Systems targeting SLC34a2 and tmprss4 and methods of use thereof

Abstract

Provided herein are polypeptides, nucleic acids, and cells comprising antigen-binding domains that specifically bind to Solute Carrier Family 34 Member 2 (SLC34A2) or Transmembrane protease, serine 4 (TMPRSS4), and methods of use thereof. Also provided are polypeptides, systems, nucleic acids, and cells comprising priming receptors comprising an antigen-binding domain that specifically binds Solute Carrier Family 34 Member 2 (SLC34A2) and chimeric antigen receptors (CAR) comprising an antigen-binding domain that specifically binds to Transmembrane protease, serine 4 (TMPRSS4).

Description

SYSTEMS TARGETING SLC34A2 AND TMPRSS4 AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 567,860, filed March 20, 2024, and U.S. Provisional Application No. 63 / 771,558, filed March 13, 2025, both 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 13, 2025, is named ANB-501WO_SL.xml, and is 1,393,781 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.

[0004] Cancer is a disease characterized by uncontrollable growth of cells. Many approaches to treating cancer have been tried, including drugs and radiation therapies. Recent cancer treatments have sought to use the body’s own immune cells to attack cancer cells. One promising approach uses T cells that are taken from a patient and genetically engineered to produce chimeric antigen receptors, or CARs, receptor proteins that give the T cells a new ability to target a specific protein. The receptors are chimeric because they combine antigen-binding and T-cell activating functions into a single receptor. Immunotherapy using CAR-T cells is promising because the modified T cells have the potential to recognize cancer cells in order to more effectively target and destroy them.

[0005] However, there remain some concerns and limitations to CAR T cell-based immunotherapy. Some CAR T cells may engage with normal cells expressing low levels of target antigens, leading to leading to on-target, off tumor toxicity. Thus, additional therapies that reduce off-tumor toxicity remain desirable.SUMMARY

[0006] In one aspect, provided herein are systems comprising: a. a first chimeric polypeptide comprising a priming receptor comprising a first antigen-binding domain that specifically binds Solute Carrier Family 34 Member 2 (SLC34A2) (SEQ ID NO: 962); and b. a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising a second antigen-binding domain that specifically binds to Transmembrane protease, serine 4 (TMPRSS4) (SEQ ID NO: 960).

[0007] In some embodiments, the first antigen-binding domain comprises a first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 1001, 1009, or 1015, and a first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR- L2, and CDR-L3, of the VL sequences set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1002, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1003, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1004, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1008; or b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014; orc. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1016, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1017, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1018, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1020, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1021, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1022.

[0008] In some embodiments, the first VH chain sequence comprises the sequence set forth in SEQ ID NO: 1001, 1009, or 1015.

[0009] In some embodiments, the first VL chain sequence comprises the sequence set forth in SEQ ID NO: 1005, 1013, 1125, or 1019.

[0010] In some embodiments, wherein the first antigen-binding domain comprises the sequence set forth in SEQ ID NO: 1107, 1108, or 1109.

[0011] In some embodiments, the second antigen-binding domain comprises a second variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 319 or 326, and a second variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NOs: 320 or 327, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; and b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR-L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331.

[0012] In some embodiments, the second VH comprises the sequence as set forth in SEQ ID NOs: 319 or 326.

[0013] In some embodiments, the second VL comprises the sequence set forth in SEQ ID NOs: 320 or 327.

[0014] In some embodiments, the second antigen binding domain comprises the sequence set forth in SEQ ID NO: 551 or 552.

[0015] In some embodiments, a. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1009, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1013 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 326, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 327; b. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1001, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1005 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 326, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 327; c. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, andCDR-H3, of the VH sequence set forth in SEQ ID NO: 1009, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1013 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 319, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 320; d. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1015, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1019 or 1125 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 319, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 320; or e. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1009, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1013 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 326, and the first variablelight (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 327.

[0016] In some embodiments, a. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR- L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331; b. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1002, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1003, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1004, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1008 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR- L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331; c. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ IDNO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; d. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1016, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1017, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1018, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1020, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1021, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1022 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; or e. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR- L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331.

[0017] In some embodiments, at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of: a. a nucleic acid encoding human Fas Cell Surface Death Receptor (FAS) comprising the sequence set forth in SEQ ID NO: 964; and / or b. a nucleic encoding human Transforming Growth factor (TGF)-P Receptor 2 (TGFBR2) comprising the sequence set forth in SEQ ID NO: 965; and / or c. a nucleic acid encoding Phosphatase Non-Receptor Type 2 (PTPN2) comprising the sequence set forth in SEQ ID NO: 966.

[0018] In some embodiments, the at least one or more nucleic acids comprises a nucleic acid comprising the sequence as set forth in SEQ ID NO: 967.

[0019] In some embodiments, the at least one or more nucleic acids comprises a nucleic acid comprising the sequence as set forth in SEQ ID NOs: 969 and / or 970.

[0020] In some embodiments, the at least one or more nucleic acids comprises a nucleic acid comprising the sequence as set forth in SEQ ID NO: 968.

[0021] In some embodiments, the at least one or more nucleic acids comprises a first nucleic acid comprising the sequence as set forth in SEQ ID NO: 967, a second nucleic acid comprising the sequence as set forth in SEQ ID NOs: 969 and / or 970, and a third nucleic acid comprising the sequence as set forth in SEQ ID NO: 968.

[0022] In some embodiments, the at least one or more nucleic acids comprises a first nucleic acid comprising the sequence as set forth in SEQ ID NO: 967, a second nucleic acid comprising the sequence as set forth in SEQ ID NO: 969, and a third nucleic acid comprising the sequence as set forth in SEQ ID NO: 970, and a fourth nucleic acid comprising the sequence as set forth in SEQ ID NO: 968.

[0023] In some embodiments,a. the nucleic acid is capable of reducing expression of FAS in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid; b. the nucleic acid is capable of reducing expression of TGFBR2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid; and / or c. the nucleic acid is capable of reducing expression of PTPN2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

[0024] In one aspect, provided herein are systems comprising: a. a first chimeric polypeptide comprising a priming receptor comprising a first antigen-binding domain that specifically binds Solute Carrier Family 34 Member 2 (SLC34A2) (SEQ ID NO: 962); b. a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising a second antigen-binding domain that specifically binds to Transmembrane protease, serine 4 (TMPRSS4) (SEQ ID NO: 960); and c. at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of: i. a nucleic acid encoding human Fas Cell Surface Death Receptor (FAS) comprising the sequence set forth in SEQ ID NO: 964; and / or ii. a nucleic acid encoding human Transforming Growth factor (TGF)-P Receptor 2 (TGFBR2) comprising the sequence set forth in SEQ ID NO: 965; and / or iii. a nucleic acid encoding Phosphatase Non-Receptor Type 2 (PTPN2) comprising the sequence set forth in SEQ ID NO: 966.

[0025] In some embodiments, the first antigen-binding domain comprises a first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 1001, 1009, or 1015, and a first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR- L2, and CDR-L3, of the VL sequences set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1002, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1003, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1004, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1008; or b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014; or c. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1016, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1017, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1018, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1020, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1021, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1022.

[0026] In some embodiments, the first VH chain sequence comprises the sequence set forth in SEQ ID NOs: 1001, 1009, or 1015.

[0027] In some embodiments, the first VL chain sequence comprises the sequence set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019.

[0028] In some embodiments, the first antigen-binding domain comprises the sequence set forth in SEQ ID NOs: 1107, 1108, or 1109.

[0029] In some embodiments, the second antigen-binding domain comprises a second variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2,and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 319 or 326, and a second variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NOs: 320 or 327, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; and b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR-L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331.

[0030] In some embodiments, the second VH comprises the sequence as set forth in SEQ ID NOs: 319 or 326.

[0031] In some embodiments, the second VL comprises the sequence set forth in SEQ ID NOs: 320 or 327.

[0032] In some embodiments, the second antigen binding domain comprises the sequence set forth in SEQ ID NOs: 551 or 552.

