, a promoter, a first gene (e.g., heavy chain of an antibody described herein), and a second gene and (e.g., light chain of an antibody described herein). In such an expression vector, the transcription of both genes can be driven by the promoter, whereas the translation of the mRNA from the first gene can be by a cap-dependent scanning mechanism and the translation of the mRNA from the second gene can be by a cap-independent mechanism, e.g., by an IRES. 64 BUSINESS.33373149.1

[0194] Once an antibody molecule described herein has been produced by recombinantexpression, it can be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Further, the antibodies described herein can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.

[0195] In specific embodiments, an antibody described herein is isolated or purified. Incertain embodiments, an isolated antibody is one that is substantially free of other antibodies with different antigenic specificities than the isolated antibody. For example, in certain embodiments, a preparation of an antibody described herein is substantially free of cellular material and / or chemical precursors. The language “substantially free of cellular material” includes preparations of an antibody in which the antibody is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, an antibody that is substantially free of cellular material includes preparations of antibody having less than about 30%, 20%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (by dry weight) of heterologous protein (also referred to herein as a “contaminating protein”) and / or variants of an antibody, for example, different post-translational modified forms of an antibody or other different versions of an antibody (e.g., antibody fragments). When the 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 the 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 which are involved in the synthesis of the protein. Accordingly, such preparations of the antibody have less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. In a specific embodiment, antibodies described herein are isolated or purified.

[0196] Anti-KLK6 (e.g., human KLK6) antibodies or fragments thereof can be producedby any method known in the art for the synthesis of proteins or antibodies, for example, by chemical synthesis or by recombinant expression techniques. The methods described herein employ, unless otherwise indicated, conventional techniques in molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields 65 BUSINESS.33373149.1within the skill of the art. These techniques are described, for example, in the references citedherein and are fully explained in the literature. See, e.g., Maniatis T et al., (1982) MolecularCloning: 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, all of which are herein incorporated by reference in their entireties.

[0197] In a specific embodiment, an antibody described herein is prepared, expressed,created, or isolated by any means that involves creation, e.g., via synthesis, genetic engineering of DNA sequences. In certain embodiments, such an antibody comprises sequences (e.g., DNA sequences or amino acid sequences) that do not naturally exist within the antibody germline repertoire of an animal or mammal (e.g., human) in vivo.

[0198] In one aspect, provided herein is a method of making an anti-KLK6 (e.g., humanKLK6) antibody comprising culturing a cell or host cell described herein. In certain embodiments, the method is performed in vitro. In a certain aspect, provided herein is a method of making an anti-KLK6 (e.g., human KLK6) antibody comprising expressing (e.g., recombinantly expressing) the antibody using a cell or host cell described herein (e.g., a cell or a host cell comprising polynucleotides encoding an antibody described herein). In certain embodiments, the cell is an isolated cell. In certain embodiments, the exogenous polynucleotides have been introduced into the cell. In certain embodiments, the method further comprises the step of purifying the antibody obtained from the cell or host cell.

[0199] In certain embodiments, an antibody is produced by expressing in a cell apolynucleotide encoding the VH and VL of an antibody described herein under suitable conditions so that the polynucleotides are expressed and the antibody is produced. In another embodiment, an antibody is produced by expressing in a cell a polynucleotide encoding the heavy chain and light chain of an antibody described herein under suitable conditions so that the polynucleotides are expressed and the antibody is produced. In certain embodiments, an antibody is produced by expressing in a cell a first polynucleotide encoding the VH of an antibody described herein, and a second polynucleotide encoding the VL of an antibody 66 BUSINESS.33373149.1described herein, under suitable conditions so that the polynucleotides are expressed and the antibody is produced. In certain embodiments, an antibody is produced by expressing in a cell a first polynucleotide encoding the heavy chain of an antibody described herein, and a second polynucleotide encoding the light chain of an antibody described herein, under suitable conditions so that the polynucleotides are expressed and the antibody is produced.

[0200] Methods for producing polyclonal antibodies are known in the art (see, e.g., Chapter11 in: Short Protocols in Molecular Biology, (2002) 5th Ed., Ausubel FM et al., eds., John Wiley and Sons, New York, which is herein incorporated by reference in its entirety).

[0201] Monoclonal antibodies can be prepared using a wide variety of techniques knownin the art, including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques, including those known in the art and taught, 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 563681 (Elsevier, N.Y., 1981), each of which is herein incorporated by reference in its entirety. The term “monoclonal antibody” as used herein is not limited to antibodies produced through hybridoma technology. For example, monoclonal antibodies can be produced recombinantly from host cells exogenously expressing an antibody described herein or a fragment thereof, for example, light chain and / or heavy chain of such antibody.

[0202] In specific embodiments, a “monoclonal antibody,” as used herein, is an antibodyproduced by a single cell (e.g., hybridoma or host cell producing a recombinant antibody), wherein the antibody specifically binds to KLK6 (e.g., human KLK6) as determined, e.g., by ELISA or other antigen-binding or competitive binding assay known in the art or in the examples provided herein. In certain embodiments, a monoclonal antibody can be a chimeric antibody or a humanized antibody. In certain embodiments, a monoclonal antibody is a monovalent antibody or multivalent (e.g., bivalent) antibody. In certain embodiments, a monoclonal antibody is a monospecific or multispecific antibody (e.g., bispecific antibody). Monoclonal antibodies described herein can, for example, be made by the hybridoma method as described in Kohler G & Milstein C (1975) Nature 256: 495, which is herein incorporated by reference in its entirety, or can, e.g., be isolated from phage libraries using the techniques as described herein, for example. Other methods for the preparation of clonal cell lines and ofmonoclonal 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).67 BUSINESS.33373149.1

[0203] As used herein, an antibody binds to an antigen multivalently (e.g., bivalently) whenthe antibody comprises at least two (e.g., two or more) monovalent binding regions, each monovalent binding region capable of binding to an epitope on the antigen. Each monovalent binding region can bind to the same or different epitopes on the antigen.

