Antigen binding proteins that bind tmprss4 and methods of use thereof

Abstract

Provided herein are antibodies and synthetic receptors that bind TMPRSS4, cells expressing such antibodies or receptors, and methods of use thereof. Also provided are systems comprising chimeric antigen receptors that bind TMPRSS4 and chimeric priming receptors, cells expressing such systems, and methods of use thereof.

Description

ANTIGEN BINDING PROTEINS THAT BIND TMPRSS4 AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 567,883, filed March 20, 2024, U.S. and U.S. Provisional Application No. 63 / 771,568, filed March 13, 2025, each of which are hereby incorporated in their entirety by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing XML which has been submitted electronically and is hereby incorporated by reference in its entirety. Said XML copy, created on March 19, 2025, is named ANB-500WO_SL.xml, and is 996,133 bytes in size.BACKGROUND

[0003] TMPRSS4, is a 48 kDa transmembrane glycoprotein that belongs to the serine protease family of proteins, a promoter of cancer cell invasion. The canonical isoform encodes a type II single pass transmembrane protein with a 384 amino acid extracellular C-terminal domain. An autocatalytic event has been reported to induce self-cleavage between amino acids 204 and 205, resulting in a 150 amino acid extracellular domain. Elevated expression of TMPRSS4 correlates with poor prognosis in colorectal cancer, gastric cancer, prostate cancer, non-small cell lung cancer, and other cancers. Therefore, cancer immunotherapy using T cells redirected with TMPRSS4 receptor may show antitumor functions.SUMMARY

[0004] Disclosed herein, in various embodiments, is an antibody or antigen-binding fragment thereof that binds to Transmembrane protease, serine 4 (TMPRSS4) (SEQ ID NO: 960), wherein the antibody or antigen binding fragment comprises heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2), and a heavy chain complementarity determining region 3 (HCDR3), and a light chain variable domain (VL) comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region (LCDR3), wherein theHCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are each from a clone listed in Table 4.

[0005] Also disclosed herein, in various embodiments, is an antibody or antigen-binding fragment thereof that binds to TMPRSS4, wherein the antibody or antigen binding fragment comprises a VH and a VL, wherein: (a) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8; (b) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (c) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 19, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 20, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 21, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23; (d) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31; (e) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3comprising the amino acid sequence set forth in SEQ ID NO: 39; (f) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (g) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 54; (h) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 62; (i) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; j) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 75, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76; (k) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 79, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81, andthe VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 82, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83; (1) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 86, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 87, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; (m) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98; (n) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 101, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 103, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 105, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 106; (o) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 109, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 111, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (p) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 115, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 119; (q) the VH comprises an HCDR1comprising the amino acid sequence set forth in SEQ ID NO: 122, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 123, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 124, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 125, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 127; (r) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 130, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 131, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 132, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; (s) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 136, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 137, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 138, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; (t) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 143, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 144, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 145, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146; (u) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; (v) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 155, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 156, and the VL comprises an LCDR1 comprising the amino acid sequenceset forth in SEQ ID NO: 157, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 158; (w) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 162, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 163, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 164, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165; (x) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 168, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 170; (y) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 174, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 175, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 176, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177; (z) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 181, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 183, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (aa) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 187, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 188, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 189, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 190; (bb) the VH comprises an HCDR1 comprising the amino acid sequence set forth inSEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 196, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 197, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 198; (cc) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204; (dd) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 207, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 208, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210; (ee) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 214, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 215, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 216, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 217; (ff) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 221, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 222, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 224; (gg) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, anLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232; (hh) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 235, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 236, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 237, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 238, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 239 and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 240; (ii) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 243, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 244, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245; jj) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 251, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252; (kk) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 255, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 256, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 257, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 258; (11) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 261, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 262, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265; (mm) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268, an HCDR2comprising the amino acid sequence set forth in SEQ ID NO: 269, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 271 an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 272, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 273; (nn) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 276, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 277, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280; (oo) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 283, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 277, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 284, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 239, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 285; (pp) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 288, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 289, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 290, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 291, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 293; (qq) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 296, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 297, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 298, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; (rr) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 301, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 302, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acidsequence set forth in SEQ ID NO: 303, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 304; (ss) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 307, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 308, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 309, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 310, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 311; (tt) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 314; (uu) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 317, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 318, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252; (vv) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 321, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 322, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 323, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 325, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ww) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 328, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 329, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 330, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 331; (xx) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 334,and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 335, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 336; (yy) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 338, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 339, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252; (zz) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 342, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 343, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 344, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 345, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 346; (aaa) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 349, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 350, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 351, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 352; (bbb) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 355, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280; (ccc) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 207, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 358, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3comprising the amino acid sequence set forth in SEQ ID NO: 359; (ddd) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 362, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 363, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 364, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 365; (eee) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 317, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 368, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 369; (fff) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 372, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 373, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 374, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 375; (ggg) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 378, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 379, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 380, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 175, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 381; (hhh) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 384, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 385, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 386, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 387; (iii) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 390, and an HCDR3 comprisingthe amino acid sequence set forth in SEQ ID NO: 163, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 75, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 391; (jjj) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 394, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 395, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 396, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 397; (kkk) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 400, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 401, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 402, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 403; (111) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 406, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 407, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 408; (mmm) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 411, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 412, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 413; (nnn) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 416, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 417, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 418, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 419;(ooo) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 19, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 422, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 423; (ppp) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 426, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 427, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 428, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 429; (qqq) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 432, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 433, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 434, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 238, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 435, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 436; (rrr) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 439, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 440, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 441, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 442, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 443, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 444; (sss) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 447, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 448, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 449, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 450, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 451; (ttt) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 454, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 455, and an HCDR3 comprising the amino acid sequence set forth in SEQID NO: 456, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 457, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (uuu) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 460, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 461, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 462, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 463, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 464; (vvv) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 467, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 468, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 469, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 470, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 471; (www) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 474, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 475, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 476, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 477, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 478, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 479; (xxx) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 474, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 482, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 483, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 484, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 485; (yyy) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 488, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 489, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 490, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 491; (zzz)the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 494, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 495, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 496, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 497, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 498; or (aaaa) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 501, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 502, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 503, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252.

[0006] In some embodiments, the VH comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 1, 9, 17, 24, 32, 40, 47, 55, 63, 71, 77, 84, 91, 99, 107, 113, 120, 128,134, 140, 147, 153, 159, 166, 171, 178, 185, 191, 199, 205, 211, 218, 225, 233, 241, 246, 253,259, 266, 274, 281, 286, 294, 299, 305, 312, 315, 319, 326, 332, 337, 340, 347, 353, 356, 360,366, 370, 376, 382, 388, 392, 398, 404, 409, 414, 420, 424, 430, 437, 445, 452, 458, 465, 472,480, 486, 492, and 499. In some embodiments, the VL comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 2, 10, 18, 25, 33, 41, 48, 56, 64, 72, 78, 85, 92, 100, 108, 114, 121, 129, 135, 141, 148, 154, 160, 167, 172, 179, 186, 192, 200, 206, 212, 219, 226, 234,242, 247, 254, 260, 267, 275, 282, 287, 295, 300, 306, 313, 316, 320, 327, 333, 341, 348, 354,357, 361, 367, 371, 377, 383, 389, 393, 399, 405, 410, 415, 421, 425, 431, 438, 446, 453, 459,466, 473, 481, 487, 493, and 500. In some embodiments, the VH comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 1, 9, 17, 24, 32, 40, 47, 55, 63, 71, 77, 84, 91, 99, 107, 113, 120, 128, 134, 140, 147, 153, 159, 166, 171, 178, 185, 191, 199, 205, 211,218, 225, 233, 241, 246, 253, 259, 266, 274, 281, 286, 294, 299, 305, 312, 315, 319, 326, 332,337, 340, 347, 353, 356, 360, 366, 370, 376, 382, 388, 392, 398, 404, 409, 414, 420, 424, 430,437, 445, 452, 458, 465, 472, 480, 486, 492, and 499, and the VL comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 2, 10, 18, 25, 33, 41, 48, 56, 64, 72, 78, 85, 92, 100, 108, 114, 121, 129, 135, 141, 148, 154, 160, 167, 172, 179, 186, 192, 200, 206, 212,219, 226, 234, 242, 247, 254, 260, 267, 275, 282, 287, 295, 300, 306, 313, 316, 320, 327, 333, 341, 348, 354, 357, 361, 367, 371, 377, 383, 389, 393, 399, 405, 410, 415, 421, 425, 431, 438, 446, 453, 459, 466, 473, 481, 487, 493, and 500.

[0007] In some embodiments, the antibody or antigen-binding fragment is selected from the group consisting of an antibody, a single chain variable fragment (scFv), an Fab fragment, a Fab' fragment, a single-chain Fab fragment (scFab), an F(ab')2 fragment, and an F(ab)v fragment. In some embodiments, the antigen-binding fragment is an scFv. In some embodiments, the scFv comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in any one of SEQ ID NOs: 504- 582. In some embodiments, the antibody is an IgGl, an IgG2, an IgG3, an IgG4, and IgA, an IgD, an IgE, or an IgM antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody or antigen-binding fragment binds to TMPRSS4 expressed on the surface of a cell.

[0008] Also disclosed herein, in various embodiments, is an antibody or antigen-binding fragment thereof that competes with the antibody or antigen-binding fragment disclosed herein for binding to TMPRSS4.

[0009] Also disclosed herein, in various embodiments, is a synthetic immune receptor comprising an extracellular antigen binding domain comprising the antibody or antigen-binding fragment provided herein. In some embodiments, the synthetic immune receptor is a chimeric antigen receptor (CAR) further comprising: (a) a transmembrane domain; (b) an intracellular costimulatory domain; and (c) an intracellular activation domain. In some embodiments, the transmembrane domain is a transmembrane domain of CD8a. In some embodiments, the intracellular co-stimulatory domain is a co-stimulatory domain of 4- IBB. In some embodiments,the intracellular activation domain is an activation domain of CD3^. In some embodiments, the CAR further comprises a hinge domain between the extracellular antigen binding domain and the transmembrane domain. In some embodiments, the hinge domain is a CD8a hinge domain.

[0010] Also disclosed herein, in various embodiments is a system comprising: (a) the synthetic immune receptor disclosed herein; and (b) a priming receptor.

[0011] Also disclosed herein, in various embodiments is a system comprising: (a) a first chimeric polypeptide comprising a priming receptor, and (b) a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising an antigen-binding domain that specifically binds to TMPRSS4, wherein the antigen-binding domain comprises a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, HCDR1, HCDR2, and HCDR3 of the VH sequences set forth in SEQ ID NOs: 315 or 319, and a second variable light (VL) chain sequence comprising three light chain CDR sequences, LCDR1, LCDR2, and LCDR3, of the VL sequence set forth in SEQ ID NOs: 316 or 320, optionally wherein: (i) HCDR1 comprises the sequence set forth in SEQ ID NO: 317, HCDR2 comprises the sequence set forth in SEQ ID NO: 194, HCDR3 comprises the sequence set forth in SEQ ID NO: 318, LCDR1 comprises the sequence set forth in SEQ ID NO: 278, LCDR2 comprises the sequence set forth in SEQ ID NO: 15, and LCDR3 comprises the sequence set forth in SEQ ID NO: 252; or (ii) HCDR1 comprises the sequence set forth in SEQ ID NO: 321, HCDR2 comprises the sequence set forth in SEQ ID NO: 322, HCDR3 comprises the sequence set forth in SEQ ID NO: 323, LCDR1 comprises the sequence set forth in SEQ ID NO: 324, LCDR2 comprises the sequence set forth in SEQ ID NO: 325, and LCDR3 comprises the sequence set forth in SEQ ID NO: 16. In some embodiments, the VH comprises the sequence set forth in SEQ ID NO: 315 or 319. In some embodiments, the VL comprises the sequence set forth in SEQ ID NO: 316 or 320 In some embodiments, the antigen-binding domain comprises the sequence set forth in SEQ ID NO: 550 or 551.

[0012] In some embodiments, the CAR comprises, from N-terminus to C-terminus, (a) the antigen-binding domain that specifically binds to TMPRSS4; (b) a transmembrane domain; (c) an intracellular co-stimulatory domain; and (d) an intracellular activation domain. In some embodiments, the CAR comprises a hinge domain. In some embodiments, the hinge domain of the CAR comprises a CD8a or truncated CD8a hinge domain. In some embodiments, the hinge domain of the CAR comprises a sequence as set forth in SEQ ID NO: 821. In someembodiments, the transmembrane domain of the CAR comprises a CD 8 a transmembrane domain. In some embodiments, the transmembrane domain of the CAR comprises a sequence as set forth in SEQ ID NO: 822. In some embodiments, the intracellular co-stimulatory domain comprises a 4- IBB domain. In some embodiments, the intracellular co-stimulatory domain comprises a sequence as set forth in SEQ ID NO: 823. In some embodiments, the intracellular activation domain comprises a CD3^ domain. In some embodiments, the intracellular activation domain comprises a sequence as set forth in SEQ ID NO: 824.

[0013] In some embodiments, the priming receptor comprises, from N-terminus to C-terminus: (a) a second extracellular antigen-binding domain; (b) a second transmembrane domain comprising one or more ligand-inducible proteolytic cleavage sites; and (c) an intracellular domain comprising a human or humanized transcriptional effector.