[0033] In some embodiments, the priming receptor comprises, from N-terminus to C-terminus, a. the first antigen-binding domain; b. a first transmembrane domain comprising one or more ligand-inducible proteolytic cleavage sites; and c. an intracellular domain comprising a human or humanized transcriptional effector, wherein binding of the first antigen-binding domain to human SCL34A2 results in cleavage at the one or more ligand-inducible proteolytic cleavage sites.

[0034] In some embodiments, the priming receptor comprises a first hinge domain positioned between the first antigen-binding domain and the first transmembrane domain.

[0035] In some embodiments, the first hinge domain comprises a CD8a or truncated CD8a hinge domain.

[0036] In some embodiments, the first hinge comprises the sequence as set forth in SEQ ID NO: 827.

[0037] In some embodiments, the first transmembrane domain comprises a Notch 1 transmembrane domain.

[0038] In some embodiments, the transmembrane domain comprises the sequence as set forth in SEQ ID NO: 828.

[0039] In some embodiments, the intracellular domain comprises an HNFla / p65 domain or a Gal4 / VP64 domain.

[0040] In some embodiments, the intracellular domain comprises the sequence as set forth in SEQ ID NO: 830, 831, or 832.

[0041] In some embodiments, the priming receptor comprises a stop-transfer-sequence or juxtamembrane domain between the first transmembrane domain and the intracellular domain.

[0042] In some embodiments, the stop-transfer-sequence or juxtamembrane domain comprises the sequence as set forth in SEQ ID NO: 829.

[0043] In some embodiments, the priming receptor comprises a sequence as set forth in SEQ ID NO: 1158, 1160, or 1162.

[0044] In some embodiments, the CAR comprises, from N-terminus to C-terminus, a. a second antigen-binding domain; b. a second transmembrane domain; c. an intracellular co-stimulatory domain; and d. an intracellular activation domain.

[0045] In some embodiments, the CAR comprises a second hinge domain.

[0046] In some embodiments, the second hinge domain comprises a CD8a or truncated CD8a hinge domain.

[0047] In some embodiments, the second hinge domain comprises a sequence as set forth in SEQ ID NO: 821.

[0048] In some embodiments, the second transmembrane domain comprises a CD8a transmembrane domain.

[0049] In some embodiments, the second transmembrane domain comprises a sequence as set forth in SEQ ID NO: 822.

[0050] In some embodiments, the intracellular co-stimulatory domain comprises a 4- IBB domain.

[0051] In some embodiments, the intracellular co-stimulatory domain comprises a sequence as set forth in SEQ ID NO: 823.

[0052] In some embodiments, the intracellular activation domain comprises a CD3^ domain.

[0053] In some embodiments, the intracellular activation domain comprises a sequence as set forth in SEQ ID NO: 824.

[0054] In some embodiments, the CAR comprises a sequence as set forth in SEQ ID NOs: 1164 or 1166.

[0055] In some embodiments, the priming receptor and the CAR are capable of binding to a same target cell if the target cell expresses SLC34A2 and TMPRSS4.

[0056] In some embodiments, the at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary a portion thereof of human FAS, human TGFBR2 and / or human PTPN2 are at least 16, 17, 18, 19, 20, 21, or 22 nucleotides in length.

[0057] In some embodiments, the at least one or more nucleic acid sequences are a short hairpin RNA (shRNA), a small interfering RNA (siRNA), a double stranded RNA (dsRNA), or an antisense oligonucleotide.

[0058] In some embodiments, the at least one or more nucleic acid sequences are shRNA.

[0059] In some embodiments, the at least one or more nucleic acids comprises a sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 967-970.

[0060] In some embodiments, the nucleic acid sequence complementary to a nucleic acid encoding human FAS comprises a sequence as set forth in SEQ ID NO: 967.

[0061] In some embodiments, the nucleic acid reduces expression of FAS in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

[0062] In some embodiments, the nucleic acid sequence complementary to a nucleic acid encoding human TGFBR2 comprises a sequence as set forth in SEQ ID NOs: 969 or 970.

[0063] In some embodiments, the nucleic acid reduces expression of TGFBR2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

[0064] In some embodiments, the system comprises at least two nucleic acid sequences complementary to a nucleic acid encoding human TGFBR2 comprising the sequences as set forth in SEQ ID NOs: 969 and 970.

[0065] In some embodiments, the nucleic acid sequence complementary to human PTPN2 comprises a sequence set forth in SEQ ID NO: 968.

[0066] In some embodiments, the nucleic acid reduces expression of PTPN2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

[0067] In some embodiments, the at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary a portion thereof of human FAS, human TGFBR2, and human PTPN2 comprises a sequence as set forth in SEQ ID NO: 1252 or 972.

[0068] In some embodiments, the nucleic acid sequence complementary to a nucleic acid encoding human FAS reduces expression of FAS in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid, the nucleic acid sequence(s) complementary to a nucleic acid encoding human TGFBR2 reduces expression of TGFBR2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise thenucleic acid, and the nucleic acid sequence complementary to a nucleic acid encoding human PTPN2 reduces expression of PTPN2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

[0069] In some embodiments, the system is encoded by: a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1238; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1239; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1240; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1241; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1242; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7257 of SEQ ID NO: 1120; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7239 of SEQ ID NO: 1121; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7621 of SEQ ID NO: 1122; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7636 of SEQ ID NO: 1123; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7621 of SEQ ID NO: 1124; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%,or 100% identity to a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123; or a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124.

[0070] In some embodiments, the system is encoded by a nucleic acid comprising a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 1120, 1121, 1122, 1123, 1124, 1238, 1239, 1240, 1241, or 1242.

[0071] In some embodiments, the target cell is a human cell.

[0072] In some embodiments, the target cell is a cancer cell expressing TMPRSS4 on its cell surface.

[0073] In some embodiments, the target cell is a cancer cell expressing SLC34A2 and TMPRSS4 on its cell surface.

[0074] In some embodiments, the cancer cell is a solid cancer cell or a liquid cancer cell.

[0075] In some embodiments, the cancer cell is a lung cell, optionally wherein the cancer cell is a non-small cell lung cancer (NSCLC) cell, ovarian cancer, cervical cancer, endometrial cancer, uterine cancer, pancreatic cancer, esophageal cancer, head and neck squamous cell cancer, thyroid cancer, bladder cancer, breast cancer, cholangiocarcinoma cancer, colon cancer, rectal cancer, kidney cancer, renal cell carcinoma, prostate cancer, stomach cancer, or gastric cancer.

[0076] In one aspect, provided herein are one or more nucleic acid(s) comprising at least one nucleic acid fragment comprising a nucleotide sequence encoding the system disclosed herein.

[0077] In some embodiments, the nucleic acid comprises a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1238; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1239; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1240; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequenceas set forth in SEQ ID NO: 1241; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1242; at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7257 of SEQ ID NO: 1120; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7239 of SEQ ID NO: 1121; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7621 of SEQ ID NO: 1122; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7636 of SEQ ID NO: 1123; or a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% identity to a sequence comprising nucleotides 481-7621 of SEQ ID NO: 1124; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1120; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1121; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1122, a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1123, a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1124; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123; or a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124.

[0078] In some embodiments, the nucleic acid comprises a sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 1120, 1121, 1122, 1123, 1124, 1238, 1239, 1240, 1241 or 1242.

[0079] In one aspect, provided herein are one or more nucleic acid(s), wherein the one or more nucleic acid(s) encode: a. a first chimeric polypeptide comprising a priming receptor comprising a first antigen-binding domain that specifically binds to human Solute Carrier Family 34 Member 2 (SLC34A2); b. a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising a second antigen-binding domain that specifically binds to human Transmembrane protease, serine 4 (TMPRSS4).

[0080] In some embodiments, the nucleic acid(s) comprise comprising at least one nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of: a. a nucleic acid encoding human Fas Cell Surface Death Receptor (FAS) comprising the sequence set forth in SEQ ID NO: 964; and / or b. a nucleic acid encoding human Transforming Growth factor (TGF)-P Receptor 2 (TGFBR2) comprising the sequence set forth in SEQ ID NO: 965; and / or c. a nucleic acid encoding Phosphatase Non-Receptor Type 2 (PTPN2) comprising the sequence set forth in SEQ ID NO: 966.