[0204] Methods for producing and screening for specific antibodies using hybridomatechnology are routine and well known in the art. For example, in the hybridoma method, a mouse or other appropriate host animal, such as a sheep, goat, rabbit, rat, hamster, or macaque monkey, is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein (e.g., KLK6 (e.g., human KLK6)) used for immunization. Alternatively, lymphocytes may be immunized in vitro. Lymphocytes then are fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding JW (Ed.), Monoclonal Antibodies: Principles and Practice, pp.59-103 (Academic Press, 1986), herein incorporated by reference in its entirety). Additionally, a RIMMS (repetitive immunization multiple sites) technique can be used to immunize an animal (Kilpatrick KE et al., (1997) Hybridoma 16:381-9, herein incorporated by reference in its entirety).

[0205] In certain embodiments, mice (or other animals, such as rats, monkeys, donkeys,pigs, sheep, hamster, or dogs) can be immunized with an antigen (e.g., KLK6 (e.g., human KLK6)), and once an immune response is detected, e.g., antibodies specific for the antigen are detected in the mouse serum, the mouse spleen is harvested and splenocytes isolated. The splenocytes are then fused by well-known techniques to any suitable myeloma cells, for example, cells from cell line SP20 available from the American Type Culture Collection (ATCC®) (Manassas, VA), to form hybridomas. Hybridomas are selected and cloned by limited dilution. In certain embodiments, lymph nodes of the immunized mice are harvested and fused with NS0 myeloma cells.

[0206] The hybridoma cells thus prepared are seeded and grown in a suitable culturemedium that preferably contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells.

[0207] Specific embodiments employ myeloma cells that fuse efficiently, support stablehigh-level production of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. Among these myeloma cell lines are murine myeloma 68 BUSINESS.33373149.1lines, such as the NS0 cell line or those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, CA, USA, and SP-2 or X63-Ag8.653 cells available from the American Type Culture Collection, Rockville, MD, USA. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor D (1984) J Immunol 133: 3001- 5; Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987), each of which is herein incorporated by reference in its entirety).

[0208] Culture medium in which hybridoma cells are growing is assayed for production ofmonoclonal antibodies directed against KLK6 (e.g., human KLK6). The binding specificity of monoclonal antibodies produced by hybridoma cells is determined by methods known in the art, for example, immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).

[0209] After hybridoma cells are identified that produce antibodies of the desiredspecificity, affinity, and / or activity, the clones may be subcloned by limiting dilution procedures and grown by standard methods (Goding JW (Ed.), Monoclonal Antibodies: Principles and Practice, supra). Suitable culture media for this purpose include, for example, D-MEM or RPMI 1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal.

[0210] The monoclonal antibodies secreted by the subclones are suitably separated fromthe culture medium, ascites fluid, or serum by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0211] Antibodies described herein include, e.g., antibody fragments which recognizeKLK6 (e.g., human KLK6), and can be generated by any technique known to those of skill in the art. For example, 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’)2fragments). A Fab fragment corresponds to one of the two identical arms of an antibody molecule and contains the complete light chain paired with the VH and CH1 domains of the heavy chain. A F(ab’)2fragment contains the two antigen- binding arms of an antibody molecule linked by disulfide bonds in the hinge region.

[0212] Further, the antibodies described herein can also be generated using various phagedisplay methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding 69 BUSINESS.33373149.1them. In particular, DNA sequences encoding VH and VL domains are amplified from animal cDNA libraries (e.g., human or murine cDNA libraries of affected tissues). The DNA encoding the VH and VL domains are recombined together with an scFv linker by PCR and cloned into a phagemid vector. The vector is electroporated in E. coli, and the E. coli is infected with helper phage. Phage used in these methods are typically filamentous phage, including fd and M13, and the VH and VL domains are usually recombinantly fused to either the phage gene III or gene VIII. Phage expressing an antigen-binding region that binds to a particular antigen can be selected or identified with antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead. Examples of phage display methods that can be used to make the antibodies described herein include those disclosed 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. WO 90 / 02809, WO 91 / 10737, WO 92 / 01047, WO 92 / 18619, WO 93 / 11236, WO 95 / 15982, WO 95 / 20401, and WO 97 / 13844; and U.S. Patent 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, all of which are herein incorporated by reference in their entireties.

[0213] As described in the above references, after phage selection, the antibody codingregions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen-binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, e.g., as described below. Techniques to recombinantly produce antibody fragments such as Fab, Fab’ and F(ab’)2fragments can also be employed using methods known in the art such as those disclosed in PCT publication No. WO 92 / 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, all of which are herein incorporated by reference in their entireties.

[0214] In certain embodiments, to generate whole antibodies, PCR primers including VHor VL nucleotide sequences, a restriction site, and a flanking sequence to protect the restriction site, can be used to amplify the VH or VL sequences from a template, e.g., scFv clones. Utilizing cloning techniques known to those of skill in the art, the PCR amplified VH domains can be cloned into vectors expressing a VH constant region, and the PCR amplified VL domains can be cloned into vectors expressing a VL constant region, e.g., human kappa or lambda constant regions. The VH and VL domains can also be cloned into one vector 70 BUSINESS.33373149.1expressing the necessary constant regions. The heavy chain conversion vectors and light chain conversion vectors are then co-transfected into cell lines to generate stable or transient cell lines that express full-length antibodies, e.g., IgG, using techniques known to those of skill in the art.