[0014] Also disclosed herein, in various embodiments, are one or more recombinant nucleic acids encoding: (a) the antibody or antigen-binding fragment disclosed herein; (b) the synthetic immune receptor disclosed herein; and / or (c) the system disclosed herein.

[0015] Also disclosed herein, in various embodiments, is an expression vector comprising a recombinant nucleic acid disclosed herein.

[0016] Also disclosed herein, in various embodiments, is an immune cell comprising: (a) the antibody or antigen-binding fragment disclosed herein; (b) the synthetic immune receptor disclosed herein; (c) the system disclosed herein; (d) the one or more recombinant nucleic acids disclosed herein; and / or (e) the expression vector disclosed herein.

[0017] Also disclosed herein, in various embodiments, is a primary immune cell comprising at least one recombinant nucleic acid comprising: (a) a nucleic acid sequence encoding the synthetic immune receptor disclosed herein; and (b) a nucleic acid sequence encoding a priming receptor comprising a second extracellular antigen-binding domain, wherein the recombinant nucleic acid is inserted into a target region of the genome of the primary immune cell, wherein the primary immune cell does not comprise a viral vector for introducing the recombinant nucleic acid into the primary immune cell.

[0018] Also disclosed herein, in various embodiments, is a viable, virus-free, primary cell comprising a ribonucleoprotein complex (RNP) and a DNA template, wherein the RNP comprises a nuclease domain and a guide RNA, and wherein the DNA template comprises: (a) a nucleic acid sequence encoding the synthetic immune receptor disclosed herein; and (b) a nucleicacid sequence encoding a priming receptor comprising a first extracellular antigen-binding domain, wherein the 5’ and 3’ ends of the DNA template comprise nucleotide sequences that are homologous to genomic sequences flanking an insertion site in the genome of the primary cell.

[0019] Also disclosed herein, in various embodiments, is a population of cells comprising a plurality of immune cells or primary cells disclosed herein.

[0020] Also disclosed herein, in various embodiments, is a pharmaceutical composition comprising the immune cell, the primary cells, or the population of cells disclosed herein, and a pharmaceutically acceptable excipient.

[0021] Also disclosed herein, in various embodiments, is a pharmaceutical composition comprising the one or more recombinant nucleic acids or the vector disclosed herein, and a pharmaceutically acceptable excipient.

[0022] Also disclosed herein, in various embodiments, is a method of editing an immune cell, comprising introducing into the cell the one or more recombinant nucleic acids disclosed herein. In some embodiments, the one or more recombinant nucleic acids are introduced non-virally. In some embodiments, the method comprises (a) providing a ribonucleoprotein (RNP) and a DNA template, wherein the RNP comprises a nuclease domain and a guide RNA, wherein the DNA template comprises the one or more recombinant nucleic acids, and wherein the 5’ and 3’ ends of the DNA template comprise nucleotide sequences that are homologous to genomic sequences flanking an insertion site in the genome of the immune cell; (b) non-virally introducing the RNP and DNA template into the immune cell, wherein the guide RNA specifically hybridizes to a target region of the genome of the primary immune cell, and wherein the nuclease domain cleaves the target region to create the insertion site in the genome of the immune cell; and (c) editing the immune cell via insertion of the one or more recombinant nucleic acids into the insertion site in the genome of the immune cell.

[0023] Also disclosed herein, in various embodiments, is a method of treating a disease in a subject comprising administering the immune cell, the primary cells, the population of cells, or the pharmaceutical composition disclosed herein to the subject. In some embodiments, the disease is a cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0024] Also disclosed herein, in various embodiments, is a method of inhibiting a target cell in a subject comprising administering the immune cell, the primary cells, or the population of cells disclosed herein to the subject, wherein the immune cell inhibits the target cell.

[0025] Also disclosed herein, in various embodiments, is a method of modulating the activity of an immune cell comprising: (a) obtaining an immune cell comprising: (i) the synthetic immune receptor disclosed herein; (ii) the system disclosed herein; (iii) the one or more recombinant nucleic acids disclosed herein; and / or (iv) the expression vector disclosed herein; and (b) contacting the immune cell with a target cell expressing TMPRSS4, wherein binding of the synthetic immune receptor to TMPRSS4 on the target cell modulates the activity of the immune cell. In some embodiments, the immune cell comprises a priming receptor that binds a priming receptor antigen expressed on the target cell, and wherein binding of the priming receptor to the priming receptor antigen on the target cell induces activation of the priming receptor and thereby induces expression of the synthetic immune receptor.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0027] FIG. 1A shows binding of the indicated antibodies to TMPRSS4-expressing cells as determined by flow cytometry and measured by gMFI. FIG. IB shows binding of TMPRSS4 antibodies to full-length and truncated TMPRSS4 lacking the membrane-proximal domain as determined by flow cytometry and measured by gMFI. FIG. 1C shows flow cytometry histograms of binding of the TMPRSS4 antibodies to HEK293T cells engineered to express full length TMPRSS4 or parental HEK293T cells.

[0028] FIG. 2 is a schematic of an exemplary construct encoding a TMPRSS4 CAR.

[0029] FIG. 3A shows the percentages of T cells expressing CARs comprising the indicated TMPRSS4 antibodies as measured by flow cytometry (gMFI). FIG. 3B shows the overall expression of CARs comprising indicated TMPRSS4 antibodies as measured by flow cytometry. FIG. 3C shows characterization of CD4+cells into central memory T cells (TCM), stem cell memory T cells (TSCM), effector memory T cells (TEM), or effector memory T cells re-expressing CD45RA (TEMRA) based on flow cytometry detection of CCR7 and CD45RA. FIG. 3D shows characterization of CD8+cells into TCM, TSCM, TEM, or TEMRA based on flow cytometry detection of CCR7 and CD45RA.

[0030] FIG. 4A shows surface expression of CD25 on T cells from donor CP5428 expressing CARs comprising the indicated TMPRSS4 antibody. FIG. 4B shows surface expression of TIM3 on T cells from donor CP5428 expressing CARs comprising the indicated TMPRSS4 antibody.FIG. 4C shows surface expression of CD25 on T cells from donor CP5917 expressing CARs comprising the indicated TMPRSS4 antibody. FIG. 4D shows surface expression of TIM3 on T cells from donor CP5917 expressing CARs comprising the indicated TMPRSS4 antibody.

[0031] FIG. 5A shows TMPRSS4 expression in LUDLU-1 and H1975 cell lines as determined by flow cytometry. FIG. 5B shows cytotoxicity (% killing) of LUDLU-1 and H1975 cell lines after incubation with TMPRSS4 CAR-expressing T cells at indicated effector: target (E:T) ratios.

[0032] FIG. 6A shows TMPRSS4 expression in H1975 cells with or without knockout of TMPRSS4 as determined by flow cytometry. FIG. 6B shows cytotoxicity (% killing) H1975 cells with or without knockout of TMPRSS4 after incubation with TMPRSS4 CAR-expressing T cells at indicated E:T ratios.

[0033] FIG. 7 shows secretion of IFNy from TMPRSS4 CAR-expressing T cells following incubation with LUDLU-1 cells. FIG. 7B shows secretion of IFNy from TMPRSS4 CAR- expressing T cells following incubation with parental H1975 cells. FIG. 7C shows secretion of IFNy from TMPRSS4 CAR-expressing T cells following incubation with H1975 cells with TMPRSS4 knockout.

[0034] FIG. 8A shows secretion of TNFa from TMPRSS4 CAR-expressing T cells following incubation with LUDLU-1 cells. FIG. 8B shows secretion of TNFa from TMPRSS4 CAR- expressing T cells following incubation with parental H1975 cells. FIG. 8C shows secretion of TNFa from TMPRSS4 CAR-expressing T cells following incubation with H1975 cells with TMPRSS4 knockout.

[0035] FIG. 9 provides schematics of TMPRSS4 variants including the wild-type protein, a protein comprising a mutation (indicated by X) that suppresses catalytic activity (“catalytic inactive”), and a truncated protein lacking the C-terminal serine protease domain (“cleaved / truncated”).

[0036] FIG. 10 shows CD69 surface expression in T cells expressing CARs comprising indicated TMPRSS4 antibody following co-culture with cells expressing indicated TMPRSS4 protein.

[0037] FIG. 11 provides a schematic of functional sorting of T cells expressing a logic gate comprising a Target 1 primeR and a TMPRSS4 CAR following co-culture with indicated H1975 target cells.

[0038] FIG. 12 provides a schematic of a workflow of analysis of preparation, activation, and sequencing analysis of TMPRSS4 CAR-expressing T cells.

[0039] FIG. 13A shows CD25 and CD62L expression on T cells following co-culture with Target l / TMPRSS4-expressing target cells. FIG. 13B shows CD25 and CD62L expression on T cells following co-culture with TMPRSS4-expressing target cells. FIG. 13C shows CD25 and CD62L expression on T cells following co-culture with Target 1-expressing target cells. FIG. 13D shows CAR expression (via FLAG tag) and CD62L surface expression of T cells following co-culture with target cells that do not express Target 1 or TMPRSS4.

[0040] FIG. 14 shows quality control analysis of library compositions for logic gateexpressing T cells from each of three donors.

[0041] FIG. 15A shows correlation of sequencing results in T cells expressing a TMPRSS4 CAR across four donors in three separate logic gate backgrounds following co-culture with cells expressing Target 1 and TMPRSS4 (left panels) or TMPRSS4 only (right panels). Numbers indicate correlation coefficients of activity scores T cells expressing the specific TMPRSS4 CAR. FIG. 15B shows correlation of sequencing analysis between TMPRSS4 CAR T cells from two donors depicted in FIG. 15 .

[0042] FIG. 16A shows correlation of sequencing results in T cells expressing a TMPRSS4 CAR across three separate logic gate backgrounds from four separate donors following coculture with cells expressing Target 1 and TMPRSS4 (left panels) or TMPRSS4 only (right panels). Numbers indicate correlation coefficients of activity scores T cells expressing the specific TMPRSS4 CAR. FIG. 16B depicts correlation of sequencing analysis between TMPRSS4 CAR T cells from two logic gate backgrounds depicted in FIG. 16A.

[0043] FIG. 17A shows the potency (e.g., cell killing, vertical axis) and leakiness (e.g., nonprimed CAR expression, horizontal axis) of an exemplary logic gate with a TMPRSS4 CAR following co-culture with target cells expressing priming receptor Target 1 and TMPRSS4 (vertical axes). FIG. 17B is an exemplary graph from FIG. 17A annotated to show functional clustering of cells expressing an exemplary logic gate with a TMPRSS4 CAR following coculture with target cells.

[0044] FIGs. 18A and 18B provide further annotation of the graphs shown in FIGs. 17A and 17B grouping the TMPRSS4 CARs based on functionality, leakiness, and non-functionality.

[0045] FIG. 19 shows the top performing logic gate constructs comprising a Target 1 primeR and TMPRSS4 CARs based on high potency and low leakiness in cells from each of four donors in each of three logic gate backgrounds.

[0046] FIG. 20 shows the potency, leakiness, prime leakiness, and parental CAR induction for the top 15 selected logic gates comprising a Target 1 primeR and a TMPRSS4 CAR constructs compared to all other constructs.

[0047] FIG. 21 shows the percent cytotoxicity of Hl 975 target cells with high expression of TMPRSS4 and expression of Target 1 following co-culture with T cells expressing the indicated TMPRSS4 CARs.

[0048] FIG. 22 shows the percent cytotoxicity of Hl 975 target cells with moderate expression of TMPRSS4 and expression of Target 1 following co-culture with T cells expressing a logic gate comprising a Target 1 primeR and the indicated TMPRSS4 CARs.

[0049] FIG. 23 shows the percent cytotoxicity of LUDLU-1 target cells with endogenous expression of TMPRSS4 and Target 1 following co-culture with T cells expressing the indicated TMPRSS4 CARs.

[0050] FIG. 24 shows the cytotoxicity of Hl 975 target cells with high expression of TMPRSS4 and expression of Target 1 in a mixed population of cells with 95% of cell lacking Target 1 expression following co-culture with T cells expressing the indicated TMPRSS4 CARs.

[0051] FIG. 25 shows the cytotoxicity of Hl 975 target cells with high expression of TMPRSS4 and lacking expression of Target 1 following co-culture with T cells expressing the indicated TMPRSS4 CARs.

[0052] FIG. 26 shows the cytotoxicity of Hl 975 target cells with expression of Target 1 and lacking expression of TMPRSS4 following co-culture with T cells expressing a Target 1 primeR and the indicated TMPRSS4 CARs.

[0053] FIG. 27 is a schematic showing screening of methods for logic gates comprising a Target 1 primeR and TMPRSS4 CARs.

[0054] FIG. 28 is a schematic showing analysis methods of T cells expressing logic gates comprising a Target 1 primeR and TMPRSS4 CARs in the screen depicted in FIG. 29.

[0055] FIG. 29 shows the percentage of cells expressing TMPRSS4 CAR and Target 1 primeR based on surface staining of Flag (CAR) and Myc (primeR).

[0056] FIG. 30 shows activation of T cells expressing logic gates comprising a Target 1 primeR and TMPRSS4 CARs following co-culture with H1975 target cells lacking expression of Target 1 and TMPRSS4 as measured by CD62L7CD25+surface staining.