[0081] In one aspect, provided herein are one or more nucleic acid(s), wherein the one or more nucleic acids encode: a. a first chimeric polypeptide comprising a priming receptor comprising a first antigen-binding domain that specifically binds to human Solute Carrier Family 34 Member 2 (SLC34A2); b. a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising a second antigen-binding domain that specifically binds to human Transmembrane protease, serine 4 (TMPRSS4); andc. at least one nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of: i. a nucleic acid encoding human Fas Cell Surface Death Receptor (FAS) comprising the sequence set forth in SEQ ID NO: 964; and / or ii. a nucleic acid encoding human Transforming Growth factor (TGF)-P Receptor 2 (TGFBR2) comprising the sequence set forth in SEQ ID NO: 965; and / or iii. a nucleic acid encoding human Protein Tyrosine Phosphatase NonReceptor Type 2 (PTPN2) comprising the sequence set forth in SEQ ID NO: 966.

[0082] In some embodiments, the first antigen-binding domain comprises a heavy chain comprising a first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 1001, 1009, or 1015, and a first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequences set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1002, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1003, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1004, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1008; or b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014; or c. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1016, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1017, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1018, CDR-L1 comprises the sequence setforth in SEQ ID NO: 1020, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1021, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1022.

[0083] In some embodiments, the first VH chain sequence comprises the VH sequence set forth in SEQ ID NOs: 1001, 1009, or 1015.

[0084] In some embodiments, the second VL comprises the sequence set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019.

[0085] In some embodiments, the first antigen-binding domain comprises the sequence set forth in SEQ ID NOs: 1107, 1108, or 1109.

[0086] In some embodiments, the second antigen-binding domain comprises a second variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 319 or 326, and a second variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NOs: 320 or 327, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; and b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR-L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331.

[0087] In some embodiments, the second VH comprises the sequence as set forth in SEQ ID NO: 319 or 326.

[0088] In some embodiments, the second VL comprises the sequence set forth in SEQ ID NOs: 320 or 327.

[0089] In some embodiments, the second antigen binding domain comprises the sequence set forth in SEQ ID NO: 551 or 552.

[0090] In some embodiments, the at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of human FAS, human TGFBR2 and / or human PTPN2 are at least 16, 17, 18, 19, 20, 21, or 22 nucleotides in length.

[0091] In some embodiments, the at least one nucleic acid sequences are a short hairpin RNA (shRNA), a small interfering RNA (siRNA), a double stranded RNA (dsRNA), or an antisense oligonucleotide.

[0092] In some embodiments, the at least one nucleic acid sequences are shRNA.

[0093] In some embodiments, the at least one or more nucleic acids comprises a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 967.

[0094] In some embodiments, the at least one or more nucleic acid reduces expression of FAS in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

[0095] In some embodiments, the at least one or more nucleic acid comprises a sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 969 and / or 970.

[0096] In some embodiments, the at least one or more nucleic acid reduces expression of TGFBR2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

[0097] In some embodiments, the at least one or more nucleic acid comprise at least one nucleic acid sequence at least 15 nucleotides in length complementary a portion thereof of to a nucleic acid encoding human PTPN2 comprising the sequence set forth in SEQ ID NO: 966.

[0098] In some embodiments, the nucleic acid sequence complementary to human PTPN2 comprises a sequence as set forth in SEQ ID NO: 968.

[0099] In some embodiments, the nucleic acid reduces expression of PTPN2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

[0100] In some embodiments, the at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary a portion thereof of to human FAS, human TGFBR2, and human PTPN2 comprises a sequence as set forth in SEQ ID NO: 1252 or 972.

[0101] In some embodiments, the at least one or more nucleic acid sequence is encoded in at least one intron region of the nucleic acid.

[0102] In one aspect, provided herein are one or more nucleic acid(s) comprising the nucleic acid(s) disclosed herein.

[0103] In some embodiments, the nucleic acid comprises two or more nucleic acid fragments.

[0104] In some embodiments, the nucleic acid comprises an inducible promoter operably linked to the nucleotide sequence encoding the CAR, wherein the inducible promoter drives the inducible expression of the CAR.

[0105] In some embodiments, the nucleic acid comprises a constitutive promoter operably linked to the nucleotide sequence encoding the priming receptor, wherein the constitutive promoter drives constitutive expression of the priming receptor.

[0106] In some embodiments, the nucleic acid comprises an inducible promoter element operably linked to the nucleotide sequence encoding the chimeric antigen receptor and a constitutive promoter operably linked to the nucleotide sequence encoding the priming receptor.

[0107] In some embodiments, the constitutive promoter is an EFla promoter.

[0108] In some embodiments, the constitutive promoter comprises a sequence as set forth in SEQ ID NO: 991.

[0109] In some embodiments, the inducible promoter comprises a YB-TATA promoter sequence and one or more Hepatocyte Nuclear Factor la (HNFla) response element(s).

[0110] In some embodiments, the YB-TATA promoter sequence comprises a sequence as set forth in SEQ ID NO: 1246.

[0111] In some embodiments, the one or more Hepatocyte Nuclear Factor la (HNFla) response element(s) comprises a sequence as set forth in SEQ ID NO: 1245.

[0112] In some embodiments, the inducible promoter comprises a sequence as set forth in SEQ ID NO: 992.

[0113] In some embodiments, the nucleic acid comprises, in a 5’ to 3’ direction, a. the constitutive promoter; b. the nucleotide sequence encoding priming receptor; c. the inducible promoter element; and d. the nucleotide sequence encoding chimeric antigen receptor.

[0114] In some embodiments, the nucleic acid comprises, in a 5’ to 3’ direction, a. the inducible promoter element; b. the nucleotide sequence encoding chimeric antigen receptor; c. the constitutive promoter; and d. the nucleotide sequence encoding priming receptor.

[0115] In some embodiments, the nucleic acid comprises, in a 5’ to 3’ direction, a. a first constitutive promoter; b. the nucleotide sequence encoding the priming receptor; c. optionally, a second constitutive promoter; d. the nucleotide sequence encoding the at least one nucleic acid complementary to human FAS, human TGFBR2, and / or human PTPN2; e. the inducible promoter element; and f. the optional nucleotide sequence encoding the chimeric antigen receptor.

[0116] In some embodiments, the nucleic acid comprises, in a 5’ to 3’ direction, a. a first constitutive promoter; b. the nucleotide sequence encoding the priming receptor; c. optionally, a second constitutive promoter;d. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; e. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; f. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; g. the inducible promoter element; and h. the nucleotide sequence encoding the chimeric antigen receptor.

[0117] In some embodiments, the nucleic acid comprises, in a 5’ to 3’ direction, a. the inducible promoter; b. the nucleotide sequence encoding the chimeric antigen receptor; c. a first constitutive promoter; d. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; e. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; f. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acidcomplementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; g. optionally, a second constitutive promoter; and h. the nucleotide sequence encoding the priming receptor.

[0118] In some embodiments, the nucleic acid comprises a 5’ homology directed repair arm and a 3’ homology directed repair arm, both of which are complementary to an insertion site in a host cell chromosome.

[0119] In some embodiments, the nucleic acid comprises a woodchuck hepatitis virus post- translational regulatory element (WPRE).

[0120] In some embodiments, the WPRE is at the 3’ end of the nucleotide sequence encoding chimeric antigen receptor and at the 5 ’ end of the nucleotide sequence encoding priming receptor or wherein the WPRE is at the 3’ end of the nucleotide sequence encoding priming receptor and at the 5’ end of the nucleotide sequence encoding chimeric antigen receptor.

[0121] In some embodiments, the nucleic acid comprises synthetic polyA signal, an SV40 polyA signal, a human growth hormone (GH) polyA signal, or a bovine growth hormone (bGH) polyA signal.

[0122] In some embodiments, the nucleic acid is incorporated into an expression cassette or a vector for viral or non- viral delivery to a cell.

[0123] In some embodiments, the vector is for non-viral delivery and is, e.g., a non-viral vector.

[0124] In one aspect, provided herein are vectors comprising the nucleic acid disclosed herein.

[0125] In some embodiments, the 5’ and 3’ ends of the nucleic acid comprise nucleotide sequences that are homologous to genomic sequences flanking an insertion site in a genome of a primary cell.