[0215] A chimeric antibody is a molecule in which different portions of the antibody arederived from different immunoglobulin molecules. For example, a chimeric antibody can contain a variable region of a mouse or rat monoclonal antibody fused to a constant region ofa human antibody. Methods for producing chimeric antibodies are known in the art. See, e.g.,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 Nos. 5,807,715, 4,816,567, 4,816,397, and 6,331,415, all of which are herein incorporated by reference in their entireties.

[0216] A humanized antibody is capable of binding to a predetermined antigen and whichcomprises a framework region having substantially the amino acid sequence of a human immunoglobulin and CDRs 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 also can include the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. A 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 produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (European Patent No. EP 239400; International Publication No. WO 91 / 09967; and U.S. Patent Nos. 5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing (European Patent Nos. EP 592106 and EP 519596; 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. Patent No. 5,565,332), and techniques disclosed in, e.g., U.S. Pat. No.6,407,213, U.S. Pat. No.5,766,886, International Publication No. WO 93 / 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): 895904; 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, all of which are herein incorporated by reference 71 BUSINESS.33373149.1in their entireties. See also, U.S. Application Publication No. US 2005 / 0042664 A1 (Feb. 24,2005), which is herein incorporated by reference in its entirety.

[0217] Methods for making multispecific antibodies (e.g., bispecific antibodies) have beendescribed, 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, all of which are herein incorporated by reference in their entireties.

[0218] Bispecific, bivalent antibodies, and methods of making them, are described, forinstance in U.S. Pat. Nos. 5,731,168; 5,807,706; 5,821,333; and U.S. Appl. Publ. Nos. 2003 / 020734 and 2002 / 0155537, each of which is herein incorporated by reference in its entirety. Bispecific tetravalent antibodies, and methods of making them are described, for instance, in Int. Appl. Publ. Nos. WO 02 / 096948 and WO 00 / 44788, the disclosures of both of which are herein incorporated by reference in its entirety. See generally, Int. Appl. Publ. Nos. WO 93 / 17715, WO 92 / 08802, WO 91 / 00360, and WO 92 / 05793; Tutt et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos.4,474,893; 4,714,681; 4,925,648; 5,573,920; and 5,601,819; and Kostelny et al., J. Immunol. 148:1547-1553 (1992); each of which is herein incorporated by reference in its entirety.

[0219] A bispecific antibody as described herein can be generated according to theDuoBody technology platform (Genmab A / S) as described, e.g., in International Publication Nos. WO 2011 / 131746, WO 2011 / 147986, WO 2008 / 119353, and WO 2013 / 060867, and in Labrijn AF et al., (2013) PNAS 110(13): 5145-5150. The DuoBody technology can be used to combine one half of a first monospecific antibody, or first antigen-binding region, containing two heavy and two light chains with one half of a second monospecific antibody, or second antigen-binding region, containing two heavy and two light chains. The resultant heterodimer contains one heavy chain and one light chain from the first antibody, or first antigen-binding region, paired with one heavy chain and one light chain from the second antibody, or second antigen-binding region. When both of the monospecific antibodies, or antigen-binding regions, recognize different epitopes on different antigens, the resultant heterodimer is a bispecific antibody.

[0220] The DuoBody technology requires that each of the monospecific antibodies, orantigen-binding regions, includes a heavy chain constant region with a single point mutation in the CH3 domain. The point mutations allow for a stronger interaction between the CH3 domains in the resultant bispecific antibody than between the CH3 domains in either of the monospecific antibodies, or antigen-binding regions. The single point mutation in each monospecific antibody, or antigen-binding region, is at residue 366, 368, 370, 399, 405, 407, 72 BUSINESS.33373149.1or 409, numbered according to the EU numbering system, in the CH3 domain of the heavy chain constant region, as described, e.g., in International Publication No. WO 2011 / 131746. Moreover, the single point mutation is located at a different residue in one monospecific antibody, or antigen-binding region, as compared to the other monospecific antibody, or antigen-binding region. For example, one monospecific antibody, or antigen-binding region, can comprise the mutation F405L (i.e., a mutation from phenylalanine to leucine at residue 405), while the other monospecific antibody, or antigen-binding region, can comprise the mutation K409R (i.e., a mutation from lysine to arginine at residue 409), numbered according to the EU numbering system. The heavy chain constant regions of the monospecific antibodies, or antigen-binding regions, can be an IgG1, IgG2, IgG3, or IgG4isotype (e.g., a human IgG1isotype), and a bispecific antibody produced by the DuoBody technology can retain Fc- mediated effector functions.

[0221] Another method for generating bispecific antibodies has been termed the “knobs-into-holes” strategy (see, e.g., Intl. Publ. WO2006 / 028936). The mispairing of Ig heavy chainsis reduced in this technology by mutating selected amino acids forming the interface of the CH3 domains in IgG. At positions within the CH3 domain at which the two heavy chains interact directly, an amino acid with a small side chain (hole) is introduced into the sequence of one heavy chain and an amino acid with a large side chain (knob) into the counterpart interacting residue location on the other heavy chain. In certain embodiments, compositions of the disclosure have immunoglobulin chains in which the CH3 domains have been modified by mutating selected amino acids that interact at the interface between two polypeptides so as to preferentially form a bispecific antibody. The bispecific antibodies can be composed of immunoglobulin chains of the same subclass (e.g., IgG1or IgG3) or different subclasses (e.g., IgG1 and IgG3, or IgG3 and IgG4).