[0057] FIG. 31 shows activation of T cells expressing logic gates comprising a Target 1 primeR and TMPRSS4 CARs following co-culture with H1975 cells expressing of TMPRSS4 and Target 1 (potency) or expressing TMPRSS4 but not Target 1 (leakiness).

[0058] FIG. 32 shows Z-scores (Desirability score) of T cells expressing logic gates comprising a Target 1 primeR and TMPRSS4 CARs following co-culture with H1975 cells expressing TMPRSS4 and Target 1 (potency) or expressing TMPRSS4 but not Target 1 (leakiness).

[0059] FIG. 33A shows T cell activation as measured by CD62L7CD25+surface staining.FIG. 33B shows IFNy secretion from logic gate-expressing T cells. For both FIG. 33A and FIG. 33B, potency indicates activation of T cells expressing logic gates comprising a Target 1 primeR and TMPRSS4 CARs following co-culture with H1975 cells expressing TMPRSS4 and Target 1. Leakiness indicates activation of T cells expressing logic gates comprising a Target 1 primeR and TMPRSS4 CARs following co-culture with H1975 cells expressing TMPRSS4 but not Target 1.

[0060] FIG. 34A shows comparison of activated T cells expressing logic gates comprising a Target 1 primeR and a TMPRSS4 CAR from donors Donor 1 and Donor 2. Data points represent a specific TMPRSS4 CAR. FIG. 34B shows comparison of activated T cells expressing logic gates comprising a Target 1 primeR and a TMPRSS4 CAR from donors Donor 3 and Donor 2. FIG. 34C shows comparison of activated T cells expressing logic gates comprising a Target 1 primeR and a TMPRSS4 CAR from donors Donor 3 and Donor 1.DETAILED DESCRIPTION OF THE INVENTION

[0061] The present disclosure provides antibodies or antigen-binding fragments thereof that bind to TMPRSS4. The present disclosure also provides synthetic immune receptors (e.g., CARs) comprising the antibodies or antigen binding fragments, cells comprising the synthetic immune receptors, and methods of making and / or using the cells.Definitions

[0062] Terms used in the claims and specification are defined as set forth below unless otherwise specified.

[0063] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0064] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a nontarget molecule). For example, an antibody that “selectively binds” or “specifically binds” an antigen is an antigen-binding moiety that binds the antigen with high affinity and does not significantly bind other unrelated antigens. Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule.

[0065] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody or antigen binding protein) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen or epitope). The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including, but not limited to, surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0066] The term “complementarity determining region” “CDR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops (“hypervariable loops,” “hypervariable region,” or “HVR”). Generally, native four-chain antibodies comprise six CDRs; three in the VH (HCDR1 / CDR-H1, HCDR2 / CDR-H2, and HCDR3 / CDR-H3), and three in the VL (LCDR1 / CDR-L1, LCDR2 / CDR- L2, and LCDR3 / CDR-L3). With the exception of CDR1 in VH, CDRs generally comprise theamino acid residues that form the hypervariable loops. Complementarity determining regions (CDRs) are also referred to as “hypervariable regions” or “HVRs”, and these terms are used herein interchangeably in reference to portions of the variable region that form the antigenbinding regions. This particular region has been described by Kabat et al., U.S. Dept, of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and by Chothia et al., J Mol Biol 196:901-917 (1987), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The exact residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.

[0067] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); Martin (Enhanced Chothia) Abhinandan and Martin, Mol Immunol. 2008 Aug;45(14):3832-9; MacCallum et al., 1996, J. Mol. Biol. 262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegger and Pliickthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0068] Table 1 provides the positions of LCDR1 / CDR-L1, LCDR2 / CDR-L2, LCDR3 / CDR- L3, HCDR1 / CDR-H1, HCDR2 / CDR-H2, and HCDR3 / CDR-H3 as identified by the Kabat and Chothia schemes. For HCDR1 / CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0069] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety. Descriptions of the various antibody numbering schemes are available at bioinf.org.uk / abs / info.html and the AbYsis program.Table 1: Residues in CDRs according to Kabat and Chothia numbering schemes.I CDRI Contact

[0070] * The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0071] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.Table 2: Example Conservative Substitutions

[0072] As used herein, the term "single-chain" refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular such embodiment, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in the single-chain Fab molecule. As described in more detail herein, an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain. Alternately the scFv comprises of polypeptide chain where in the C- terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.

[0073] The “Fab fragment” (also referred to as fragment antigen-binding) contains the constant domain (CL) of the light chain and the first constant domain (CHI) of the heavy chain along with the variable domains VL and VH on the light and heavy chains respectively. The variable domains comprise the complementarity determining loops (CDR, also referred to as hypervariable region) that are involved in antigen-binding. Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region.

[0074] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab')2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab') fragments can be dissociated, for example, by treatment with P-mercaptoethanol.

[0075] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0076] The “Single-chain Fv” or “scFv” includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In one embodiment, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding. For a review of scFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994). HER2 antibody scFv fragments are described in WO93 / 16185; U.S. Pat. No. 5,571,894; and U.S. Pat. No. 5,587,458.

[0077] The term “single domain antibody” or “sdAb” refers to a molecule in which one variable domain of an antibody specifically binds to an antigen without the presence of the other variable domain. Single domain antibodies, and fragments thereof, are described in Arabi Ghahroudi et al., FEBS Letters, 1998, 414:521-526 and Muyldermans et al., Trends in Biochem.Sci., 2001, 26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies. Sdabs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (Harmsen MM, De Haard HJ (2007). "Properties, production, and applications of camelid single-domain antibody fragments". Appl. Microbiol Biotechnol. 77(1): 13-22). As used herein, the term "single-chain" refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular such embodiment, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in the single-chain Fab molecule. As described in more detail herein, an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain. Alternately the scFv comprises of polypeptide chain where in the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.

[0078] As used herein, the term “gene” refers to the basic unit of heredity, consisting of a segment of DNA arranged along a chromosome, which codes for a specific protein or segment of protein. A gene typically includes a promoter, a 5' untranslated region, one or more coding sequences (exons), optionally introns, and a 3' untranslated region. The gene may further comprise a terminator, enhancers and / or silencers.

[0079] The terms “genetic engineering,” “gene editing,” or “genome editing”, as used herein, refer to a type of genetic manipulation in which DNA is inserted, replaced, or removed from the genome using artificially manipulated nucleases or “molecular scissors”. It is a useful tool for elucidating the function and effect of sequence-specific genes or proteins or altering cell behavior (e.g., for therapeutic purposes).

[0080] Gene editing, as contemplated herein, may involve a gene (or nucleotide sequence) knock-in or knock-out. As used herein, the term “knock-in” refers to an addition of a DNA sequence, or fragment thereof into a genome. Such DNA sequences to be knocked-in may include an entire gene or genes, may include regulatory sequences associated with a gene or any portion or fragment of the foregoing. For example, a polynucleotide donor construct encoding a recombinant protein may be inserted into the genome of a cell carrying a mutant gene. In some embodiments, a knock-in strategy involves substitution of an existing sequence with the provided sequence, e.g., substitution of a mutant allele with a wild-type copy. On the other hand, the term “knock-out” refers to the elimination of a gene or the expression of a gene. Forexample, a gene can be knocked out by either a deletion or an addition of a nucleotide sequence that leads to a disruption of the reading frame. As another example, a gene may be knocked out by replacing a part of the gene with an irrelevant (e.g., non-coding) sequence.

[0081] Currently available genome editing tools include zinc finger nucleases (ZFN) and transcription activator-like effector nucleases (TALENs) to incorporate genes at safe harbor loci (e.g., the adeno-associated virus integration site 1 (AAVS1) safe harbor locus or any other safe harbor loci disclosed herein). The DICE (dual integrase cassette exchange) system utilizing phiC31 integrase and Bxbl integrase is a tool for target integration. Additionally, clustered regularly interspaced short palindromic repeat / Cas (CRISPR / Cas) techniques can be used for targeted gene insertion. Site specific gene editing approaches can include homology dependent mechanisms or homology independent mechanisms. All methods known in the art for targeted insertion of gene sequences are contemplated in the methods described herein to insert constructs at gene targets or safe harbor loci.

[0082] The “CRISPR / Cas” system refers to a widespread class of bacterial systems for defense against foreign nucleic acid. CRISPR / Cas systems are found in a wide range of eubacterial and archaeal organisms. CRISPR / Cas systems include type I, II, and III sub-types. Wild-type type II CRISPR / Cas systems utilize an RNA-mediated nuclease, Cas9 in complex with guide and activating RNA to recognize and cleave foreign nucleic acid. Guide RNAs having the activity of both a guide RNA and an activating RNA are also known in the art. In some cases, such dual activity guide RNAs are referred to as a small guide RNA (sgRNA).

[0083] As used herein, a polypeptide referred to as a “Cas endonuclease” or having “Cas endonuclease activity” refers to a CRIS PR-related (Cas) polypeptide encoded by a Cas gene, wherein a Cas polypeptide is a target DNA sequence that can be cleaved when operably linked to one or more guide polynucleotides (see, e.g., US Pat. No. 8,697,359). Also included in this definition are variants of Cas endonuclease that retain guide polynucleotide-dependent endonuclease activity. The Cas endonuclease used in the donor DNA insertion method detailed herein is an endonuclease that introduces double-strand breaks into DNA at the target site (e.g., within the target locus or at the safe harbor site).

[0084] As used herein, the term “Cas9” refers to an RNA-mediated nuclease (e.g., of bacterial or archeal origin, or derived therefrom). Exemplary RNA-mediated nucleases include the foregoing Cas9 proteins and homologs thereof, and include but are not limited to, CPF1 (See,e.g., Zetsche et al., Cell, Volume 163, Issue 3, p759-771, 22 October 2015). Similarly, as used herein, the term “Cas9 ribonucleoprotein” complex and the like refers to a complex between the Cas9 protein, and a crRNA (e.g., guide RNA or small guide RNA), the Cas9 protein and a transactivating crRNA (tracrRNA), the Cas9 protein and a small guide RNA, or a combination thereof (e.g., a complex containing the Cas9 protein, a tracrRNA, and a crRNA guide RNA). Cas9 homologs are found in a wide variety of eubacteria, including, but not limited to bacteria of the following taxonomic groups: Actinobacteria, Aquificae, Bacteroidetes -Chlorobi, Chlamydiae- Verrucomicrobia, Chlroflexi, Cyanobacteria, Firmicutes, Proteobacteria, Spirochaetes, and Thermotogae. An exemplary Cas9 protein is the Streptococcus pyogenes Cas9 protein.Additional Cas9 proteins and homologs thereof are described in, e.g., Chylinksi, et al., RNA Biol. 2013 May 1; 10(5): 726-737 ; Nat. Rev. Microbiol. 2011 June; 9(6): 467-477; Hou, et al., Proc Natl Acad Sci U S A. 2013 Sep 24;110(39): 15644-9; Sampson et al., Nature. 2013 May 9;497(7448):254-7; and Jinek, et al., Science. 2012 Aug 17;337(6096):816-21. The Cas9 nuclease domain can be optimized for efficient activity or enhanced stability in the host cell.

[0085] As used herein, the term “guide polynucleotide” relates to a polynucleotide sequence capable of complexing with a Cas endonuclease and allowing the Cas endonuclease to recognize and cleave a DNA target site. The guide polynucleotide can be a single molecule or a double molecule. The guide polynucleotide sequence can be an RNA sequence, a DNA sequence, or a combination thereof (RNA-DNA combination sequence). A guide polynucleotide comprising only ribonucleic acid is also referred to as “guide RNA”. In some embodiments, a polynucleotide donor construct is inserted at a safe harbor locus using a guide RNA (gRNA) in combination with a Cas endonuclease (e.g., Cas9 endonuclease).

[0086] As used herein, the term “homology directed repair” or HDR refers to a cellular process in which cut or nicked ends of a DNA strand are repaired by polymerization from a homologous template nucleic acid. Thus, the original sequence is replaced with the sequence of the template. The homologous template nucleic acid can be provided by homologous sequences elsewhere in the genome (sister chromatids, homologous chromosomes, or repeated regions on the same or different chromosomes). Alternatively, an exogenous template nucleic acid can be introduced to obtain a specific HDR-induced change of the sequence at the target site. In this way, specific mutations can be introduced at the cut site.

[0087] As used herein, the term “non-homologous end joining” or NHEJ refers to a cellular process in which cut or nicked ends of a DNA strand are directly ligated without the need for a homologous template nucleic acid. NHEJ can lead to the addition, the deletion, substitution, or a combination thereof, of one or more nucleotides at the repair site.

[0088] As used herein, the term “integration” refers to the process of stably inserting one or more nucleotides of a construct into the cell genome, i.e., covalently linking to a nucleic acid sequence in the chromosomal DNA of the cell. It may also refer to nucleotide deletions at a site of integration. Where there is a deletion at the insertion site, “integration” may further include substitution of the endogenous sequence or nucleotide deleted with one or more inserted nucleotides.

[0089] As used herein, the term “locus” refers to a specific, fixed physical location on a chromosome where a gene or genetic marker is located.