[0126] In some embodiments, the insertion site is located at a genomic safe harbor (GSH) locus.

[0127] In some embodiments, the GSH locus is a GS94 locus (chrl 1: 128340000-128350000).

[0128] In some embodiments, the nucleotide sequences that are homologous to genomic sequences flanking the GS94 locus insertion site comprise nucleotides 24-473 and 7258-7707 of SEQ ID NO: 1120; nucleotides 24-473 and 7240-7689 of SEQ ID NO: 1121; nucleotides 24-473 and 7622-8071 of SEQ ID NO: 1122; nucleotides 24-473 and 7637-8086 of SEQ ID NO: 1123; or nucleotides 24-473 and 7622-8071 of SEQ ID NO: 1124.

[0129] In some embodiments, the nucleotide sequences that are homologous to genomic sequences flanking the GS94 locus insertion site comprise SEQ ID NOs: 1235 and 1236.

[0130] In some embodiments, nucleotide sequences comprise homology regions to the gRNA of the RNP complex used for inserting the nucleic acid into the genome of a cell.

[0131] In some embodiments, the sequences of the gRNA homology regions comprise SEQ ID NOs: 932 and 1237.

[0132] In one aspect, provided herein are isolated cells comprising: a. the system disclosed herein; b. at least one nucleic acid disclosed herein; and / or c. the vector disclosed herein.

[0133] In some embodiments, the cell is an immune cell.

[0134] In one aspect, provided herein are isolated immune cells comprising: a. the system disclosed herein; b. at least one nucleic acid disclosed herein; and / or c. the vector disclosed herein.

[0135] In some embodiments, the immune cell is a primary human immune cell.

[0136] In some embodiments, the primary immune cell is a natural killer (NK) cell, a T cell, a CD8+ T cell, a CD4+ T cell, a primary T cell, or a T cell progenitor.

[0137] In some embodiments, the primary immune cell is a primary T cell.

[0138] In some embodiments, the primary immune cell is a primary human T cell.

[0139] In one aspect, provided here are a population of isolated cells comprising a plurality of cells or immune cells disclosed herein.

[0140] In one aspect, provided here are pharmaceutical compositions comprising the isolated cells or immune cell disclosed herein or the population of isolated cells disclosed herein, and a pharmaceutically acceptable excipient.

[0141] In one aspect, provided here are pharmaceutical compositions comprising the nucleic acid disclosed herein or the vector disclosed herein, and a pharmaceutically acceptable excipient.

[0142] In one aspect, provided here are methods of editing a cell, comprising inserting the nucleic acid disclosed herein into a genome of the cell.

[0143] In some embodiments, the nucleic acid is inserted into a genomic safe harbor (GSH) locus.

[0144] In some embodiments, the GSH locus is a GS94 locus (chrl 1: 128340000-128350000).

[0145] In one aspect, provided here are methods of killing a target cell in a subject comprising administering the immune cell or population of immune cells disclosed herein to the subject, wherein the immune cell kills the target cell and / or triggers cytolysis of the target cell.

[0146] In one aspect, provided here are methods of inhibiting a target cell in a subject comprising administering the immune cell or population of immune cells disclosed herein to the subject, wherein the immune cell inhibits the target cell.

[0147] In some embodiments, the target cell expresses human TMRPSS4 or human TMPRSS4 and human SCL34A2.

[0148] In some embodiments, the target cell is a cancer cell.

[0149] In one aspect, provided here are methods of treating a disease in a human subject comprising administering the cells or immune cell or population of cells or immune cells disclosed herein or the pharmaceutical composition disclosed herein to the subject.

[0150] In some embodiments, the disease is cancer.

[0151] In one aspect, provided here are methods of treating cancer in a human subject, comprising administering the immune cell or population of immune cells disclosed herein or thepharmaceutical composition disclosed herein to the subject, wherein the immune cells are primary immune cells obtained from the subject.

[0152] In some embodiments, the cancer cells express human TMRPSS4 or human TMPRSS4 and human SCL34A2 on the cell membrane.

[0153] In one aspect, provided here are method of treating a disease in a subject comprising: a. determining or having determined the presence of human SLC34A2-positive (SLC34A2+) cells in a cancer sample obtained from the subject; and / or b. determining or having determined the presence of human TMPRSS4-positive (TMPRSS4+) cells in a cancer sample obtained from the subject; and c. administering the cell or immune cell disclosed herein or the pharmaceutical composition disclosed herein to the subject.

[0154] In some embodiments, the cancer is a solid cancer or a liquid cancer.

[0155] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), ovarian cancer, cervical cancer, endometrial cancer, uterine cancer, pancreatic cancer, esophageal cancer, head and neck squamous cell cancer, thyroid cancer, bladder cancer, breast cancer, cholangiocarcinoma cancer, colon cancer, rectal cancer, kidney cancer, renal cell carcinoma, prostate cancer, stomach cancer, or gastric cancer.

[0156] In some embodiments, the administration of the immune cell to the subject enhances an immune response in the subject or kills, or induces cytolysis, of the cancer cells.

[0157] In one aspect, provided here are methods of modulating the activity of a cell or immune cell comprising: a. obtaining a cell or immune cell comprising b. the system disclosed herein; c. the nucleic acid disclosed herein; and / or d. the vector disclosed herein; and e. contacting the cell or immune cell with a target cell expressing SLC34A2 and TMPRSS4, wherein binding of the priming receptor to SLC34A2 on the targetcell induces activation of the priming receptor and expression of the chimeric antigen receptor and wherein binding of the chimeric antigen receptor to TMPRSS4 on the target cell modulates the activity of the immune cell.

[0158] In some embodiments, the immune cell activity is cytolytic activity.

[0159] In some embodiments, the modulation of the immune cell activity comprises enhancing an immune response.

[0160] In some embodiments, the enhanced immune response is an adaptive immune response.

[0161] In some embodiments, the enhanced immune response is an innate immune response.

[0162] In some embodiments, the enhanced immune response is an increased expression of at least one cytokine or chemokine.

[0163] In some embodiments, the cytokine is interferon-gamma (IFNy).

[0164] In some embodiments, the method comprises administering an immunotherapy to the subject concurrently with the cell or immune cell or subsequently to the cell or immune cell.

[0165] In one aspect, provided here are methods of inducing expression of a chimeric antigen receptor with a priming receptor in a cell comprising: a. obtaining a cell or immune cell comprising b. the system disclosed herein; c. the nucleic acid disclosed herein; and / or d. the vector disclosed herein; and e. contacting the cell or immune cell with a cell expressing SLC34A2, wherein binding of the priming receptor to SLC34A2 on the cell induces activation of the priming receptor and expression of the chimeric antigen receptor.

[0166] In one aspect, provided here are nucleic acids comprising a nucleic acid sequence that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NOs: 1120, 1121, 1122, 1123, 1124, 1238, 1239, 1240, 1241, or 1242, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120, at least 80%, 85%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123, or at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124; wherein the nucleic acid encodes a priming receptor comprising a first antigen binding domain that binds to SLC34A2 and a chimeric antigen receptor comprising a second antigen binding domain that binds to TMPRSS4.

[0167] In some embodiments, any difference in the nucleotide sequence as compared to SEQ ID NOs: 1120, 1121, 1122, 1123, 1124, 1238, 1239, 1240, 1241, 1242, or a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120, a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121, a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122, a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123, or a sequence comprising nucleotides 24- 8071 of SEQ ID NO: 1124 does not affect the activity of any of the elements provided in Table 19.

[0168] In some embodiments, the nucleic acids comprise a sequence selected from the sequences as set forth in SEQ ID NOs: 1122, 1123, 1124, 1238, 1239, 1240, 1241, or 1242 or a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120, a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121, a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122, a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123, or a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124.

[0169] In one aspect, provided here are isolated human cells comprising the nucleic acid disclosed herein.

[0170] In some embodiments, the nucleic acid is inserted into a genomic safe harbor (GSH) locus of the cell.

[0171] In some embodiments, the GSH locus is a GS94 locus (chrl 1: 128340000-128350000).