[0222] Bispecific antibodies can, in certain instances contain, IgG4 and IgG1, IgG4 andIgG2, IgG4 and IgG3, or IgG1 and IgG3 chain heterodimers. Such heterodimeric heavy chain antibodies can routinely be engineered by, for example, modifying selected amino acids forming the interface of the CH3 domains in human IgG4and the IgG1or IgG3, so as to favor heterodimeric heavy chain formation.

[0223] In certain embodiments, an antibody described herein, which binds to the sameepitope of KLK6 (e.g., human KLK6) as an anti-KLK6 (e.g., human KLK6) antibody described herein, is a human antibody. In certain embodiments, an antibody described herein, which competitively blocks (e.g., in a dose-dependent manner) any one of the antibodies described herein, from binding to KLK6 (e.g., human KLK6), is a human antibody. Human antibodies 73 BUSINESS.33373149.1can be produced using any method known in the art. For example, transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes, can be used. In particular, the human heavy and light chain immunoglobulin gene complexes can be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region can be introduced into mouse embryonic stem cells in addition to the 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. In particular, homozygous deletion of the JHregion 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 which express human antibodies. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of an antigen (e.g., KLK6 (e.g., human KLK6)). Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM, and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg N & Huszar D (1995) Int Rev Immunol 13: 65- 93, herein incorporated by reference in its entirety. For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producingsuch antibodies, see, e.g., International Publication Nos. WO 98 / 24893, WO 96 / 34096, andWO 96 / 33735; and U.S. Patent 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, all of which are herein incorporated by reference in their entireties. Examples of mice capable of producing human antibodies include the XenoMouseTM(Abgenix, Inc.; U.S. Patent Nos. 6,075,181 and 6,150,184), the HuAb-MouseTM(Medarex, Inc. / Gen Pharm; U.S. Patent Nos. 5,545,806 and 5,569, 825), the TransChromo MouseTM(Kirin) and the KM MouseTM(Medarex / Kirin), all of which are herein incorporated by reference in their entireties.

[0224] Human antibodies that specifically bind to KLK6 (e.g., human KLK6) can be madeby a variety of methods known in the art, including the phage display methods described aboveusing antibody libraries derived from human immunoglobulin sequences. See also, U.S. PatentNos. 4,444,887, 4,716,111, and 5,885,793; and International Publication Nos. WO 98 / 46645, 74 BUSINESS.33373149.1WO 98 / 50433, WO 98 / 24893, WO 98 / 16654, WO 96 / 34096, WO 96 / 33735, and WO 91 / 10741, all of which are herein incorporated by reference in their entireties.

[0225] In certain embodiments, human antibodies can be produced using mouse–humanhybridomas. For example, human peripheral blood lymphocytes transformed with Epstein-Barr virus (EBV) can be fused with mouse myeloma cells to produce mouse–human hybridomas secreting human monoclonal antibodies, and these mouse–human hybridomas can be screened to determine ones which secrete human monoclonal antibodies that specifically bind to a target antigen (e.g., KLK6 (e.g., human KLK6)). Such methods are known and are described in theart, see, e.g., Shinmoto H et al., (2004) Cytotechnology 46: 19-23; Naganawa Y et al., (2005)Human Antibodies 14: 27-31, each of which is herein incorporated by reference in its entirety. Kits

[0226] Also provided are kits comprising one or more antibodies described herein, orpharmaceutical compositions or conjugates thereof. In a specific embodiment, provided herein is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein, such as one or more antibodies provided herein. In certain embodiments, the kits contain a pharmaceutical composition described herein and any prophylactic or therapeutic agent, such as those described herein. In certain embodiments, the kits may contain a T cell mitogen, such as, e.g., phytohaemagglutinin (PHA) and / or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0227] Also provided are kits that can be used in the above methods. In certainembodiments, a kit comprises an antibody described herein, preferably purified antibody, in one or more containers. In a specific embodiment, kits described herein contain a substantially isolated KLK6 (e.g., human KLK6) antigen as a control. In another specific embodiment, the kits described herein further comprise a control antibody which does not react with KLK6 (e.g., human KLK6) antigen. In another specific embodiment, kits described herein contain one or more elements for detecting the binding of an antibody to a KLK6 (e.g., human KLK6) antigen (e.g., the antibody can be conjugated to a detectable substrate such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second 75 BUSINESS.33373149.1antibody which recognizes the first antibody can be conjugated to a detectable substrate). In specific embodiments, a kit provided herein can include a recombinantly produced or chemically synthesized KLK6 (e.g., human KLK6) antigen. The KLK6 (e.g., human KLK6) antigen provided in the kit can also be attached to a solid support. In a more specific embodiment, the detecting means of the above-described kit includes a solid support to which a KLK6 (e.g., human KLK6) antigen is attached. Such a kit can also include a non-attached reporter-labeled anti-human antibody or anti-mouse / rat antibody. In this embodiment, binding of the antibody to the KLK6 (e.g., human KLK6) antigen can be detected by binding of the said reporter-labeled antibody. In certain embodiments, the present disclosure relates to the use of a kit of the present disclosure for in vitro assaying and / or detecting KLK6 (e.g., human KLK6) antigen in a biological sample. EXAMPLES

[0228] The following examples are offered by way of illustration and not by way oflimitation. Example 1: Generation of anti-KLK6 antibodies