[0090] The term “safe harbor locus” refers to a locus at which genes or genetic elements can be incorporated without disruption to expression or regulation of adjacent genes. These safe harbor loci are also referred to as safe harbor sites (SHS) or genomic safe harbor (GSH) sites. As used herein, a safe harbor locus refers to an “integration site” or “knock-in site” at which a sequence encoding a transgene, as defined herein, can be inserted. In some embodiments the insertion occurs with replacement of a sequence that is located at the integration site. In some embodiments, the insertion occurs without replacement of a sequence at the integration site. Examples of integration sites contemplated are provided in Table 10.

[0091] A “chemotherapeutic agent” refers to a chemical compound useful in the treatment of cancer. Chemotherapeutic agents include “anti-hormonal agents” or “endocrine therapeutics” which act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer.

[0092] The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate protein aggregation in a cell.

[0093] The term “therapeutically effective amount” is an amount that is effective to ameliorate a symptom of a disease.

[0094] As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0095] As used herein, the term “complementary” or “complementarity” refers to specific base pairing between nucleotides or nucleic acids. Complementary nucleotides are, generally, A and T (or A and U), and G and C. The guide RNAs described herein can comprise sequences, for example, DNA targeting sequence that are perfectly complementary or substantially complementary (e.g., having 1-4 mismatches) to a genomic sequence in a cell.

[0096] The term “composition” refers to a mixture that contains, e.g., an engineered cell or protein contemplated herein. In some embodiments, the composition may contain additional components, such as adjuvants, stabilizers, excipients, and the like. The term “composition” or “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition.

[0097] As used herein, the term “construct” refers to a complex of molecules, including macromolecules or polynucleotides.

[0098] As used herein, the term “developmental cell states” refers to, for example, states when the cell is inactive, actively expressing, differentiating, senescent, etc. developmental cell state may also refer to a cell in a precursor state (e.g., a T cell precursor).

[0099] The term “ameliorating” refers to any therapeutically beneficial result in the treatment of a disease state, e.g., a cancer disease state, lessening in the severity or progression, remission, or cure thereof.

[0100] As used herein, the term “effective amount” refers to the amount of a compound (e.g., a compositions described herein, cells described herein) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

[0101] As used herein the term “expression cassette” is a polynucleotide construct, generated recombinantly or synthetically, comprising regulatory sequences operably linked to a selected polynucleotide to facilitate expression of the selected polynucleotide in a host cell. For example, the regulatory sequences can facilitate transcription of the selected polynucleotide in a host cell, or transcription and translation of the selected polynucleotide in a host cell. An expression cassette can, for example, be integrated in the genome of a host cell or be present in an expression vector.

[0102] As used, the term “encoding” refers to a sequence of nucleotides which codes for a protein or polypeptide of interest or non-protein coding sequences. The nucleic acid sequence may be either a molecule of DNA or RNA. In preferred embodiments, the molecule is a DNA molecule. In other preferred embodiments, the molecule is a RNA molecule. When present as a RNA molecule, it will comprise sequences which direct the ribosomes of the host cell to start translation (e.g., a start codon, ATG) and direct the ribosomes to end translation (e.g., a stop codon). Between the start codon and stop codon is an open reading frame (ORF). Such terms are known to one of ordinary skill in the art. Non-protein coding sequences include, but are not limited to, short hairpin RNA (shRNA), small interfering RNA (siRNA), double stranded RNA (dsRNA), or antisense oligonucleotides.

[0103] As used herein, a single-stranded DNA template or a double-stranded DNA template refers to a DNA oligonucleotide that can be used by a cell as a template for HDR. Generally, the single-stranded DNA template or a double-stranded DNA template has at least one region of homology to a target site. In some cases, the single-stranded DNA template or double-stranded DNA template has two homologous regions flanking a region that contains a heterologous sequence to be inserted at a target cut site.

[0104] The term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN or other algorithms available to persons of skill) or by visual inspection. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.

[0105] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0106] Optimal alignment of sequences for comparison can be conducted, e.g. , by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0107] One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

[0108] As used herein, the term “to insert” or “inserting” refers to process of integrating a nucleotide sequence into the genome of a cell, such as at a target locus or safe harbor site. The term “insert” also can be used to refer to the genes or genetic elements that are incorporated at the target locus or safe harbor site using, for example, homology-directed repair (HDR) CRISPR / Cas (e.g., CRISPR / Cas9) genome-editing or other methods for inserting nucleotide sequences into a genomic region known to those of ordinary skill in the art. As used herein, the phrase “introducing” in the context of introducing a nucleic acid or a complex comprising a nucleic acid, for example, an RNP-DNA template complex, refers to the translocation of the nucleic acid sequence or the RNP-DNA template complex from outside a cell to inside the cell. In some cases, introducing refers to translocation of the nucleic acid or the complex from outside the cell to inside the nucleus of the cell. Various methods of such translocation are contemplated, including but not limited to, electroporation, contact with nano wires or nanotubes, receptor mediated internalization, translocation via cell penetrating peptides, liposome mediated translocation, and the like.

[0109] As used herein, the term “operably linked” or “operatively linked” refers to the binding of a nucleic acid sequence to a single nucleic acid fragment such that one function is affected by the other. For example, if a promoter is capable of affecting the expression of a coding sequence or functional RNA (i.e., the coding sequence or functional RNA is under transcriptional control by the promoter), the promoter is operably linked thereto. Coding sequences can be operably linked to control sequences in both sense and antisense orientation.

[0110] As used herein, a “polynucleotide donor construct” refers to a nucleotide sequence (e.g., DNA sequence) that is genetically inserted into a polynucleotide and is exogenous to that polynucleotide. The polynucleotide donor construct is transcribed into RNA and optionally translated into a polypeptide. The polynucleotide donor construct can include prokaryotic sequences, cDNA from eukaryotic mRNA, genomic DNA sequences from eukaryotic (e.g., mammalian) DNA, and synthetic DNA sequences. For example, the polynucleotide donor construct can be a miRNA, shRNA, natural polypeptide (i.e., a naturally occurring polypeptide) or fragment thereof or a variant polypeptide (e.g., a natural polypeptide having less than 100% sequence identity with the natural polypeptide) or fragments thereof.

[0111] As used herein, the term “promoter” refers to a nucleotide sequence (e.g., DNA sequence) capable of controlling the expression of a coding sequence or functional RNA. The promoter sequence consists of proximal and more distal upstream elements, the latter elements often referred to as enhancers. A promoter can be derived from natural genes in its entirety, can be composed of different elements from different promoters found in nature, and / or may comprise synthetic DNA segments. A promoter, as contemplated herein, can be endogenous to the cell of interest or exogenous to the cell of interest. It is appreciated by those skilled in the art that different promoters can induce gene expression in different tissue or cell types, or at different developmental stages, or in response to different environmental conditions. As is known in the art, a promoter can be selected according to the strength of the promoter and / or the conditions under which the promoter is active, e.g., constitutive promoter, strong promoter, weak promoter, inducible / repressible promoter, tissue specific Or developmentally regulated promoters, cell cycle-dependent promoters, and the like.

[0112] A promoter can be an inducible promoter (e.g., a heat shock promoter, tetracycline- regulated promoter, steroid-regulated promoter, metal-regulated promoter, estrogen receptor- regulated promoter, etc.). In some embodiments, an inducible promoter comprises one or more inducible response elements (e.g., Hepatocyte Nuclear Factor la (HNFla) response elements) operably linked to a basal promoter element. The promoter can be a constitutive promoter (e.g., CMV promoter, UBC promoter). In some embodiments, the promoter can be a spatially restricted and / or temporally restricted promoter (e.g., a tissue specific promoter, a cell type specific promoter, etc.). See for example US Publication 2018 / 0127786, the disclosure of which is herein incorporated by reference in its entirety.

[0113] As used herein, the term “transgene” refers to a polynucleotide that has been transferred naturally, or by any of a number of genetic engineering techniques from one organism to another. It is optionally translated into a polypeptide. It is optionally translated into a recombinant protein. A “recombinant protein” is a protein encoded by a gene - recombinant DNA - that has been cloned in a system that supports expression of the gene and translation of messenger RNA (see expression system). The recombinant protein can be a therapeutic agent, e.g. , a protein that treats a disease or disorder disclosed herein. As used, transgene can refer to a polynucleotide that encodes a polypeptide.

[0114] The terms “vector” and “plasmid” are used interchangeably and as used herein refer to polynucleotide vehicles useful to introduce genetic material into a cell. Vectors can be linear or circular. Vectors can integrate into a target genome of a host cell or replicate independently in a host cell. Vectors can comprise, for example, an origin of replication, a multicloning site, and / or a selectable marker. An expression vector typically comprises an expression cassette. Vectors and plasmids include, but are not limited to, integrating vectors, prokaryotic plasmids, eukaryotic plasmids, plant synthetic chromosomes, episomes, cosmids, and artificial chromosomes.

[0115] The term “z’n vivo” refers to processes that occur in a living organism.

[0116] The term “z’n situ” refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.

[0117] As used herein, the term “ex vivo” generally includes experiments or measurements made in or on living tissue, preferably in an artificial environment outside the organism, preferably with minimal differences from natural conditions.

[0118] As used herein, the phrase “hematopoietic stem cell” refers to a type of stem cell that can give rise to a blood cell. Hematopoietic stem cells can give rise to cells of the myeloid or lymphoid lineages, or a combination thereof. Hematopoietic stem cells are predominantly found in the bone marrow, although they can be isolated from peripheral blood, or a fraction thereof. Various cell surface markers can be used to identify, sort, or purify hematopoietic stem cells. In some cases, hematopoietic stem cells are identified as c-Kit+and lin". In some cases, human hematopoietic stem cells are identified as CD34+, CD59+, Thyl / CD90+, CD38lo / _, C-kit / CD117+, lin". In some cases, human hematopoietic stem cells are identified as CD34", CD59+, Thyl / CD90+, CD38lo / _, C-kit / CDl 17+, lin". In some cases, human hematopoietic stem cells are identified as CD133+, CD59+, Thyl / CD90+, CD38lo / ", C-kit / CD117+, lin . In some cases, mousehematopoietic stem cells are identified as CD34lo / _, SCA-1+, Thyl+ / 10, CD38+, C-kit+, 1 i n . In some cases, the hematopoietic stem cells are CD150+CD48 CD244-.

[0119] As used herein, the phrase “hematopoietic cell” refers to a cell derived from a hematopoietic stem cell. The hematopoietic cell may be obtained or provided by isolation from an organism, system, organ, or tissue (e.g., blood, or a fraction thereof). Alternatively, an hematopoietic stem cell can be isolated and the hematopoietic cell obtained or provided by differentiating the stem cell. Hematopoietic cells include cells with limited potential to differentiate into further cell types. Such hematopoietic cells include, but are not limited to, multipotent progenitor cells, lineage-restricted progenitor cells, common myeloid progenitor cells, granulocyte-macrophage progenitor cells, or megakaryocyte-erythroid progenitor cells. Hematopoietic cells include cells of the lymphoid and myeloid lineages, such as lymphocytes, erythrocytes, granulocytes, monocytes, and thrombocytes.

[0120] As used herein, the phrase “immune cell” is inclusive of all cell types that can give rise to immune cells, including hematopoietic cells such hematopoietic stem cells, pluripotent stem cells, and induced pluripotent stem cells (iPSCs). In some embodiments, the immune cell is a B cell, macrophage, a natural killer (NK) cell, an induced pluripotent stem cell (iPSC), a human pluripotent stem cell (HSPC), a T cell or a T cell progenitor or dendritic cell. In some embodiments, the cell is an innate immune cell.

[0121] As used herein, the terms “T lymphocyte” and “T cell” are used interchangeably and refer to cells that have completed maturation in the thymus, and identify certain foreign antigens in the body. The terms also refer to the major leukocyte types that have various roles in the immune system, including activation and deactivation of other immune cells. The T cell can be any T cell such as a cultured T cell, e.g., a primary T cell, or a T cell derived from a cultured T cell line, e.g., a Jurkat, SupTl, etc., or a T cell obtained from a mammal. T cells include, but are not limited to, naive T cells, stimulated T cells, primary T cells (e.g., uncultured), cultured T cells, immortalized T cells, helper T cells, cytotoxic T cells, memory T cells, regulatory T cells, natural killer T cells, combinations thereof, or sub-populations thereof. The T cell can be a CD3+cell. T cells can be CD4+, CD8+, or CD4+and CD8+. The T cell can be any type of T cell, CD4+ / CD8+double positive T cells, CD4+helper T cells (e.g., THI and TH2 cells), CD8+T cells (e.g., cytotoxic T cells), peripheral Including but not limited to blood mononuclear cells (PBMC), peripheral blood leukocytes (PBL), tumor infiltrating lymphocytes (TIL), memory Tcells, naive T cells, regulatory T cells, y8 T cells, etc. It can be any T cell at any stage of development. Additional types of helper T cells include TH3 (Treg) cells, TH17 cells, TH9 cells, or TFH cells. Additional types of memory T cells include cells such as central memory T cells (TCM cells), stem cell memory T cells (TSCM cells), effector memory T cells (TEM cells and TEMRA cells). A T cell can also refer to a genetically modified T cell, such as a T cell that has been modified to express a T cell receptor (TCR) or a chimeric antigen receptor (CAR). T cells can also be differentiated from stem cells or progenitor cells.