[0172] In some embodiments, comprising a sequence selected from the sequences set forth in SEQ ID Nos: 1238, 1239, 1240, 1241 and 1242.

[0173] In one aspect, provided here are isolated human cells expressing a priming receptor comprising an antigen-binding domain that specifically binds to human SLC34A2 and a CAR comprising an antigen-binding domain that specifically binds to human TMPPRSS4, wherein binding of the priming receptor to SLC34A2 on the surface of a target cell and binding of the CAR to TMPRSS4 on the surface of a target cell induces lysis of the cell expressing TMPRSS4.

[0174] In some embodiments, where the cell expressing TMPRSS4 comprises SLC34A2 surface expression.

[0175] In one aspect, provided here are one or more nucleic acids comprising a nucleic acid sequence encoding a first cell surface receptor that specifically binds to human SLC34A2 and a nucleic acid sequence encoding a second cell surface receptor that specifically binds to human TMPRSS4, wherein binding of the first and second cell surface receptors to SLC34A2 and TMPRSS4 on the surface of a human cell, respectively, induces lysis of the human cell with TMPRSS4 on the surface.

[0176] In some embodiments, the first and the second cell surface receptor comprise the VH and VL of any of the SLC34A2 or TMPRSS4 antigen binding domains described herein, or their VH and VL CDRs.BRIEF DESCRIPTION OF THE DRAWINGS

[0177] 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:

[0178] 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 catalytically inactive 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.

[0179] FIG. 2 is a schematic of an exemplary construct encoding a TMPRSS4 CAR.

[0180] FIG. 3 A 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 the 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 reexpressing 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.

[0181] FIG. 4A shows surface expression of CD25 on T cells from donor CP5428 expressing CARs comprising the indicated TMPRSS4 antibodies. FIG. 4B shows surface expression of TIM3 on T cells from donor CP5428 expressing CARs comprising the indicated TMPRSS4 antibodies. FIG. 4C shows surface expression of CD25 on T cells from donor CP5917 expressing CARs comprising the indicated TMPRSS4 antibodies. FIG. 4D shows surface expression of TIM3 on T cells from donor CP5917 expressing CARs comprising the indicated TMPRSS4 antibodies.

[0182] 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.

[0183] 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.

[0184] FIG. 7A 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.

[0185] 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 ofTNFa from TMPRSS4 CAR-expressing T cells following incubation with H1975 cells with TMPRSS4 knockout.

[0186] FIG. 9 provides schematics of TMPRSS4 variants including the wild-type protein, a protein comprising a D290A mutation (indicated by X) that suppresses catalytic activity (“catalytic inactive”), and a truncated protein lacking the C-terminal serine protease domain (“cleaved / truncated”).

[0187] FIG. 10 shows CD69 surface expression in T cells expressing CARs comprising the indicated TMPRSS4 antibodies following co-culture with cells expressing the indicated TMPRSS4 protein.

[0188] FIG. 11 provides a schematic of the T cell engineering process and the first tier of the selection process.

[0189] FIG. 12 provides a schematic of functional sorting of T cells expressing a logic gate comprising an SLC34A2 primeR and a TMPRSS4 CAR following co-culture with indicated Hl 975 target cells.

[0190] FIG. 13A shows the percent knock-in (KI%) of genes in engineered T cells expressing a logic gate circuit in T cells from Donor A and Donor B. FIG. 13B shows the CAR expression / % KI (% conversion) of engineered T cells expressing a logic gate circuit in T cells from Donor A and Donor B. FIG. 13C shows the primeR expression in engineered T cells expressing a logic gate circuit in T cells from Donor A and Donor B.

[0191] FIG. 14 shows a schematic of the second tier of the selection process.

[0192] FIG. 15 shows SLC34A2 and TMPRSS4 expression in the indicated cell lines.

[0193] FIG. 16A shows the % killing (cytotoxicity) by engineered logic gate T cells from Donor B compared to the % killing (cytotoxicity) by engineered logic gate T cells from Donor A of TMPRSS4 knockout (KO) cells. FIG. 16B shows the % killing (cytotoxicity) by engineered logic gate T cells from Donor B compared to the % killing (cytotoxicity) by engineered logic gate T cells from Donor A of TMPRSS4hl(high TMPRSS4 expression) cells. FIG. 16C shows the % killing (cytotoxicity) by engineered logic gate T cells from Donor B compared to the % killing (cytotoxicity) by engineered logic gate T cells from Donor A of SLC34A2hl(high SLC34A2 expression)-TMPRSS4 knockout (KO) cells. FIG. 16D shows the % killing(cytotoxicity) by engineered logic gate T cells from Donor B compared to the % killing (cytotoxicity) by engineered logic gate T cells from Donor A of SLC34A2-TMPRSS4 expressing cells.

[0194] FIG. 17A shows IFNy secretion by engineered T cells from donor A incubated with target cells expressing the TMPRSS4 protein. FIG. 17B shows IFNy secretion by engineered T cells from donor B incubated with target cells expressing the TMPRSS4 protein.

[0195] FIG. 18A shows the result of the repetitive stimulation assay (RSA) of T cells from Donor A incubated with target cells expressing the TMPRSS4 protein. FIG. 18B shows the result of the RSA of T cells from Donor B incubated with target cells expressing the TMPRSS4 protein.

[0196] FIG. 19A shows a comparison of the % KI (cytotoxicity) by the engineered T cells from Donor A when incubated with cells expressing only TMPRSS4 (H1975-TMPhl) as compared to the % KI (cytotoxicity) by the engineered T cells when incubated with cells expressing both SLC34A2 and TMPRSS4 (H975-dual). FIG. 19B shows a comparison of the % KI (cytotoxicity) by the engineered T cells from Donor B when incubated with cells expressing only TMPRSS4 (H1975-TMPhl) as compared to the % KI (cytotoxicity) by the engineered T cells when incubated with cells expressing both SLC34A2 and TMPRSS4 (H1975-dual). The development candidates showed low % KI (cytotoxicity) when incubated with cells expressing only TMPRSS4 and high % KI (cytotoxicity) when incubated with cells expressing both SLC34A2 and TMPRSS4.

[0197] FIG. 20 shows the % cytotoxicity of T cells expressing the indicated logic gate when incubated with the indicated cell line.

[0198] FIG. 21 shows a schematic of the selection criteria for the lead logic gate candidates.

[0199] FIG. 22 shows additional characterization for leakiness and potency of the lead candidate logic gate T cells..

[0200] FIG. 23 shows the % cytotoxicity of T cells expressing the indicated logic gate when incubated with the indicated cell line.

[0201] FIG. 24 shows a diagram of exemplary logic gate circuits.

[0202] FIG. 25 shows binding of the indicated antibodies to cell expressing wild type and the D290A TMPRSS4 protein, as determined by flow cytometry and measured by gMFI.

[0203] FIG. 26A shows representative flow cytometry histograms of FAS (left panel) and TGFBR2 (right panel) expression in transgene-negative (PrimeR-) or transgene-positive (PrimeR+) T cells including the FAS / PTPN2 / 2xTFGBR2 shRNA module. PrimeR+ T cells showed reduced levels of FAS and TGFBR2 expression compared to PrimeR- T cells. FIG. 26B shows a Western blot image of PTPN2 expression in transgene-positive (PrimeR+) and transgene-negative (PrimeR-) T cells expressing the indicated logic gates including the FAS / PTPN2 / 2xTFGBR2 shRNA module. Transgene-positive T cells expressing the shRNA module had less PTPN2 expression as compared to transgene-negative T cells. FIG. 26C shows the quantified reduction of FAS (left), TGFBR2 (center), and PTPN2 expression (right) in engineered logic gate T cells expressing the indicated logic gate with the shRNA module. The data is presented as an average of 3 donors with standard deviation.

[0204] FIG. 27A shows cytotoxicity (% killing) of H2347 cells that endogenously express TMPRSS4 and SLC34A2 after incubation with the indicated engineered logic gate T cells at the indicated Effector: Target cell (E:T) ratios. FIG. 27B shows cytotoxicity (% killing) of H1648 cells that endogenously expresses TMPRSS4 and SLC34A2 after incubation with the indicated engineered logic gate T cells at the indicated E:T ratios. FIG. 27C shows the cytotoxicity (% killing) of H1975-SLC34A2 / TMPRSS4 cells that expressed median levels of both target antigens after incubation with the indicated engineered logic gate T cells at the indicated E:T ratios

[0205] FIG. 28 shows quantification of the IFNy production of the indicated logic gate T cells after incubation with a mixture of 786-O-SLC34A2 cells and aHEK293T-TMPRSS4 WT or HEK293T-TMPRSS4 D290A cells.