[0229] Anti-KLK6 antibodies were generated via immunization of mice in a standardRIMMS protocol using human KLK6 as the immunogen at 10 ug / site. When test bleed titers of greater than 5000 by ELISA on KLK6 were achieved, bone marrow and spleen were harvested. Both plasma B cells and antigen reactive B cells were sorted into single wells by FACS staining with dye labeled KLK6 and standard B cell and plasma B markers and VH and VL sequences were amplified by PCR. Transient transfection of CHOs with unique VH and VL sequences was then used to select mAbs that were reactive with KLK6 by Carterra but not an irrelevant Her2-His labeled protein. Expression of the selected antibodies was quantified using the Carterra LSA system. The Carterra chip coated with an anti-human-Fc-lawn was used to capture antibodies directly from CHO supernatants. As shown in Table 7, the response from each of the captured antibodies demonstrates a suitable level of expression. Table 7. Expression of selected anti-KLK6 antibodies. Ab CHO LSA76 BUSINESS.33373149.17680 829.17684 1130.6plary anti-KLK6 antibodies for human KLK6

[0230] The affinity of the anti-KLK6 antibodies for an immature preprotein form of humanKLK6 (“Pro-huKLK6”) and a purified, activated mature form of human KLK6 (“huKLK6”) was measured using surface plasmon resonance. To measure binding kinetics of human KLK6 antibodies, a capture and binding assay was performed on the Carterra LSA system. Briefly, an amine-coupled anti-human IgG lawn was generated using an HC30M chip with anti-human IgG-Fc specific antibody (Jackson Immuno-Research). All test antibodies were expressed at 1mL scale in CHO cells for 6 days, and supernatant was cleared of cells by centrifugation. 77 BUSINESS.33373149.1CHO supernatants were diluted to approximately 1ug / mL antibody and injected over the capture chip, resulting in a captured antibody array. Non-regenerative kinetics were measured by injection of Pro-huKLK6-his or huKLK6-his starting at a concentration of 2.06E-09 M, with 3-fold increase in concentration up to 1.50E-06 M. Each analyte injection was flowed over the array for a 5-minute association phase, followed by a 10-minute buffer dissociation phase. Binding was detected and relative response units (RU) were collected for each antibody on the surface. Kinetic values were determined using the Carterra Kinetics Data Analysis software. The results are shown in Table 8 and Table 9 (“ka”: K association; “kd”: K dissociation). With the exception of antibodies 9902, 9924, and 9999, each of the anti-KLK6 antibodies tested showed a high level of binding to both pro-huKLK6 and huKLK6. Table 8. Affinity of exemplary anti-KLK6 antibodies for Pro-huKLK6. Pro-huKLK6- Ab his RU @ 1.5 ka (1 / Ms) kd (1 / s) Pro-huKLK6- his KD8 BUSINESS.33373149.18671 383.2 5.72E+05 1.65E-03 2.88E-098677 457.6 5.82E+05 8.72E-05 1.50E-10Table 9. Affinity of exemplary anti-KLK6 antibodies for huKLK6. Ab huKLK6-his huKLK6-his RU @ 1.5 uM ka (M-1 s-1) kd (s-1) KD79 BUSINESS.33373149.18679 495.4 2.98E+05 6.79E-04 2.27E-099902 107.0 7.96E+03 3.75E-04 4.71E-08anti-KLK6antibodies

[0231] The species-cross-reactivity of the anti-KLK6 antibodies was tested by measuringaffinity of the antibodies for immature preprotein forms of KLK6 from cynomolgus monkey (“cyno-KLK6”) and from mouse (“mouse-KLK6”) using surface plasmon resonance. To measure binding kinetics, a capture and binding assay was performed on the Carterra LSA system. The assay was performed similarly to the assay described in Example 2, using his- tagged forms of cyno-KLK6 and mouse-KLK6 over the same titrations described for human KLK6. Binding was detected and relative response units (RU) were collected for each antibody on the surface. The results are shown in Table 10. With the exception of antibodies 9902, 9924, and 9999, each of the anti-KLK6 antibodies tested showed a high level of cross-reactivity for cyno-KLK6, and many showed strong binding to mouse-KLK6 as well. Table 10. Affinity of exemplary anti-KLK6 antibodies for cyno-KLK6 and mouse-KLK6. Ab Pro-huKLK6-his cyno-KLK6-his Mouse-KLK6-his RU @ 1.5 uM* RU @ 0.5 uM RU @ 0.5 uM80 BUSINESS.33373149.18561 126.0 101.5 38.08563 179.7 185.1 36.9parison

[0232] The selectivity of the anti-KLK6 antibodies for human KLK6 was also tested bymeasuring the affinity of the antibodies for human KLK family proteins KLK2, KLK4, and KLK13. Binding of the antibodies to HER3 was also tested as a negative control. To measure binding kinetics, a capture and binding assay was performed on the Carterra LSA system. The assay was performed similarly to the assay described in Example 2, using his-tagged forms of human KLK2, KLK4, KLK13, and HER3. Binding was detected and relative response units (RU) were collected for each antibody on the surface. The results are shown in Table 11. Table 11. Affinity of exemplary anti-KLK6 antibodies for human KLK family proteins. Ab huKLK6-his huKLK2-his huKLK4-his huKLK13-his HER3-his * M81 BUSINESS.33373149.17693 216.6 18.8 -3.5 17.4 -5.57696 314.9 154.4 -5.8 18.2 -10.6Example 4. Ability of anti-KLK6 antibodies to neutralize KLK6 enzymatic activity

[0233] An assay was developed to screen antibodies that block the enzymatic activity ofKLK6. Pro-huKLK6 was activated by enzymatic removal of the N-terminal pro-peptide. Active KLK6 was then incubated with anti-KLK6 antibodies and KLK6 enzyme activity was measured by its ability to cleave a fluorogenic peptide substrate (relative fluorescent units (RFU)). Anti-KLK6 antibodies blocking KLK6 enzymatic activity led to reduced fluorescent signal in the KLK6 enzyme assay. As shown in FIG.1, incubation of a goat anti-human KLK6 polyclonal antibody (KLK6 pAb, R&D, #AF2008) with 20 nM of activated KLK6 at a 1.25:1 82 BUSINESS.33373149.1molar ratio (anti-KLK6 antibody:active KLK6 enzyme) resulted in complete inhibition of KLK activity.