[0122] “CD4+T cells” refers to a subset of T cells that express CD4 on their surface and are associated with a cellular immune response. CD4+T cells are characterized by a post-stimulation secretion profile that can include secretion of cytokines such as IFN-y, TNF-a, IL-2, IL-4 and IL- 10. “CD4” is a 55 kD glycoprotein originally defined as a differentiation antigen on T lymphocytes, but was also found on other cells including monocytes / macrophages. The CD4 antigen is a member of the immunoglobulin superfamily and has been implicated as an associative recognition element in MHC (major histocompatibility complex) class II restricted immune responses. On T lymphocytes, the CD4 antigen defines a helper / inducer subset.

[0123] “CD8+T cells” refers to a subset of T cells that express CD8 on their surface, are MHC class I restricted, and function as cytotoxic T cells. The “CD8” molecule is a differentiation antigen present on thymocytes, as well as on cytotoxic and suppressor T lymphocytes. The CD8 antigen is a member of the immunoglobulin superfamily and is an associative recognition element in major histocompatibility complex class I restriction interactions.

[0124] As used herein, the term “primary” in the context of a primary cell or primary stem cell refers to a cell that has not been transformed or immortalized. Such primary cells can be cultured, sub-cultured, or passaged a limited number of times (e.g., cultured 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times). In some cases, the primary cells are adapted to in vitro culture conditions. In some cases, the primary cells are isolated from an organism, system, organ, or tissue, optionally sorted, and utilized, e.g., directly without culturing or sub-culturing. In some cases, the primary cells are stimulated, activated, or differentiated. For example, primary T cells can be activated by contact with (e.g., culturing in the presence of) CD3, CD28 agonists, IL-2, IFNy, or a combination thereof.

[0125] As used herein, the term “exogenous” refers to a molecule or activity that has been introduced into a host cell and is not native to that cell. The molecule can be introduced, forexample, by introduction of the encoding nucleic acid into host genetic material, such as by integration into a host chromosome, or as non-chromosomal genetic material, such as a plasmid. Thus, the term, when used in connection with expression of an encoding nucleic acid, refers to the introduction of the encoding nucleic acid into a cell in an expressible form. The term “endogenous” refers to a molecule or activity that is present in a host cell under natural, unedited conditions. Similarly, the term, when used in connection with expression of the encoding nucleic acid, refers to expression of the encoding nucleic acid that is contained within the cell and not introduced exogenously.

[0126] The term “heterologous” refers to a nucleic acid or polypeptide sequence or domain which is not native to a flanking sequence, e.g., wherein the heterologous sequence is not found in nature coupled to the nucleic acid or polypeptide sequences occurring at one or both ends.

[0127] The term “homologous” refers to a nucleic acid or polypeptide sequence or domain which is native to a flanking sequence, e.g., wherein the homologous sequence is found in nature coupled to the nucleic acid or polypeptide sequences occurring at one or both ends.

[0128] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0129] The term “mammal” as used herein includes both humans and non-humans and include but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0130] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0131] The terms “protein,” “polypeptide,” and “peptide” are used herein interchangeably.

[0132] The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0133] As used herein, the term “subject” refers to a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs and sheep. In certain embodiments, the subject is a human. In some embodiments the subject has a disease or condition that can be treated with an engineered cell provided herein or population thereof. In some aspects, the disease or condition is a cancer.TMPRSS4 Antigen Binding Domains

[0134] In some aspects, provided herein are antigen binding domains (e.g., antibodies or antigen binding fragments thereof) that bind to TMPRSS4. In some aspects, provided herein are means for binding to TMPRSS4. In some embodiments, the means for binding to TMPRSS4 comprises an antibody or antigen-binding fragment provided herein. In some embodiments, a TMPRSS4 antibody or antigen-binding fragment or equivalent thereof comprises means for binding a TMPRSS4 protein, optionally binding a human TMPRSS4 protein in the region(s) of human TMPRSS4 bound by the TMPRSS4 antigen binding domains (e.g., an antibody or antigen binding fragment thereof as described in the Examples below). In some embodiments, the means binds a TMPRSS4 protein. In some embodiments, the means binds a human TMPRSS4 protein. In some embodiments, the means is a TMPRSS4 antibody or antigen-binding fragment or equivalent thereof (e.g., a full length antibody or a F(ab')2 fragment, a Fab fragment, a single chain variable fragment (scFv), and a single domain antibody (sdAb), or a functional fragment thereof) means for binding a TMPRSS4 protein. In some embodiments, the means for binding TMPRSS4 includes the anti-TMPRSS4 antibodies and antigen-binding fragments or equivalents thereof described herein.

[0135] Transmembrane protease, serine 4 (TMPRSS4 HGNC: 11878, NCBI Entrez Gene: 56649; UniProtKB / Swiss-Prot: Q9NRS4), otherwise known as Transmembrane Serine Protease 4; Membrane-Type Serine Protease 2 (MT-SP2); Channel-Activating Serine Protease 2 (CAP2); Type II Membrane Serine Protease; or CAPH2, is a 48 kDa transmembrane glycoprotein that belongs to the serine protease family of proteins, a promoter of cancer cell invasion. The canonical isoform encodes a type II single pass transmembrane protein with a 384 amino acid extracellular C-terminal domain. An autocatalytic event has been reported to induce selfcleavage between amino acids 204 and 205, resulting in a 150 amino acid extracellular region.

[0136] The amino acid and nucleic acid sequences of TMPRSS4 are provided below in Table 3, as well as the amino acid sequences of a catalytically inactive TMPRSS4 and a truncated TMPRSS4 mutant.Table 3: TMPRSS4 sequences

[0137] In some embodiments, the TMPRSS4 antigen-binding moiety (e.g., an antigen binding protein or domain such as an antibody of antigen binding fragment thereof) is selected from the group consisting of an antibody, a nanobody, a diabody, a triabody, or a minibody, a F(ab')2 fragment, a Fab fragment, a single chain variable fragment (scFv), and a single domain antibody (sdAb), or a functional fragment thereof. In some embodiments, the antigen-binding moiety comprises an scFv. The antigen-binding moiety can include naturally-occurring amino acidsequences or can be engineered, designed, or modified so as to provide desired and / or improved properties, e.g., increased binding affinity.

[0138] Table 4 provides exemplary amino acid sequences of antibody heavy chain variable domains (VHs) and light chain variable domains (VLs) that, in combination, bind to TMPRSS4, with HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences noted below the respective VH or VL sequence. The CDR sequences provided in Table 4 are annotated using the Kabat scheme.Table 4: TMPRSS4 VH and VL Amino Acid Sequences

[0139] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2), and a heavy chain complementarity determining region 3 (HCDR3), and a light chain variable domain (VL) comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region (LCDR3), wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are each from a clone listed in Table 4.

[0140] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH and a VL each comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of a VH and a VL of a clone listed in Table 4.

[0141] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to an amino acid sequence as set forth in SEQ ID NOs: 1, 9, 17, 24, 32, 40, 47, 55, 63, 71, 77, 84, 91, 99, 107, 113, 120, 128, 134, 140, 147, 153, 159, 166, 171, 178, 185, 191, 199, 205, 211, 218, 225, 233, 241, 246,253, 259, 266, 274, 281, 286, 294, 299, 305, 312, 315, 319, 326, 332, 337, 340, 347, 353, 356,360, 366, 370, 376, 382, 388, 392, 398, 404, 409, 414, 420, 424, 430, 437, 554, 452, 458, 465,472, 480, 486, 492, or 499, optionally wherein the VH CDRs and the VL CDRs are identical to those in the respective sequence. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to an amino acid sequence as set forth in SEQ ID NOs: 2, 10, 18, 25, 33, 41, 48, 56, 64, 72, 78, 85, 92, 100, 108, 114, 121, 129, 135, 141, 148, 154, 160, 167, 172, 179, 186, 192, 200, 206, 212, 219, 226, 234, 242, 247, 254, 260, 267, 275, 282, 287, 295, 300, 306, 313, 316, 320, 327, 333,316, 341, 348, 254, 357, 361, 367, 371, 377, 383, 389, 393, 399, 405, 410, 415, 421, 425, 431,438, 446, 435, 459, 466, 473, 481, 487, 493, or 500, optionally wherein the VH CDRs and theVL CDRs are identical to those in the respective sequence. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to an amino acid sequence as set forth in SEQ ID NOs: 1, 9, 17, 24, 32, 40, 47, 55, 63, 71, 77, 84, 91, 99, 107, 113, 120, 128, 134, 140, 147, 153, 159, 166, 171, 178, 185, 191, 199, 205, 211, 218, 225, 233, 241, 246, 253, 259, 266, 274, 281, 286, 294, 299, 305, 312, 315, 319, 326, 332, 337, 340, 347, 353, 356, 360, 366, 370, 376, 382, 388, 392, 398, 404, 409, 414, 420, 424, 430, 437, 554, 452, 458, 465, 472, 480, 486, 492, or 499, optionally wherein the VH CDRs and the VL CDRs are identical to those in the respective sequence, and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 2, 10, 18, 25, 33, 41, 48, 56, 64, 72, 78, 85, 92, 100, 108, 114, 121, 129, 135, 141, 148, 154, 160, 167, 172, 179, 186, 192, 200, 206, 212, 219, 226, 234, 242, 247, 254, 260, 267, 275, 282, 287, 295, 300,306, 313, 316, 320, 327, 333, 316, 341, 348, 254, 357, 361, 367, 371, 377, 383, 389, 393, 399,405, 410, 415, 421, 425, 431, 438, 446, 435, 459, 466, 473, 481, 487, 493, or 500, optionally wherein the VH CDRs and the VL CDRs are identical to those in the respective sequence.

[0142] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Abl. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a VL comprising an LCDR1 comprising the amino acid sequence setforth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0143] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 2.

[0144] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab2. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 9 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 9 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 10.

[0145] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab3. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 19, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 20, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18.

[0146] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab4. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 24 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 24 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 25.

[0147] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab5. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 32 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 32 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 33.

[0148] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab6. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. Insome embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 40 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 41. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 40 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 41.

[0149] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab7. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 47 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 48. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 47 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 48.

[0150] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab8. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprisingthe amino acid sequence set forth in SEQ ID NO: 57, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 55 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 56. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 55 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 56.

[0151] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab9. In some embodiments, the antibody or antigenbinding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66 and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 63 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 64. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acidsequence set forth in SEQ ID NO: 63 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 64.

[0152] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab 10. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 75, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 71 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 72. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 71 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 72.

[0153] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab 11. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 79, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 82, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 77 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 78. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 77 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 78.

[0154] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab 12. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 86, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 87, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 84 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 85. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 84 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 85.

[0155] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Abl3. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VL comprising an LCDR1 comprising the aminoacid sequence set forth in SEQ ID NO: 96, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 91 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 91 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 92.

[0156] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab 14. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 101, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 103, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 105, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 106. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 99 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 100. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 99 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 100.

[0157] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Abl5. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 109, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 111, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 107 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 107 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 108.

[0158] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Abl6. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 115, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 119. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 113 and a VL comprising an amino acid sequence at least80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 113 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 114.

[0159] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab 17. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 122, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 123, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 124, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 125, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 127. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 120 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 121. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 120 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 121.

[0160] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab 18. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 130, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 131, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQID NO: 133. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 128 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 129. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 128 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0161] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab 19. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 136, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 137, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 138, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 134 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 135. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 134 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 135.

[0162] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab20. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 143, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 144, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 145, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 140 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 141. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 140 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 141.

[0163] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab21. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 147 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 148. In some embodiments, to TMPRSS4comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 147 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 148.

[0164] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab22. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 155, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 156, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 157, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 158. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 153 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 154. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 153 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 154.

[0165] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab23. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 162, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 163, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 164, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 159 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 160. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 159 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 160.

[0166] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab24. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 168, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 170. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 166 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 166 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 167.

[0167] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab25. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 174, and a VL comprising an LCDR1 comprising the aminoacid sequence set forth in SEQ ID NO: 175, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 176, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 171 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 172. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 171 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 172.

[0168] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab26. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 181, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 183, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 178 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 179. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 178 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 179.

[0169] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab27. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 187, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 188, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 189, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 190. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 185 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 186. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 185 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 186.

[0170] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab28. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 196, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 197, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 198. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 191 and a VL comprising an amino acid sequence at least80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 192. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 191 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 192.

[0171] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab29. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 199 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 200. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 199 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 200.

[0172] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab30. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 207, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 208, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQID NO: 210. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 205 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 206. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 205 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 206.

[0173] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab31. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 214, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 215, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 216, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 217. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 211 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 212. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 211 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 212.

[0174] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab32. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 221, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 222, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 224. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 218 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 219. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 218 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 219.

[0175] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab33. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 225 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 226. In some embodiments, to TMPRSS4comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 225 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 226.

[0176] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab34. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 235, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 236, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 237, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 238, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 239, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 240. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 233 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 234. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 233 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 234.

[0177] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab35. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 243, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 244, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 241 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 242. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 241 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 242.

[0178] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab36. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 251, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 246 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 247. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 246 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 247.

[0179] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab37. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 255, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 256, and a VL comprising an LCDR1 comprising the aminoacid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 257, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 258. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 253 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 254. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 253 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 254.

[0180] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab38. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 261, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 262, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 259 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 260. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 259 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 260.

[0181] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab39. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 271, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 272, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 273. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 266 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 267. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 266 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 267.

[0182] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab40. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 276, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 277, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 274 and a VL comprising an amino acid sequence at least80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 275. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 274 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 275.