[0206] FIG. 29A shows a representative flow plot of priming receptor and CAR expression in the engineered logic gate T-cells after co-culture with a 786-0 parental cell line that does not express SLC34A2 (left) and a SLC34A2 positive cell line (right). FIG. 29B shows prime antigen dependent % CAR expression induction (left) and CAR expression (mean fluorescent intensity, MFI) (right) for the indicated engineered logic gate T cells over time when co-cultured with a cell line expressing the SLC34A2 priming antigen. FIG. 29C shows representative flow plots ofCAR and priming receptor expression in engineered logic gate T cells in an “ON” state (left) after co-culture with cells expressing the priming antigen (left, “ON” state) and after co-culture with cells lacking expression of the priming antigen (right, “OFF” state). FIG. 29D shows prime antigen dependent % CAR expression induction (left) and CAR expression (mean fluorescent intensity, MFI) (right) over time after removal of the priming antigen.

[0207] FIG. 30 shows long term cytotoxicity of T cells in a repetitive stimulation assay (RS A). The indicated logic gate T cells were incubated with a H1975-SLC34A2 / TMPRSS4 overexpressing target cell line and rechallenged with new target cells over time. Lines indicate target cell restimulation times. Target cell killing was determined by measuring the fluorescence intensity of GFP expressed by the target cells.

[0208] FIG. 31A shows a priming antigen heterogeneity cytotoxicity assay, where the indicated logic gate T cells were incubated at a 1: 1 E:T ratio with a mixture of H1975-EFG- SLC34A2 / TMPRSS4 and H1975-EFG-TMPRSS4 cells at the indicated target cell heterogeneity ratios. FIG. 31B shows a priming antigen heterogeneity cytotoxicity assay, where the indicated logic gate T cells were incubated at a 1:3 E:T ratio with a mixture of H1975-EFG- SLC34A2 / TMPRSS4 and H1975-EFG-TMPRSS4 cells at the indicated target cell heterogeneity ratios. FIG. 31C shows a priming antigen heterogeneity cytotoxicity assay, where the indicated logic gate T cells were incubated at a 1:9 E:T ratio with a mixture of H1975-EFG- SLC34A2 / TMPRSS4 D20A and H1975-EFG-TMPRSS4 cells at the indicated target cell heterogeneity ratios.

[0209] FIG. 32 shows in vivo tumor-growth inhibition over time of H1975-nEFG-SLC43A2- TMPRSS4 lung adenocarcinoma tumors after treatment with the indicated logic gate T cells.

[0210] FIG. 33A shows in vivo tumor-growth inhibition over time of Hl 975 tumors expressing SLC34A2-TMPRSS4 in a dual flank lung adenocarcinoma xenograft model after treatment with the indicated logic gate T cells. FIG. 33B shows in vivo tumor-growth inhibition over time of tumors expressing only TMPRSS4 in a dual flank lung adenocarcinoma xenograft model after treatment with the indicated logic gate T cells.

[0211] FIG. 34A shows the % reduction of FAS expression by flow cytometry in LG 47 T cells expressing the indicated shRNA. FIG. 34B shows long term cytotoxicity of the indicated T cells in a repetitive stimulation assay (RSA), after incubation of the indicated logic gate T cellswith a H1975-SLC34A2 / TMPRSS4 + FASL overexpressing target cell line and rechallenged with new target cells over time. Arrows indicate target cell restimulation times. FIG. 34C shows a representative histogram of Fas (left panel) and FasL (right panel) expression in the indicated cell lines. Batimastat treatment was used to inhibit cleavage of cell surface expressed FASL.

[0212] FIG. 35A shows long term cytotoxicity and T cell proliferation of the indicated T cells in a repetitive stimulation assay (RSA) after incubation of the indicated LG T cells with a K562- SLC34A2 / TMPRSS4 target cell line and restimulated over time. Arrows indicate target cell restimulation times. T cell counts are shown in white shading with a solid line, target cell counts are shown in gray shading with a dotted line. FIG. 35B shows T cell proliferation across RSA rounds in the indicated logic gate T cells from 3 donors. Data for both is the mean with standard deviation across 3 donors.

[0213] FIG. 36A shows the % reduction of TGFBR2 expression by flow cytometry in T cells expressing the Logic Gate 47 priming receptor and CAR and the indicated shRNA. FIG. 36B shows quantification of phosphorylated SMAD (gMFI) in in transgene-positive (PrimeR+) and transgene-negative (PrimeR-) T cells expressing the Logic Gate 47 priming receptor and CAR and the indicated shRNA, with the addition of TGF0 (left) or without TGF0 (right). FIG. 36C shows long term cytotoxicity of the indicated T cells in a repetitive stimulation assay (RSA). The indicated logic gate T cells were incubated with a H1975-SLC34A2 / TMPRSS4 overexpressing target cell line and rechallenged with new target cells over time. The T cells were restimulated with the target cells at times indicated by gray arrows.

[0214] FIG. 37 shows in vivo tumor-growth inhibition over time of H1975-nEFG-SLC43A2- TMPRSS4 lung adenocarcinoma tumors after treatment with the indicated logic gate T cells derived from two donors. The logic gate T cells expressed the full FAS / PTPN2 / 2xTGFBR2 shRNA, or a quad luciferase (quad luc) control shRNA module.DETAILED DESCRIPTION OF THE INVENTION

[0215] The present disclosure provides polypeptide systems of synthetic transcriptional modulators that comprise antigen binding domains that bind to SLC34A2 and synthetic immune receptors (e.g., CARs) that comprise antigen binding domains that bind to TMPRSS4. The present disclosure also provides nucleic acids encoding the systems, cells comprising the polypeptide systems, and methods of making and / or using the cells.Definitions

[0216] Terms used in the claims and specification are defined as set forth below unless otherwise specified.

[0217] 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.

[0218] 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.

[0219] “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®).

[0220] 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 the amino 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.

[0221] 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.

[0222] 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.

[0223] 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 thevarious 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.

[0224] * 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.

[0225] 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

[0226] 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 a Fab light chain is connected to the N-terminus of a Fab heavy chain in a 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 or linker. Alternately an scFv comprises a polypeptide chain wherein the C-terminal end of a VH is connected to the N-terminal end of a VL by a polypeptide chain or linker.

[0227] 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.

[0228] “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.

[0229] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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).

[0234] 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 DNAsequence, 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. For example, 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.

[0235] 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.

[0236] 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).

[0237] 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 toone 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).

[0238] 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.

[0239] 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).

[0240] 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.

[0241] 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.

[0242] 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.

[0243] As used herein, the term “locus” refers to a specific, fixed physical location on a chromosome where a gene or genetic marker is located.

[0244] 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 9.

[0245] 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.

[0246] 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.

[0247] The term “therapeutically effective amount” is an amount that is effective to ameliorate a symptom of a disease.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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).

[0252] 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.

[0253] 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 desiredresults. 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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 visualinspection. 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.

[0258] 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.

[0259] 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).

[0260] 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 / ).

[0261] 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.

[0262] As used herein, the phrase “introducing” in the context of introducing into a cell 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 translocationof 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 nanowires or nanotubes, receptor mediated internalization, translocation via cell penetrating peptides, liposome mediated translocation, and the like.

[0263] 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.

[0264] 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.

[0265] 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, weakpromoter, inducible / repressible promoter, tissue specific or developmentally regulated promoters, cell cycle-dependent promoters, and the like.

[0266] 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 (e.g., a YB-TATA promoter). 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.

[0267] 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.

[0268] 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.

[0269] The term “m vivo” refers to processes that occur in a living organism.

[0270] The term “m situ” refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.

[0271] As used herein, the term “ex vzvo” 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.