[0234] The ability of selected anti-KLK6 antibodies to neutralize KLK6 enzymatic activitywas tested using the assay described above. 20 nM of activated KLK6 was incubated with 80 nM anti-KLK6 antibody. As shown in FIG.2 and Table 12, 10 of the 37 anti-KLK6 antibodies tested (indicated with arrows in FIG. 2 and with bold type in Table 12) reduced KLK6 enzymatic activity by 75% or more. Table 12. KLK6 neutralization ability of exemplary anti-KLK6 antibodies. Ab KLK6 neutralization (% of max activity remaining) (n=2) huKLK6-his KD*83 BUSINESS.33373149.19924 11.9 41.6 9936 62.4 257.6 ontitrated with 20 nM activeKLK6 in the KLK6 enzyme assay described above to determine the EC50 for neutralization of KLK6 enzymatic activity. The enzymatic assay results at the titrated anti-KLK6 neutralizing antibody concentrations are shown in FIG. 3 and Table 13, and Table 14 shows the EC50 values for the five antibodies that completely inhibit KLK6 enzymatic activity at a 2:1 ratio (anti-KLK6 antibody:KLK6). Table 13. KLK6 neutralization ability of selected anti-KLK6 antibodies at various concentrations. KLK6 enzymatic activity (RFU) at indicated antibody concentration (nM) Ab 100 33333 11111 3704 1235 0412 0137 004684 BUSINESS.33373149.110071 405 532 1050 1410 1270 1240 1260 1380 Control Ig (M ) 1280 1410 1390 1340 1410 1220 1380 1500Table 14. EC50 values of selected anti-KLK6 neutralizing antibodies. Ab EC50 (nM)* y is 5 nM KLK6* * *

[0236] The invention is not to be limited in scope by the specific embodiments describedherein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0237] All references (e.g., publications or patents or patent applications) cited herein areincorporated herein by reference in their entireties and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0238] Other embodiments are within the following claims.85 BUSINESS.33373149.1

Claims

WHAT IS CLAIMED:

1. An antibody that specifically binds human KLK6, the antibody comprising: a VHcomprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in any one of SEQ ID NOs: 1-37; and a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74.

2. The antibody of claim 1, wherein the VH amino acid sequence and VL amino acidsequence are as set forth in: SEQ ID NOs: 1 and 38, 2 and 39, 3 and 40, 4 and 41, 5 and 42, 6 and 43, 7 and 44, 8 and 45, 9 and 46, 10 and 47, 11 and 48, 12 and 49, 13 and 50, 14 and 51, 15 and 52, 16 and 53, 17 and 54, 18 and 55, 19 and 56, 20 and 57, 21 and 58, 22 and 59, 23 and 60, 24 and 61, 25 and 62, 26 and 63, 27 and 64, 28 and 65, 29 and 66, 30 and 67, 31 and 68, 32 and 69, 33 and 70, 34 and 71, 35 and 72, 36 and 73, or 37 and 74, respectively.

3. The antibody of any one of the preceding claims, wherein the antibody comprises theCDRH1, CDRH2, and CDRH3 amino acid sequences set forth in: SEQ ID NOs: 75, 99, and 132; 75, 100, and 133; 76, 101, and 134; 77, 102, and 135; 78, 103, and 136; 79, 104, and 137; 80, 105, and 138; 81, 106, and 139; 82, 107, and 140; 77, 108, and 141; 83, 109, and 142; 84, 110, and 143; 75, 111, and 144; 85, 112, and 145; 77, 113, and 146; 86, 114, and 147; 87, 115, and 148; 88, 116, and 149; 89, 104, and 150; 90, 117, and 151; 80, 105, and 152; 80, 118, and 153; 89, 119, and 154; 80, 101, and 155; 91, 120, and 156; 92, 121, and 157; 93, 122, and 158; 94, 123, and 159; 76, 124, and 160; 76, 101, and 161; 95, 125, and 162; 76, 126, and 163; 96, 127, and 164; 79, 128, and 165; 97, 129, and 166; 98, 130, and 167; or 91, 131, and 168, respectively.

4. The antibody of any one of the preceding claims, wherein the antibody comprises theCDRL1, CDRL2, and CDRL3 amino acid sequences set forth in: SEQ ID NOs: 169, 194, and 215; 170, 195, and 216; 171, 196, and 217; 172, 197, and 218; 173, 198, and 219; 174, 196, and 220; 175, 199, and 221; 176, 195, and 222; 173, 195, and 223; 172, 197, and 224; 170, 195, and 225; 177, 200, and 226; 178, 195, and 227; 177, 201, and 228; 179, 202, and 229; 180, 203, and 230; 181, 196, and 231; 170, 195, and 232; 182, 204, and 233; 170, 205, and 234; 177, 206, and 221; 171, 196, and 231; 183, 196, and 220; 184, 207, and 235; 185, 208, and 236; 170, 209, and 237; 186, 206, and 238; 176, 210, and 239; 187, 196, and 231; 184, 211, and 240; 188, 212, 86 BUSINESS.33373149.1and 241; 177, 199, and 242; 189, 213, and 243; 190, 196, and 220; 191, 195, and 244; 192, 195, and 245; or 193, 214, and 246, respectively.