[0183] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab41. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 283, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 277, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 284, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 239, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 285. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 281 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 282. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 281 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 282.

[0184] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab42. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 288, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 289, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 290, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 291, and an LCDR3 comprising the amino acid sequence set forth in SEQID NO: 293. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 286 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 287. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 286 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 287.

[0185] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab43. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 296, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 297, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 298, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 294 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 295. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 294 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 295.

[0186] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab44. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1comprising the amino acid sequence set forth in SEQ ID NO: 301, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 302, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 303, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 304. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 299 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 300. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 299 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0187] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab45. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 307, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 308, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 309, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 310, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 311. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 305 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 306. In some embodiments, to TMPRSS4comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 305 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 306.

[0188] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab46. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 314. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 312 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 313. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 312 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 313.

[0189] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab47. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 317, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 318, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 315 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 316. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 315 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 316.

[0190] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab48. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 321, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 322, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 323, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 325, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 319 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 320. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 319 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 320.

[0191] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab49. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 328, and a VL comprising an LCDR1 comprising the aminoacid sequence set forth in SEQ ID NO: 329, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 330, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 331. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 326 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 327. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 326 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 327.

[0192] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab50. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 334, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 335, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 336. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 332 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 333. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 332 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 333.

[0193] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab51. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 338, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 339, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 337 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 316. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 337 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 316.

[0194] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab52. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 342, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 343, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 344, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 345, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 346. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 340 and a VL comprising an amino acid sequence at least80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 341. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 340 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 341.

[0195] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab53. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 349, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 350, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 351, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 352. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 347 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 348. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 347 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 348.

[0196] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab54. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 355, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQID NO: 280. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 353 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 354. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 353 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 354.

[0197] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab55. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 207, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 358, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 359. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 356 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 357. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 356 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 357.

[0198] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab56. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1comprising the amino acid sequence set forth in SEQ ID NO: 362, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 363, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 364, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 365. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 360 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 361. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 360 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 361.

[0199] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab57. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 317, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 368, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 369. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 366 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 367. In some embodiments, to TMPRSS4comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 366 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 367.

[0200] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab58. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 372, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 373, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 374, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 375. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 370 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 371. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 370 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 371.

[0201] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab59. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 378, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 379, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 380, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 175, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 381. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 376 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 377. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 376 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 377.

[0202] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab60. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 384, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 385, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 386, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 387. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 382 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 383. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 382 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 383.

[0203] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab61. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 390, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 163, and a VL comprising an LCDR1 comprising the aminoacid sequence set forth in SEQ ID NO: 75, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 391. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 388 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 389. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 388 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 389.

[0204] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab62. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 394, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 395, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 396, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 397. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 392 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 393. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 392 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 393.

[0205] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab63. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 400, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 401, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 402, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 403. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 398 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 399. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 398 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 399.

[0206] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab64. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 406, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 407, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 408. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 404 and a VL comprising an amino acid sequence at least80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 405. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 404 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 405.

[0207] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab65. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 411, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 412, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 413. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 409 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 410. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 409 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 410.

[0208] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab66. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 416, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 417, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 418, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQID NO: 419. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 414 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 415. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 414 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 415.

[0209] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab67. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 19, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 422, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 423. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 420 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 421. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 420 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 421.

[0210] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab68. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1comprising the amino acid sequence set forth in SEQ ID NO: 426, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 427, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 428, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 429. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 424 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 425. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 424 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 425.

[0211] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab69. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 432, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 433, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 434, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 238, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 435, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 436. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 430 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 431. In some embodiments, to TMPRSS4comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 430 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 431.

[0212] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab70. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 439, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 440, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 441, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 442, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 443, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 444. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 437 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 438. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 437 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 438.

[0213] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab71. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 447, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 448, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 449, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 450, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 451. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 445 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 446. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 445 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 446.

[0214] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab72. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 454, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 455, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 456, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 457, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 452 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 453. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 452 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 453.

[0215] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab73. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 460, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 461, and a VL comprising an LCDR1 comprising the aminoacid sequence set forth in SEQ ID NO: 462, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 463, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 464. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 458 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 459. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 458 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 459.

[0216] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab74. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 467, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 468, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 469, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 470, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 471. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 465 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 466. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 465 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 466.

[0217] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab75. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 474, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 475, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 476, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 477, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 478, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 479. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 472 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 473. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 472 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 473.

[0218] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab76. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 474, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 482, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 483, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 484, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 485. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 480 and a VL comprising an amino acid sequence at least80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 481. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 480 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 481.

[0219] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab77. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 488, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 489, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 490, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 491. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 486 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 487. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 486 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 487.

[0220] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab78. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 494, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 495, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 496, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 497, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQID NO: 498. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 492 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 493. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 492 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 493.

[0221] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 is or is derived from TMPRSS4 Ab79. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 501, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 502, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 503, and a VL comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises a VH comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 499 and a VL comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 500. In some embodiments, to TMPRSS4 comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 499 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 500.

[0222] In various embodiments, the antigen-binding fragment that binds to TMPRSS2 comprises an scFv. In some embodiments, the scFv has the format VH-L-VL or VL-L-VH, wherein L is a linker peptide. In some embodiments, the scFv has the format VH-L-VL, whereinL is a linker peptide. In some embodiments, the linker peptide comprises the amino acid sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 819). In some embodiments, the linker peptide comprises the amino acid sequence of GGGGSGSGGGGSGGGGS (SEQ ID NO: 820). Table 5 provides exemplary amino acid sequences of scFvs that bind to TMPRSS4. The linker peptide linking the VH to the VL is indicated in bold italic text.Table 5: TMPRSS4 scFv Amino Acid Sequences

[0223]

[0224] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 504. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 504.

[0225] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 505. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 505.

[0226] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 506. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 506.

[0227] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 507. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 507.

[0228] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 508. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 508.

[0229] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 509. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 509.

[0230] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 510. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 510.

[0231] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 511. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 511.

[0232] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 512. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 512.

[0233] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 513. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 513.

[0234] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 514. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 514.

[0235] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 515. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 515.

[0236] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 516. In some embodiments, the antibody or antigen-bindingfragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 516.

[0237] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 517. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 517.

[0238] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 518. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 518.

[0239] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 519. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 519.

[0240] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 520. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 520.

[0241] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 521. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 521.

[0242] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 522. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 522.

[0243] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 523. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 523.

[0244] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 524. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 524.

[0245] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 525. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 525.

[0246] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 526. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 526.

[0247] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 527. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 527.

[0248] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 528. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 528.

[0249] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 529. In some embodiments, the antibody or antigen-bindingfragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 529.

[0250] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 530. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 530.

[0251] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 531. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 531.

[0252] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 532. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 532.

[0253] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 533. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 533.

[0254] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 534. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 534.

[0255] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 535. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 535.

[0256] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 536. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 536.

[0257] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 537. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 537.

[0258] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 538. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 538.

[0259] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 539. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 539.

[0260] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 540. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 540.

[0261] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 541. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 541.

[0262] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 542. In some embodiments, the antibody or antigen-bindingfragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 542.

[0263] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 543. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 543.

[0264] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 544. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 544.

[0265] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 545. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 545.

[0266] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 546. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 546.

[0267] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 547. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 547.

[0268] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 548. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 548.

[0269] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 549. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 549.

[0270] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 550. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 550.

[0271] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 551. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 551.

[0272] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 552. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 552.

[0273] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 553. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 553.

[0274] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 554. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 554.

[0275] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 555. In some embodiments, the antibody or antigen-bindingfragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 555.

[0276] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 556. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 556.

[0277] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 557. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 557.

[0278] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 558. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 558.

[0279] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 559. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 559.

[0280] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 560. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 560.

[0281] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 561. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 561.

[0282] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 562. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 562.

[0283] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 563. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 563.

[0284] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 564. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 564.

[0285] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 565. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 565.

[0286] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 566. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 566.

[0287] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 567. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 567.

[0288] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 568. In some embodiments, the antibody or antigen-bindingfragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 568.

[0289] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 569. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 569.

[0290] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 570. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 570.

[0291] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 571. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 571.

[0292] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 572. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 572.

[0293] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 573. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 573.

[0294] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 574. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 574.

[0295] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 575. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 575.

[0296] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 576. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 576.

[0297] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 577. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 577.

[0298] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 578. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 578.

[0299] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 579. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 579.

[0300] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 580. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 580.

[0301] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 581. In some embodiments, the antibody or antigen-bindingfragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 581.

[0302] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 582. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv comprising the amino acid sequence set forth in SEQ ID NO: 582.

[0303] Table 6 provides exemplary nucleic acid sequences encoding VH and VL domains that, in combination, bind to TMPRSS4. In some embodiments, the VH and the VL of the antibody or antigen-binding fragment that binds to TMPRSS4 are each encoded by a sequence set forth in Table 6.Table 6: TMPRSS4 VH and VL Nucleic Acid Sequences

[0304] In some embodiments, the VH of the antibody or antigen-binding fragment that binds to TMPRSS4 is encoded by a nucleic acid comprising a sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 583, 585, 587, 589, 591, 592, 593, 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 635, 637, 639, 641, 643, 645, 647, 649,651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 684, 686,688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724,726, 728, 730, 732, 734, 736, or 738. In some embodiments the VL of the antibody or antigenbinding fragment that binds to TMPRSS4 is encoded by a nucleic acid comprising a sequence atleast 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 584, 586, 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642,644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680,682, 685, 687, 689, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 713, 715, 717, 719,721, 723, 725, 727, 729, 731, 733, 735, 737, 739 or 968. Table 7 provides exemplary nucleic acid sequences encoding scFvs that bind to TMPRSS4. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv encoded by a nucleic acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to a nucleic acid sequence set forth in Table 7.Table 7: TMPRSS4 scFv Nucleotide Sequences

[0305] In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv encoded by a nucleic acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence set forth in any one of SEQ ID NOs: 740-818. In some embodiments, the antibody or antigen-binding fragment that binds to TMPRSS4 comprises an scFv encoded by the nucleic acid sequence set forth in any one of SEQ ID NOs: 740-818Synthetic Immune Receptors

[0306] In some aspects, the present disclosure provides a synthetic immune receptor. In some embodiments, the synthetic immune receptor comprises an extracellular domain comprising a TMPRSS4 antibody or antigen-binding fragment thereof provided herein.Chimeric Antigen Receptors

[0307] In some aspects, the synthetic immune receptor is a chimeric antigen receptor (CAR). The CAR may be a human CAR, comprising fully human sequences, e.g. natural human sequences.

[0308] In some embodiments, the chimeric antigen receptor includes an extracellular portion comprising an antigen binding domain. The antigen recognition domain of a receptor such as a CAR can be linked to one or more intracellular signaling components, such as signaling components that mimic activation through an antigen receptor complex, such as a TCR complex,in the case of a CAR, and / or signal via another cell surface receptor. Thus, in some embodiments, the extracellular binding component (e.g., ligand-binding or antigen-binding domain) is linked to one or more transmembrane and intracellular signaling domains. In some embodiments, the transmembrane domain is fused to the extracellular domain. In one embodiment, a transmembrane domain that naturally is associated with one of the domains in the receptor, e.g., CAR, is used. In some instances, the transmembrane domain is selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins to minimize interactions with other members of the receptor complex.

[0309] In various embodiments, a CAR comprises means for binding a TMPRSS4 protein, optionally binding a human TMPRSS4 protein in the region(s) of human TMPRSS4 bound by the TMPRSS4 antibody or antigen binding fragment (e.g., as described in the Examples below). In some embodiments, the means binds a TMPRSS4 protein. In some embodiments, the means binds a human TMPRSS4 protein. In some embodiments, the means is a TMPRSS4 antibody or antigen-binding fragment or equivalent thereof (e.g., a full length antibody or a F(ab')2 fragment, a Fab fragment, a single chain variable fragment (scFv), and a single domain antibody (sdAb), or a functional fragment thereof) means for binding a TMPRSS4 protein. In some embodiments, the means for binding TMPRSS4 includes the anti-TMPRSS4 antibodies and antigen-binding fragments or equivalents thereof described herein.

[0310] In some aspects, the chimeric antigen receptor includes an extracellular portion comprising an antigen binding domain described herein and an intracellular signaling domain. In some embodiments, the antigen binding domain (e.g., an antibody or antigen binding fragment thereof) is referred to as a “binder.” In some embodiments, the antigen-binding domain is selected from the group consisting of an antibody, a nanobody, a diabody, a triabody, or a minibody, a F(ab')2 fragment, a Fab fragment, a single chain variable fragment (scFv), and a single domain antibody (sdAb), or a functional fragment thereof. In some embodiments, the antigen-binding moiety comprises an scFv. The antigen-binding moiety can include naturally- occurring amino acid sequences or can be engineered, designed, or modified so as to provide desired and / or improved properties, e.g., increased binding affinity. In some embodiments, an antibody or fragment includes an scFv, a VH, or a single-domain VH antibody and the intracellular domain contains an IT AM. In some aspects, the intracellular signaling domainincludes a signaling domain of a zeta chain of a CD3-zeta (CD3) chain. In some embodiments, the chimeric antigen receptor includes a transmembrane domain linking the extracellular domain and the intracellular signaling domain.