[0272] 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, mouse hematopoietic stem cells are identified as CD34lo / _, SCA-1+, Thyl+ / 10, CD38+, C-kit+, lin". In some cases, the hematopoietic stem cells are CD150+CD48 CD244-.

[0273] 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.

[0274] 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 humanpluripotent stem cell (HSPC), a T cell or a T cell progenitor or dendritic cell. In some embodiments, the cell is an innate immune cell.

[0275] 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 blood mononuclear cells (PBMC), peripheral blood leukocytes (PBL), tumor infiltrating lymphocytes (TIL), memory T cells, 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.

[0276] “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.

[0277] “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.

[0278] 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.

[0279] As used herein, the term “exogenous” in the context of an element in a cell refers to an element, e.g., a molecule or activity, that has been introduced into a host cell and is not native to that cell. The molecule can be introduced, for example, 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.

[0280] The term “heterologous” in the context of a nucleic acid 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.

[0281] The term “homologous” in the context of a nucleic acid refers to a nucleic acid or polypeptide sequence or domain which is native to a flanking sequence, e.g., wherein thehomologous sequence is found in nature coupled to the nucleic acid or polypeptide sequences occurring at one or both ends.

[0282] 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.

[0283] 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.

[0284] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0285] The terms “protein,” “polypeptide,” and “peptide” are used herein interchangeably.

[0286] 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.

[0287] As used herein, the term “subject” refers to a human subject. 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.

[0288] Certain amino acids of a protein can be modified post-transcriptionally and the amino acid sequences provided herein include amino acids that contain a post-translational modification, e.g., deamidation, glycosylation, formation of pyroglutamate, and deletion of C- terminal lysine or other amino acids. For heavy or light chains or their VH or VL domains disclosed herein that have an N-terminal glutamine (Q) or glutamic acid / glutamate (E), the N- terminal Q or E can be replaced by a pyro-glutamate. Accordingly, any VH or VL amino acid sequence disclosed herein having a Q or an E as N-terminal amino acid sequence should be understood to encompass those in which the Q or E is replaced by a pyro-glutamate. Also provided are compositions comprising proteins comprising an N-terminal VH or VL having an N-terminal Q or E, wherein at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of the proteins in the composition have a pyro-glutamate at the N-terminal amino acid of the VH and / or VL.TMPRSS4 Antigen Binding Domains

[0289] 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 (e.g., the TMPRSS4 protein of SEQ ID NO: 960) and related isoforms and orthologs. 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.

[0290] 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.

[0291] 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 (comprising a D290A mutation) and a truncated TMPRSS4 mutant.Table 3: TMPRSS4 sequencesTable 3

[0292] 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.

[0293] 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 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

[0294] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 3. In some embodiments, the combination of six CDRs (a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2 and a CDR-L3) is according to Kabat, Chothia, AbM, IMGT, or Contact numbering.

[0295] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 3, optionally wherein the VH CDRs and the VL CDRs are identical to those of the respective sequences in Table 3.

[0296] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 tothose 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 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: 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. 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.

[0297] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 acidsequence 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 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.

[0298] In some embodiments, the antibody or antigen-binding fragment that binds to human 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.

[0299] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or, 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.

[0300] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0301] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 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 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.

[0302] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0303] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 least99.5% 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.

[0304] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0305] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 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 and / orthe 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.

[0306] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 acid sequence set forth in SEQ ID NO: 63 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 64.

[0307] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 acidsequence 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 and / or 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.

[0308] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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: 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.

[0309] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0310] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 and / or 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 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: 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.

[0311] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0312] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQID NO: 112 and / or 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.

[0313] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 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: 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.

[0314] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 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 and / or 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.

[0315] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQ ID NO: 133 and / or 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 aminoacid sequence set forth in SEQ ID NO: 128 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0316] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0317] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 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 and / or 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%, atleast 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.

[0318] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 TMPRSS4 comprises 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.

[0319] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 aminoacid 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 and / or 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.

[0320] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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: 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.

[0321] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0322] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 and / or 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%, atleast 91%, 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.

[0323] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0324] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQID NO: 190 and / or 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.

[0325] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 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: 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.

[0326] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 HCDR1comprising 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 and / or 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.

[0327] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQ ID NO: 210 and / or 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 aminoacid sequence set forth in SEQ ID NO: 205 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 206.

[0328] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0329] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 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 and / or 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%, atleast 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.

[0330] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 TMPRSS4 comprises 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.

[0331] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 aminoacid 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 and / or 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.

[0332] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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: 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.

[0333] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0334] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 and / or 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%, atleast 91%, 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.

[0335] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0336] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQID NO: 273 and / or 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.

[0337] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 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: 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.

[0338] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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: 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 and / or 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.

[0339] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQ ID NO: 293 and / or 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 aminoacid sequence set forth in SEQ ID NO: 286 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 287.

[0340] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0341] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 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 and / or 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%, atleast 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.

[0342] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 TMPRSS4 comprises 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.

[0343] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 aminoacid 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 and / or 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.

[0344] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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: 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.

[0345] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0346] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 and / or 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%, atleast 91%, 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.

[0347] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0348] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQID NO: 252 and / or 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.

[0349] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 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: 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.

[0350] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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: 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 and / or 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.

[0351] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQ ID NO: 280 and / or 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 aminoacid sequence set forth in SEQ ID NO: 353 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 354.

[0352] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0353] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 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 and / or 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%, atleast 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.

[0354] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 TMPRSS4 comprises 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.

[0355] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 aminoacid 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 and / or 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.

[0356] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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: 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.

[0357] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0358] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 and / or 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%, atleast 91%, 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.

[0359] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0360] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQID NO: 403 and / or 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.

[0361] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 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: 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.

[0362] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 HCDR1comprising 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 and / or 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.

[0363] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQ ID NO: 419 and / or 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 aminoI l lacid sequence set forth in SEQ ID NO: 414 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 415.

[0364] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0365] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 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 and / or 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%, atleast 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.

[0366] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 TMPRSS4 comprises 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.

[0367] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 aminoacid 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 and / or 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.

[0368] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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: 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.

[0369] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0370] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 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 and / or 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%, atleast 91%, 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.

[0371] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0372] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQID NO: 479 and / or 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.

[0373] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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 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: 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.

[0374] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 HCDR1comprising 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 and / or 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.

[0375] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 SEQ ID NO: 498 and / or 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 aminoacid sequence set forth in SEQ ID NO: 492 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 493.

[0376] In some embodiments, the antibody or antigen-binding fragment that binds to human 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 and / or 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.

[0377] In various embodiments, the antigen-binding fragment that binds to TMPRSS4 comprises an scFv. In some embodiments, the scFv has the format VH-L-VL or VL-L-VH, wherein L is a linker peptide and the VH and VL are any VH and VL disclosed herein. In some embodiments, the scFv has the format VH-L-VL, wherein L is a linker peptide. In some embodiments, the scFv has the format VL-L-VH, wherein L 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

[0378] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0379] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0380] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0381] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0382] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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: 508.

[0383] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0384] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0385] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0386] 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 acidsequence set forth in SEQ ID NO: 512, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0387] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0388] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0389] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0390] In some embodiments, the antibody or antigen-binding fragment that binds toTMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, atleast 90%, at least 91%, 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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: 516.

[0391] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0392] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0393] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0394] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0395] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0396] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0397] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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: 523.

[0398] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0399] 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: 525, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0400] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0401] 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 acidsequence set forth in SEQ ID NO: 527, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0402] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0403] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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: 529.

[0404] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0405] In some embodiments, the antibody or antigen-binding fragment that binds toTMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, atleast 90%, at least 91%, 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, and optionally comprises VH CD Rs and VL CDRs that are 100% identical to those therein. 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.

[0406] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0407] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0408] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0409] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0410] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0411] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0412] 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: 538, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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: 538.

[0413] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0414] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0415] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0416] 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 acidsequence set forth in SEQ ID NO: 542, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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: 542.

[0417] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0418] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0419] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0420] In some embodiments, the antibody or antigen-binding fragment that binds toTMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, atleast 90%, at least 91%, 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0421] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0422] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0423] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0424] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0425] 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: 551, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0426] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0427] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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: 553.

[0428] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0429] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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: 555.