5. The antibody of any one of the preceding claims, wherein the antibody comprises theCDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in: SEQ ID NOs: 75, 99, 132, 169, 194, and 215; 75, 100, 133, 170, 195, and 216; 76, 101, 134, 171, 196, and 217; 77, 102, 135, 172, 197, and 218; 78, 103, 136, 173, 198, and 219; 79, 104, 137, 174, 196, and 220; 80, 105, 138, 175, 199, and 221; 81, 106, 139, 176, 195, and 222; 82, 107, 140, 173, 195, and 223; 77, 108, 141, 172, 197, and 224; 83, 109, 142, 170, 195, and 225; 84, 110, 143, 177, 200, and 226; 75, 111, 144, 178, 195, and 227; 85, 112, 145, 177, 201, and 228; 77, 113, 146, 179, 202, and 229; 86, 114, 147, 180, 203, and 230; 87, 115, 148, 181, 196, and 231; 88, 116, 149, 170, 195, and 232; 89, 104, 150, 182, 204, and 233; 90, 117, 151, 170, 205, and 234; 80, 105, 152, 177, 206, and 221; 80, 118, 153, 171, 196, and 231; 89, 119, 154, 183, 196, and 220; 80, 101, 155, 184, 207, and 235; 91, 120, 156, 185, 208, and 236; 92, 121, 157, 170, 209, and 237; 93, 122, 158, 186, 206, and 238; 94, 123, 159, 176, 210, and 239; 76, 124, 160, 187, 196, and 231; 76, 101, 161, 184, 211, and 240; 95, 125, 162, 188, 212, and 241; 76, 126, 163, 177, 199, and 242; 96, 127, 164, 189, 213, and 243; 79, 128, 165, 190, 196, and 220; 97, 129, 166, 191, 195, and 244; 98, 130, 167, 192, 195, and 245; 91, 131, 168, 193, 214, and 246, respectively.

6. The antibody of any one of the preceding claims, wherein the antibody comprises theVH amino acid sequence set forth in any one of SEQ ID NOs: 1-37.

7. The antibody of any one of the preceding claims, wherein the antibody comprises aheavy chain constant region, optionally selected from the group consisting of human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

8. The antibody of any one of the preceding claims, wherein the antibody comprises aheavy chain constant region that is a variant of a wild-type heavy chain constant region, wherein the variant heavy chain constant region binds to an FcγR with lower affinity than the wild-type heavy chain constant region binds to the FcγR.

9. The antibody of any one of the preceding claims, wherein the antibody comprises aheavy chain constant region comprising the amino acid sequence of SEQ ID NO: 247 or 248. 87 BUSINESS.33373149.

110. The antibody of any one of the preceding claims, wherein the antibody comprises theVL amino acid sequence set forth in any one of SEQ ID NOs: 38-74.

11. The antibody of any one of the preceding claims, wherein the antibody comprises alight chain constant region comprising the amino acid sequence of SEQ ID NO: 249 or 250.

12. The antibody of any one of the preceding claims, wherein the VH and VL comprise theamino acid sequences set forth in: SEQ ID NOs: 1 and 38, 2 and 39, 3 and 40, 4 and 41, 5 and 42, 6 and 43, 7 and 44, 8 and 45, 9 and 46, 10 and 47, 11 and 48, 12 and 49, 13 and 50, 14 and 51, 15 and 52, 16 and 53, 17 and 54, 18 and 55, 19 and 56, 20 and 57, 21 and 58, 22 and 59, 23 and 60, 24 and 61, 25 and 62, 26 and 63, 27 and 64, 28 and 65, 29 and 66, 30 and 67, 31 and 68, 32 and 69, 33 and 70, 34 and 71, 35 and 72, 36 and 73, or 37 and 74, respectively.

13. The antibody of any one of the preceding claims, wherein the antibody reduces orinhibits a function of KLK6.

14. A polypeptide comprising a VH comprising the CDRH1, CDRH2, and CDRH3 aminoacid sequences of the VH amino acid sequence set forth in any one of SEQ ID NOs: 1-37.

15. The polypeptide of claim 14, wherein the VH comprises the CDRH1, CDRH2, andCDRH3 amino acid sequences set forth in SEQ ID NOs: 75, 99, and 132; 75, 100, and 133; 76, 101, and 134; 77, 102, and 135; 78, 103, and 136; 79, 104, and 137; 80, 105, and 138; 81, 106, and 139; 82, 107, and 140; 77, 108, and 141; 83, 109, and 142; 84, 110, and 143; 75, 111, and 144; 85, 112, and 145; 77, 113, and 146; 86, 114, and 147; 87, 115, and 148; 88, 116, and 149; 89, 104, and 150; 90, 117, and 151; 80, 105, and 152; 80, 118, and 153; 89, 119, and 154; 80, 101, and 155; 91, 120, and 156; 92, 121, and 157; 93, 122, and 158; 94, 123, and 159; 76, 124, and 160; 76, 101, and 161; 95, 125, and 162; 76, 126, and 163; 96, 127, and 164; 79, 128, and 165; 97, 129, and 166; 98, 130, and 167; or 91, 131, and 168, respectively.