[0311] In some aspects, the transmembrane domain contains a transmembrane portion of CD8a or CD28. The extracellular domain and transmembrane can be linked directly or indirectly. In some embodiments, the extracellular domain and transmembrane are linked by a spacer, such as any described herein. In some embodiments, the chimeric antigen receptor contains an intracellular domain of a T cell costimulatory molecule, such as between the transmembrane domain and intracellular signaling domain. In some aspects, the T cell costimulatory molecule is CD28 or 4-1BB.CAR Transmembrane Domain

[0312] The transmembrane domain in some embodiments is derived either from a natural or from a synthetic source. Where the source is natural, the domain in some aspects is derived from any membrane-bound or transmembrane protein. Transmembrane regions include those derived from (z.e. comprise at least the transmembrane region(s) of) the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CDS, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD 134, CD 137, and / or CD 154. Alternatively the transmembrane domain in some embodiments is synthetic. In some aspects, the synthetic transmembrane domain comprises predominantly hydrophobic residues such as leucine and valine. In some aspects, a triplet of phenylalanine, tryptophan and valine will be found at each end of a synthetic transmembrane domain. In some embodiments, the linkage is by linkers, spacers, and / or transmembrane domain(s).

[0313] In some embodiments, the transmembrane domain of the receptor, e.g., the CAR, is a transmembrane domain of human CD28 or variant thereof, e.g., a 27-amino acid transmembrane domain of a human CD28 (Accession No.: Pl 0747.1).

[0314] In some embodiments, the CAR comprises a CD8a transmembrane domain. In some embodiments, the CD8a transmembrane domain comprises the sequence set forth in SEQ ID NO: 822.CAR Hinge

[0315] In some embodiments, the CAR further includes a spacer, which may be or include at least a portion of an immunoglobulin constant region or variant or modified version thereof, suchas a hinge region, e.g., a CD8a hinge, an IgG4 hinge region, and / or a CH1 / CL and / or Fc region. In some embodiments, the constant region or portion is of a human IgG, such as IgG4 or IgGl. In some aspects, the portion of the constant region serves as a spacer region between the antigenrecognition component, e.g., scFv, and transmembrane domain. The spacer can be of a length that provides for increased responsiveness of the cell following antigen binding, as compared to in the absence of the spacer. In some examples, the spacer is at or about 12 amino acids in length or is no more than 12 amino acids in length. Exemplary spacers include those having at least about 10 to 229 amino acids, about 10 to 200 amino acids, about 10 to 175 amino acids, about 10 to 150 amino acids, about 10 to 125 amino acids, about 10 to 100 amino acids, about 10 to 75 amino acids, about 10 to 50 amino acids, about 10 to 40 amino acids, about 10 to 30 amino acids, about 10 to 20 amino acids, or about 10 to 15 amino acids, and including any integer between the endpoints of any of the listed ranges. In some embodiments, a spacer region has about 12 amino acids or less, about 119 amino acids or less, or about 229 amino acids or less. Exemplary spacers include CD8a hinge, IgG4 hinge alone, IgG4 hinge linked to CH2 and CH3 domains, or IgG4 hinge linked to the CH3 domain. Exemplary spacers include, but are not limited to, those described in Hudecek et al. (2013) Clin. Cancer Res., 19:3153 or international patent application publication number WO2014031687. In some embodiments, the CAR hinge comprises a CD8a hinge. In some embodiments, the CD8a hinge comprises the sequence set forth in SEQ ID NO: 821.

[0316] Among the intracellular signaling domains are those that mimic or approximate a signal through a natural antigen receptor, a signal through such a receptor in combination with a costimulatory receptor, and / or a signal through a costimulatory receptor alone. In some embodiments, a short oligo- or polypeptide linker, for example, a linker of between 2 and 10 amino acids in length, such as one containing glycines and serines, e.g., glycine-serine doublet, is present and forms a linkage between the transmembrane domain and the cytoplasmic signaling domain of the receptor.CAR Intracellular Domain

[0317] In some embodiments, upon ligation of the CAR, the cytoplasmic domain or intracellular signaling domain of the receptor activates at least one of the normal effector functions or responses of the immune cell, e.g., T cell engineered to express the receptor. In some embodiments, the CAR comprises means for activating at least one of the normal effectorfunctions or responses of the immune cell, e.g., T cell engineered to express the receptor. For example, in some contexts, the receptor induces a function of a T cell such as cytolytic activity or T-helper activity, such as secretion of cytokines or other factors. In some embodiments, a truncated portion of an intracellular signaling domain of an antigen receptor component or costimulatory molecule is used in place of an intact immunostimulatory chain, for example, if it transduces the effector function signal. In some embodiments, the intracellular signaling domain or domains include the cytoplasmic sequences of the T cell receptor (TCR), and in some aspects also those of co-receptors that in the natural context act in concert with such receptor to initiate signal transduction following antigen receptor engagement, and / or any derivative or variant of such molecules, and / or any synthetic sequence that has the same functional capability. In some embodiments, the means for at least one of the normal effector functions or responses of the immune cell comprises an CAR intracellular activation domain, e.g., an intracellular activation domain provided herein or an equivalent thereof. In some embodiments, the means for at least one of the normal effector functions or responses of the immune cell comprises an CAR intracellular activation domain and a CAR co-stimulatory domain, e.g., a co-stimulatory domain provided herein or an equivalent thereof.

[0318] In some aspects, the receptor includes a primary cytoplasmic signaling sequence that regulates primary activation of the TCR complex. Primary cytoplasmic signaling sequences that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or IT AMs. Examples of IT AM containing primary cytoplasmic signaling sequences include those derived from TCR or CD3 zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CDS, CD22, CD79a, CD79b, and CD66d. In some embodiments, cytoplasmic signaling molecule(s) in the CAR contain(s) a cytoplasmic signaling domain, portion thereof, or sequence derived from CD3 zeta.

[0319] In some embodiments, the intracellular signaling domain comprises a human CD3 zeta stimulatory signaling domain or functional variant thereof, such as a 112 AA cytoplasmic domain of isoform 3 of human CD3.zeta. (Accession No.: P20963.2) or a CD3 zeta signaling domain as described in U.S. Pat. No. 7,446,190 or U.S. Pat. No. 8,911,993.

[0320] The receptor, e.g., the CAR, can include at least one intracellular signaling component or components. In some embodiments, the receptor includes an intracellular component of a TCR complex, such as a TCR CD3 chain that mediates T-cell activation and cytotoxicity, e.g.,CD3 zeta chain. Thus, in some aspects, the extracellular domain is linked to one or more cell signaling modules. In some embodiments, cell signaling modules include CD3 transmembrane domain, CD3 intracellular signaling domains, and / or other CD transmembrane domains. In some embodiments, the receptor, e.g., CAR, further includes a portion of one or more additional molecules such as Fc receptor-gamma, CD8, CD4, CD25, or CD16. For example, in some aspects, the CAR includes a chimeric molecule between CD3-zeta or Fc receptor-gamma and CD8, CD4, CD25 or CD16. In some embodiments, the CAR comprises a CD3^ activation domain comprising the sequence set forth in SEQ ID NO: 824.

[0321] In some embodiments, the intracellular domain comprises an intracellular costimulatory signaling domain of 4- IBB or functional variant or portion thereof, such as a 42-amino acid cytoplasmic domain of a human 4-1BB (Accession No. Q07011.1) or functional variant or portion thereof.

[0322] In some embodiments, the receptor encompasses one or more, e.g., two or more, costimulatory domains and an activation domain, e.g., primary activation domain, in the cytoplasmic portion. Exemplary receptors include intracellular components of CD3-zeta, CD28, and 4- IBB. In some embodiments, the chimeric antigen receptor contains an intracellular domain of a T cell costimulatory molecule. In some aspects, the T cell costimulatory molecule is 4- IBB.

[0323] In some embodiments, the receptor includes a signaling domain and / or transmembrane portion of a costimulatory receptor, such as CD28, 4-1BB, 0X40, DAP10, and ICOS. In some aspects, the same receptor includes both the activating and costimulatory components.

[0324] In certain embodiments, the intracellular signaling domain comprises a CD 8 a transmembrane and signaling domain linked to a CD3 (e.g., CD3-zeta) intracellular domain. In some embodiments, the intracellular signaling domain comprises a 4- IBB (CD 137, TNFRSF9) co-stimulatory domains, linked to a CD3 zeta intracellular domain. In some embodiments, the CAR comprises a 4-1BB co-stimulatory domain. In some embodiments, the 4-1BB costimulatory domain comprises the sequence as set forth in SEQ ID NO: 823.

[0325] In some embodiments, the CAR or other antigen receptor further includes a marker, such as a cell surface marker, which may be used to confirm transduction or engineering of the cell to express the receptor, such as a truncated version of a cell surface receptor, such as truncated EGFR (tEGFR). In some aspects, the marker includes all or part (e.g., truncated form) of CD34, a nerve growth factor receptor (NGFR), or epidermal growth factor receptor (e.g.,tEGFR). In some embodiments, the nucleic acid encoding the marker is operably linked to a polynucleotide encoding for a linker sequence, such as a cleavable linker sequence or a rib...

Claims

WHAT IS CLAIMED IS:

1. An antibody or antigen-binding fragment thereof that binds to Transmembrane protease, serine 4 (TMPRSS4) (SEQ ID NO: 960), wherein the antibody or antigen binding fragment comprises heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2), and a heavy chain complementarity determining region 3 (HCDR3), and a light chain variable domain (VL) comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region (LCDR3), wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are each from a clone listed in Table 4.

2. An antibody or antigen-binding fragment thereof that binds to TMPRSS4, wherein the antibody or antigen binding fragment comprises a VH and a VL, wherein:(a) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8;(b) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16;(c) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 19, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 20, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 21, and the VL comprises an LCDR1 comprising the amino acid sequenceset forth in SEQ ID NO: 22, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23;(d) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31;(e) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39;(f) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46;(g) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 54;(h) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 62;(i) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; j) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 75, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76;(k) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 79, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 82, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83;(l) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 86, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 87, and an HCDR3 comprising the amino acid sequence set forth in SEQID NO: 88, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70;(m) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98;(n) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 101, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 103, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 105, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 106;(o) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 109, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 111, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112;(p) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 115, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117, an LCDR2 comprising the amino acidsequence set forth in SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 119;(q) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 122, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 123, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 124, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 125, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 127;(r) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 130, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 131, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 132, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133;(s) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 136, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 137, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 138, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70;(t) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 143, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 144, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 145, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146;(u) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152;(v) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 155, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 156, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 157, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 158;(w) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 162, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 163, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 164, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165;(x) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 168, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 170;(y) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth inSEQ ID NO: 174, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 175, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 176, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177;(z) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 181, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 183, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184;(aa) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 187, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 188, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 189, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 190;(bb) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 196, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 197, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 198;(cc) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acidsequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204;(dd) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 207, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 208, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210;(ee) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 214, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 215, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 216, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 217;(ff) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 221, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 222, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 224;(gg) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232;(hh) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 235, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 236, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 237, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 238, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 239 and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 240;(ii) the VH comprises an HCDR1 comprising the amino acid sequence set forth inSEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 243, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 244, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245; jj) the VH comprises an HCDR1 comprising the amino acid sequence set forth inSEQ ID NO: 248, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 251, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252;(kk) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 255, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 256, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 257, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 258;(11) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 261, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and an HCDR3 comprising the amino acid sequence set forth inSEQ ID NO: 262, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265;(mm) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 271 an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 272, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 273;(nn) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 276, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 277, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280;(oo) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 283, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 277, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 284, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 239, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 285;(pp) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 288, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 289, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 290, an LCDR2 comprising the amino acidsequence set forth in SEQ ID NO: 291, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 293;(qq) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 296, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 297, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 298, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152;(rr) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 301, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 302, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 303, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 304;(ss) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 307, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 308, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 309, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 310, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 311;(tt) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 314;(uu) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 317, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 318, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252;(vv) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 321, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 322, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 323, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 325, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16;(ww) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 328, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 329, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 330, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 331;(xx) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 334, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 335, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 336;(yy) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 338, and an HCDR3 comprising the amino acid sequence set forth in SEQID NO: 339, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252;(zz) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 342, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 343, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 344, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 345, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 346;(aaa) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 349, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 350, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 351, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 352;(bbb) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 355, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280;(ccc) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 207, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 358, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acidsequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 359;(ddd) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 362, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 363, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 364, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 365;(eee) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 317, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 368, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 369;(fff) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 372, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 373, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 374, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 375;(ggg) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 378, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 379, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 380, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 175, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 381;(hhh) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 384, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 385, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 386, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 387;(iii) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 390, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 163, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 75, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 391;(jjj) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 394, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 395, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 396, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 397;(kkk) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 400, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 401, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 402, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 403;(111) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 406, and an HCDR3 comprising the amino acid sequence set forth inSEQ ID NO: 407, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 408;(mmm)the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 411, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 412, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 413;(nnn) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 416, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 417, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 418, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 419;(ooo) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 19, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 422, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 423;(ppp) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 426, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 427, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 428, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139, an LCDR2 comprising the amino acidsequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 429;(qqq) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 432, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 433, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 434, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 238, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 435, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 436;(rrr) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 439, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 440, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 441, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 442, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 443, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 444;(sss) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 447, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 448, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 449, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 450, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 451;(ttt) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 454, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 455, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 456, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 457, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112;(uuu) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 460, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 461, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 462, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 463, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 464;(vvv) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 467, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 468, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 469, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 470, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 471;(www) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 474, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 475, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 476, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 477, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 478, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 479;(xxx) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 474, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 482, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 483, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 484, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 485;(yyy) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 488, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 489, and an HCDR3 comprising the amino acid sequence set forth inSEQ ID NO: 490, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 491;(zzz) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 494, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 495, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 496, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 497, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 498; or(aaaa) the VH comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 501, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 502, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 503, and the VL comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 252.

3. The antibody or antigen binding fragment of claim 1, wherein the VH comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 1, 9, 17, 24, 32, 40, 47, 55, 63, 71, 77, 84, 91, 99, 107, 113, 120, 128, 134, 140, 147, 153, 159, 166, 171, 178, 185, 191, 199, 205, 211, 218, 225, 233, 241, 246, 253, 259, 266, 274, 281,286, 294, 299, 305, 312, 315, 319, 326, 332, 337, 340, 347, 353, 356, 360, 366, 370, 376,382, 388, 392, 398, 404, 409, 414, 420, 424, 430, 437, 445, 452, 458, 465, 472, 480, 486,492, and 499.

4. The antibody or antigen binding fragment of claim 1 or 3, wherein the VL comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 2, 10, 18,25, 33, 41, 48, 56, 64, 72, 78, 85, 92, 100, 108, 114, 121, 129, 135, 141, 148, 154, 160,167, 172, 179, 186, 192, 200, 206, 212, 219, 226, 234, 242, 247, 254, 260, 267, 275, 282,287, 295, 300, 306, 313, 316, 320, 327, 333, 341, 348, 354, 357, 361, 367, 371, 377, 383,389, 393, 399, 405, 410, 415, 421, 425, 431, 438, 446, 453, 459, 466, 473, 481, 487, 493, and 500.

5. The antibody or antigen binding fragment thereof of any one of claims 1-4, wherein theVH comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 1, 9, 17, 24, 32, 40, 47, 55, 63, 71, 77, 84, 91, 99, 107, 113, 120, 128, 134, 140, 147, 153, 159, 166, 171, 178, 185, 191, 199, 205, 211, 218, 225, 233, 241, 246, 253, 259,266, 274, 281, 286, 294, 299, 305, 312, 315, 319, 326, 332, 337, 340, 347, 353, 356, 360,366, 370, 376, 382, 388, 392, 398, 404, 409, 414, 420, 424, 430, 437, 445, 452, 458, 465,472, 480, 486, 492, and 499, and the VL comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to the sequence set forth in SEQ ID NO: 2, 10, 18, 25, 33, 41, 48, 56, 64, 72, 78, 85, 92, 100, 108, 114, 121, 129, 135, 141, 148, 154, 160, 167, 172, 179, 186, 192, 200, 206, 212, 219, 226, 234, 242, 247, 254, 260, 267, 275, 282, 287, 295, 300, 306, 313, 316,320, 327, 333, 341, 348, 354, 357, 361, 367, 371, 377, 383, 389, 393, 399, 405, 410, 415,421, 425, 431, 438, 446, 453, 459, 466, 473, 481, 487, 493, and 500.

6. The antibody or antigen-binding fragment of any one of claims 1-5, wherein the antibody or antigen-binding fragment is selected from the group consisting of an antibody, a single chain variable fragment (scFv), an Fab fragment, a Fab' fragment, a single-chain Fab fragment (scFab), an F(ab')2 fragment, and an F(ab)v fragment.

7. The antibody or antigen binding fragment of any one of claims 1-6, wherein the antigenbinding fragment is an scFv.

8. The antibody or antigen-binding fragment of claim 7, wherein the scFv comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, at least 99.5% or 100% identical to the sequence set forth in any one of SEQ ID NOs: 504-582.

9. The antibody or antigen-binding fragment of any one of claims 1-8, wherein the antibody is an IgGl, an IgG2, an IgG3, an IgG4, and IgA, an IgD, an IgE, or an IgM antibody.

10. The antibody or antigen-binding fragment of claim 9, wherein the antibody is an IgG2 antibody.

11. The antibody or antigen-binding fragment of any one of claims 1-10, wherein the antibody or antigen-binding fragment binds to TMPRSS4 expressed on the surface of a cell.

12. An antibody or antigen-binding fragment thereof that competes with the antibody or antigen-binding fragment of any one of claims 1-11 for binding to TMPRSS4.

13. A synthetic immune receptor comprising an extracellular antigen binding domain comprising the antibody or antigen-binding fragment of any one of claims 1-12.

14. The synthetic immune receptor of claim 13, wherein the synthetic immune receptor is a chimeric antigen receptor (CAR) further comprising:(a) a transmembrane domain;(b) an intracellular co-stimulatory domain; and(c) an intracellular activation domain.

15. The synthetic immune receptor of claim 14, wherein the transmembrane domain is a transmembrane domain of CD 8 a.

16. The synthetic immune receptor of claim 14 or 15, wherein the intracellular co-stimulatory domain is a co-stimulatory domain of 4- IBB.

17. The synthetic immune receptor of any one of claims 14-16, wherein the intracellular activation domain is an activation domain of CD3^.

18. The synthetic immune receptor of any one of claims 14-17, wherein the CAR further comprises a hinge domain between the extracellular antigen binding domain and the transmembrane domain.

19. The synthetic immune receptor of claim 18, wherein the hinge domain is a CD8a hinge domain.

20. A system comprising:(a) the synthetic immune receptor of any one of claims 13-19; and(b) a priming receptor.

21. A system comprising :(a) a first chimeric polypeptide comprising a priming receptor, and(b) a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising an antigen-binding domain that specifically binds to TMPRSS4, wherein the antigen-binding domain comprises a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, HCDR1, HCDR2, and HCDR3 of the VH sequences set forth in SEQ ID NOs: 315 or 319, and a second variable light (VL) chain sequence comprising three light chain CDR sequences, LCDR1, LCDR2, and LCDR3, of the VL sequence set forth in SEQ ID NOs: 316 or 320, optionally wherein:(i) HCDR1 comprises the sequence set forth in SEQ ID NO: 317, HCDR2 comprises the sequence set forth in SEQ ID NO: 194, HCDR3 comprises the sequence set forth in SEQ ID NO: 318, LCDR1 comprises the sequence set forth in SEQ ID NO: 278, LCDR2 comprises the sequence set forth in SEQ ID NO: 15, and LCDR3 comprises the sequence set forth in SEQ ID NO: 252; or(ii) HCDR1 comprises the sequence set forth in SEQ ID NO: 321, HCDR2 comprises the sequence set forth in SEQ ID NO: 322, HCDR3 comprises the sequence set forth in SEQ ID NO: 323, LCDR1 comprises the sequence set forth in SEQ ID NO: 324, LCDR2 comprises the sequence set forth in SEQ ID NO: 325, and LCDR3 comprises the sequence set forth in SEQ ID NO: 16.

22. The system of claim 21, wherein the VH comprises the sequence set forth in SEQ ID NO: 315 or 319.

23. The system of claim 21 or 22, wherein the VL comprises the sequence set forth in SEQ ID NO: 316 or 320.

24. The system of any one of claims 21-23, wherein the antigen-binding domain comprises the sequence set forth in SEQ ID NO: 550 or 551.

25. The system of any one of claims 21 to 24, wherein the CAR comprises, from N-terminus to C-terminus,(a) the antigen-binding domain that specifically binds to TMPRSS4;(b) a transmembrane domain;(c) an intracellular co-stimulatory domain; and(d) an intracellular activation domain.

26. The system of any one of claims 21-25, wherein the CAR comprises a hinge domain.

27. The system of claim 26, wherein the hinge domain of the CAR comprises a CD8a or truncated CD8a hinge domain.

28. The system of claim 27, wherein the hinge domain of the CAR comprises a sequence as set forth in SEQ ID NO: 821.

29. The system of any one of claims 25-27, wherein the transmembrane domain of the CAR comprises a CD8a transmembrane domain.

30. The system of claim 29, wherein the transmembrane domain of the CAR comprises a sequence as set forth in SEQ ID NO: 822.

31. The system of any one of claims 25-29, wherein the intracellular co-stimulatory domain comprises a 4- IBB domain.

32. The system of claim 31, wherein the intracellular co-stimulatory domain comprises a sequence as set forth in SEQ ID NO: 823.

33. The system of any one of claims 25-32, wherein the intracellular activation domain comprises a CD3^ domain.

34. The system of claim 33, wherein the intracellular activation domain comprises a sequence as set forth in SEQ ID NO: 824.

35. The system of any one of claims 20-34, wherein the priming receptor comprises, from N- terminus to C-terminus:(a) a second extracellular antigen-binding domain;(b) a second transmembrane domain comprising one or more ligand-inducible proteolytic cleavage sites; and(c) an intracellular domain comprising a human or humanized transcriptional effector.

36. One or more recombinant nucleic acids encoding:(a) the antibody or antigen-binding fragment of any one of claims 1-12;(b) the synthetic immune receptor of any one of claims 13-19; and / or(c) the system of any one of claims 20-35.

37. An expression vector comprising a recombinant nucleic acid of claim 36.

38. A host cell comprising the antibody or antigen-binding fragment of any one of claims 1-12, the one or more recombinant nucleic acids of claim 36; and / or the expression vector of claim 37.

39. An immune cell comprising:(a) the antibody or antigen-binding fragment of any one of claims 1-12;(b) the synthetic immune receptor of any one of claims 13-19;(c) the system of any one of claims 20-35;(d) the one or more recombinant nucleic acids of claim 36; and / or(e) the expression vector of claim 37.

40. A primary immune cell comprising at least one recombinant nucleic acid comprising:(a) a nucleic acid sequence encoding the synthetic immune receptor of any one of claims 13-19; and(b) a nucleic acid sequence encoding a priming receptor comprising a second extracellular antigen-binding domain, wherein the recombinant nucleic acid is inserted into a target region of the genome of the primary immune cell, wherein the primary immune cell does not comprise a viral vector for introducing the recombinant nucleic acid into the primary immune cell.

41. A viable, virus-free, primary cell comprising a ribonucleoprotein complex (RNP) and a DNA template, wherein the RNP comprises a nuclease domain and a guide RNA, and wherein the DNA template comprises:(a) a nucleic acid sequence encoding the synthetic immune receptor of any one of claims 13-19; and(b) a nucleic acid sequence encoding a priming receptor comprising a first extracellular antigen-binding domain, wherein the 5’ and 3’ ends of the DNA template comprise nucleotide sequences that are homologous to genomic sequences flanking an insertion site in the genome of the primary cell.

42. A population of cells comprising a plurality of immune cells of claim 39 or primary cells of claim 40 or 41.

43. A pharmaceutical composition comprising the immune cells of claim 39 or primary cells of claim 40 or 41, or the population of cells of claim 42, and a pharmaceutically acceptable excipient.

44. A pharmaceutical composition comprising the one or more recombinant nucleic acids of claim 36 or the vector of claim 37, and a pharmaceutically acceptable excipient.

45. A method of editing an immune cell, comprising introducing into the cell the one or more recombinant nucleic acids of claim 36.

46. The method of claim 45, wherein the one or more recombinant nucleic acids are introduced non-virally.

47. The method of claim 45 or 46, the method comprising:(a) providing a ribonucleoprotein (RNP) and a DNA template, wherein the RNP comprises a nuclease domain and a guide RNA, wherein the DNA template comprises the one or more recombinant nucleic acids, and wherein the 5’ and 3’ ends of the DNA template comprise nucleotide sequences that are homologous to genomic sequences flanking an insertion site in the genome of the immune cell;(b) non-virally introducing the RNP and DNA template into the immune cell, wherein the guide RNA specifically hybridizes to a target region of the genome of the primary immune cell, and wherein the nuclease domain cleaves the target region to create the insertion site in the genome of the immune cell; and(c) editing the immune cell via insertion of the one or more recombinant nucleic acids into the insertion site in the genome of the immune cell.

48. A method of treating a disease in a subject comprising administering the immune cells of claim 39 or primary cells of claim 40 or 41 , the population of cells of claim 42, or the pharmaceutical composition of claim 43 or 44 to the subject.

49. The method of claim 48, wherein the disease is a cancer.

50. The method of claim 49, wherein the cancer is non-small cell lung cancer (NSCLC).

51. A method of inhibiting a target cell in a subject comprising administering the immune cells of claim 39 or primary cells of claim 40 or 41, the population of cells of claim 42, or the pharmaceutical composition of claim 43 or 44 to the subject, wherein the immune cell inhibits the target cell.

52. A method of modulating the activity of an immune cell comprising:(a) obtaining an immune cell comprising:(i) the synthetic immune receptor of any one of claims 13-19;(ii) the system of any one of claims 20-35;(iii) the one or more recombinant nucleic acids of claim 36; and / or(iv) the expression vector of claim 37; and(b) contacting the immune cell with a target cell expressing TMPRSS4, wherein binding of the synthetic immune receptor to TMPRSS4 on the target cell modulates the activity of the immune cell.

53. The method of claim 52, wherein the immune cell comprises a priming receptor that binds a priming receptor antigen expressed on the target cell, and wherein binding of the priming receptor to the priming receptor antigen on the target cell induces activation of the priming receptor and thereby induces expression of the synthetic immune receptor.

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