16. A polypeptide comprising a VL comprising the CDRL1, CDRL2, and CDRL3 aminoacid sequences of the VL amino acid sequence set forth in any one of SEQ ID NOs: 38-74. 88 BUSINESS.33373149.

117. The polypeptide of claim 16, wherein the VL comprises the CDRL1, CDRL2, andCDRL3 amino acid sequences set forth in SEQ ID NOs: 169, 194, and 215; 170, 195, and 216; 171, 196, and 217; 172, 197, and 218; 173, 198, and 219; 174, 196, and 220; 175, 199, and 221; 176, 195, and 222; 173, 195, and 223; 172, 197, and 224; 170, 195, and 225; 177, 200, and 226; 178, 195, and 227; 177, 201, and 228; 179, 202, and 229; 180, 203, and 230; 181, 196, and 231; 170, 195, and 232; 182, 204, and 233; 170, 205, and 234; 177, 206, and 221; 171, 196, and 231; 183, 196, and 220; 184, 207, and 235; 185, 208, and 236; 170, 209, and 237; 186, 206, and 238; 176, 210, and 239; 187, 196, and 231; 184, 211, and 240; 188, 212, and 241; 177, 199, and 242; 189, 213, and 243; 190, 196, and 220; 191, 195, and 244; 192, 195, and 245; or 193, 214, and 246, respectively.

18. A polypeptide comprising the amino acid sequence set forth in any one of SEQ ID NOs:1-74.

19. The antibody or polypeptide of any one of the preceding claims, wherein the antibodyor polypeptide is conjugated to a cytotoxic agent, cytostatic agent, toxin, radionuclide, or detectable label.

20. A polynucleotide or plurality of polynucleotides encoding: a VH, a VL, a heavy chain,and / or a light chain of an antibody of any one of claims 1-13; or a polypeptide of any one of claims 14-18.

21. A vector or plurality of vectors comprising the polynucleotide or plurality ofpolynucleotides of claim 20.

22. A recombinant host cell comprising:(a) the polynucleotide or plurality of polynucleotides of claim 20;(b) the vector or plurality of vectors of claim 21;(c) a first polynucleotide encoding a heavy chain variable region or a heavy chain ofthe antibody of any one of claims 1-13 and a second polynucleotide encoding a light chain variable region or a light chain of the antibody of any one of claims 1-13; and / or (d) a first vector comprising a first polynucleotide encoding a heavy chain variableregion or a heavy chain of the antibody of any one of claims 1-13 and a second 89 BUSINESS.33373149.1vector comprising a second polynucleotide encoding a light chain variable region or a light chain of the antibody of any one of claims 1-13.

23. A composition comprising the antibody of any one of claims 1-13 or 19, the polypeptideof any one of claims 14-19, the polynucleotide or plurality of polynucleotides of claim 20, the vector or plurality of vectors of claim 21, or the host cell of claim 22, and a pharmaceutically acceptable carrier or excipient.

24. A method of producing an antibody, the method comprising culturing the host cell ofclaim 22 under suitable conditions such that the polynucleotide is expressed, and the antibody is produced.

25. A method of treating a KLK6-associated disease or disorder in a subject, the methodcomprising administering to the subject an effective amount of: the antibody of any one of claims 1-13 or 19, the polypeptide of any one of claims 14-19, the polynucleotide or plurality of polynucleotides of claim 20, the vector or plurality of vectors of claim 21, the host cell of claim 22; or the composition of claim 23.

26. The method of claim 25, wherein administering the antibody, polypeptide,polynucleotide or plurality of polynucleotides, vector or plurality of vectors, host cell, or composition results in a reduction or inhibition of a KLK6 function in the subject.

27. The method of claim 25 or 26, wherein the KLK6-associated disease or disorder iscancer, Alzheimer’s disease, a demyelinating disease, or multiple sclerosis.

28. The method of any one of claims 25-27, further comprising administering an additionaltherapeutic agent to the subject.

29. The method of claim 28, wherein the additional therapeutic agent is a chemotherapeutic,a radiotherapeutic, or a checkpoint targeting agent.

30. The method of claim 29, wherein the checkpoint targeting agent is selected from thegroup consisting of an antagonist anti-PD-1 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, an antagonist anti-CTLA-4 antibody, an antagonist anti-TIM- 90 BUSINESS.33373149.13 antibody, an antagonist anti-LAG-3 antibody, an antagonist anti-VISTA antibody, an antagonist anti-TIGIT antibody, an antagonist anti-CD96 antibody, an antagonist anti- CEACAM1 antibody, an agonist anti-CD137 antibody, an agonist anti-GITR antibody, and an agonist anti-OX40 antibody.

31. Use of the antibody of any one of claims 1-13 or 19, the polypeptide of any one ofclaims 14-19, the polynucleotide or plurality of polynucleotides of claim 20, the vector or plurality of vectors of claim 21, the host cell of claim 22; or the composition of claim 23, for the manufacture of a medicament for treating cancer, Alzheimer’s disease, a demyelinating disease, or multiple sclerosis.

32. The antibody of any one of claims 1-13 or 19, the polypeptide of any one of claims 14-19, the polynucleotide or plurality of polynucleotides of claim 20, the vector or plurality of vectors of claim 21, the host cell of claim 22; or the composition of claim 23, for use in medicine.

33. The antibody of any one of claims 1-13 or 19, the polypeptide of any one of claims 14-19, the polynucleotide or plurality of polynucleotides of claim 20, the vector or plurality of vectors of claim 21, the host cell of claim 22; or the composition of claim 23, for use in treating cancer, Alzheimer’s disease, a demyelinating disease, or multiple sclerosis in a subject. 91 BUSINESS.33373149.1

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