[0430] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0431] 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 acidsequence set forth in SEQ ID NO: 557, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0432] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0433] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0434] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0435] In some embodiments, the antibody or antigen-binding fragment that binds toTMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, atleast 90%, at least 91%, 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0436] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0437] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0438] 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: 564, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0439] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0440] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0441] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0442] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0443] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0444] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0445] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0446] 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 acidsequence set forth in SEQ ID NO: 572, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0447] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0448] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0449] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0450] In some embodiments, the antibody or antigen-binding fragment that binds toTMPRSS4 comprises an scFv comprising an amino acid sequence at least 80%, at least 85%, atleast 90%, at least 91%, 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0451] 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: 577, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0452] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0453] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to those therein. 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.

[0454] 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, and optionally comprises VH CDRs and VL CDRs that are 100% identical to th...

Claims

WHAT IS CLAIMED IS:

1. A system comprising: a. a first chimeric polypeptide comprising a priming receptor comprising a first antigen-binding domain that specifically binds to Solute Carrier Family 34 Member 2 (SLC34A2) (SEQ ID NO: 962); and b. a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising a second antigen-binding domain that specifically binds to Transmembrane protease, serine 4 (TMPRSS4) (SEQ ID NO: 960).

2. The system of claim 1 , wherein the first antigen-binding domain comprises a first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 1001, 1009, or 1015, and a first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequences set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1002, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1003, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1004, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1008; or b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014; or c. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1016, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1017, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1018, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1020, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1021, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1022.

3. The system of claim 1 or 2, wherein the first VH chain sequence comprises the sequence set forth in SEQ ID NO: 1001, 1009, or 1015.

4. The system of claims 1-3, wherein the first VL chain sequence comprises the sequence set forth in SEQ ID NO: 1005, 1013, 1125, or 1019.

5. The system of claims 1-4, wherein the first antigen-binding domain comprises the sequence set forth in SEQ ID NO: 1107, 1108, or 1109.

6. The system of claims 1-5, wherein the second antigen-binding domain comprises a second variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 319 or 326, and a second variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NOs: 320 or 327, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; and b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR-L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331.

7. The system of claim 6, wherein the second VH comprises the sequence as set forth in SEQ ID NOs: 319 or 326.

8. The system of claim 6 or 7, wherein the second VL comprises the sequence set forth in SEQ ID NOs: 320 or 327.

9. The system of any one of claims 6-8, wherein the second antigen binding domain comprises the sequence set forth in SEQ ID NO: 551 or 552.

10. The system of any one of claims 6-8, whereina. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1009, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1013 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 326, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 327; b. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1001, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1005 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 326, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 327; c. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1009, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1013 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, andCDR-H3, of the VH sequence set forth in SEQ ID NO: 319, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 320; d. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1015, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1019 or 1125 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 319, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 320; or e. the first antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 1009, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 1013 and the second antigen-binding domain comprises the first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequence set forth in SEQ ID NO: 326, and the first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NO: 327.

11. The system of any one of claims 1-10, wherein a. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR-LI comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR- L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331; b. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1002, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1003, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1004, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1008 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR- L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331; c. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323,CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; d. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1016, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1017, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1018, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1020, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1021, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1022 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; or e. the first antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR- L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014 and the second antigen-binding domain comprises a CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR- L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331.

12. The system of any one of claims 1-11, comprising at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of:a. a nucleic acid encoding human Fas Cell Surface Death Receptor (FAS) comprising the sequence set forth in SEQ ID NO: 964; and / or b. a nucleic encoding human Transforming Growth factor (TGF)-P Receptor 2 (TGFBR2) comprising the sequence set forth in SEQ ID NO: 965; and / or c. a nucleic acid encoding Phosphatase Non-Receptor Type 2 (PTPN2) comprising the sequence set forth in SEQ ID NO: 966.

13. The system of claim 12 wherein the at least one or more nucleic acids comprises a nucleic acid comprising the sequence as set forth in SEQ ID NO: 967.

14. The system of any one of claims 12-13, wherein the at least one or more nucleic acids comprises a nucleic acid comprising the sequence as set forth in SEQ ID NOs: 969 and / or 970.

15. The system of any one of claims 12-14, wherein the at least one or more nucleic acids comprises a nucleic acid comprising the sequence as set forth in SEQ ID NO: 968.

16. The system of any one of claims 12-15, wherein the at least one or more nucleic acids comprises a first nucleic acid comprising the sequence as set forth in SEQ ID NO: 967, a second nucleic acid comprising the sequence as set forth in SEQ ID NOs: 969 and / or 970, and a third nucleic acid comprising the sequence as set forth in SEQ ID NO: 968.

17. The system of any one of claims 12-16, wherein the at least one or more nucleic acids comprises a first nucleic acid comprising the sequence as set forth in SEQ ID NO: 967, a second nucleic acid comprising the sequence as set forth in SEQ ID NO: 969, and a third nucleic acid comprising the sequence as set forth in SEQ ID NO: 970, and a fourth nucleic acid comprising the sequence as set forth in SEQ ID NO: 968.

18. The system of any one of claims 12-17, wherein a. the at least one or more nucleic acids is capable of reducing expression of FAS in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid; b. the at least one or more nucleic acids is capable of reducing expression of TGFBR2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid; and / or c. the at least one or more nucleic acids is capable of reducing expression of PTPN2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

19. A system comprising: a. a first chimeric polypeptide comprising a priming receptor comprising a first antigen-binding domain that specifically binds Solute Carrier Family 34 Member 2 (SLC34A2) (SEQ ID NO: 962); b. a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising a second antigen-binding domain that specifically binds to Transmembrane protease, serine 4 (TMPRSS4) (SEQ ID NO: 960); and c. at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of: i. a nucleic acid encoding human Fas Cell Surface Death Receptor (FAS) comprising the sequence set forth in SEQ ID NO: 964; and / or ii. a nucleic acid encoding human Transforming Growth factor (TGF)-P Receptor 2 (TGFBR2) comprising the sequence set forth in SEQ ID NO: 965; and / or iii. a nucleic acid encoding Phosphatase Non-Receptor Type 2 (PTPN2) comprising the sequence set forth in SEQ ID NO: 966.

20. The system of claim 19, wherein the first antigen-binding domain comprises a first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 1001, 1009, or 1015, and a first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequences set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019, optionally wherein:a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1002, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1003, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1004, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1008; or b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014; or c. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1016, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1017, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1018, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1020, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1021, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1022.

21. The system of claim 19 or 20, wherein the first VH chain sequence comprises the sequence set forth in SEQ ID NOs: 1001, 1009, or 1015.

22. The system of claims 19-21, wherein the first VL chain sequence comprises the sequence set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019.

23. The system of claims 19-22, wherein the first antigen-binding domain comprises the sequence set forth in SEQ ID NOs: 1107, 1108, or 1109.

24. The system of claims 19-23, wherein the second antigen-binding domain comprises a second variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 319 or 326, and a second variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NOs: 320 or 327, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises thesequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; and b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR-L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331.

25. The system of claim 24, wherein the second VH comprises the sequence as set forth in SEQ ID NOs: 319 or 326.

26. The system of claim 24 or 25, wherein the second VL comprises the sequence set forth in SEQ ID NOs: 320 or 327.

27. The system of any one of claims 24-26, wherein the second antigen binding domain comprises the sequence set forth in SEQ ID NOs: 551 or 552.

28. The system of any one of claims 1-27, wherein the priming receptor comprises, from N- terminus to C-terminus, a. the first antigen-binding domain; b. a first transmembrane domain comprising one or more ligand-inducible proteolytic cleavage sites; and c. an intracellular domain comprising a human or humanized transcriptional effector, wherein binding of the first antigen-binding domain to human SCL34A2 results in cleavage at the one or more ligand-inducible proteolytic cleavage sites.

29. The system of claim 28, wherein the priming receptor comprises a first hinge domain positioned between the first antigen-binding domain and the first transmembrane domain.

30. The system of claim 29, wherein the first hinge domain comprises a CD8a or truncated CD 8 a hinge domain.

31. The system of claim 30, wherein the first hinge comprises the sequence as set forth in SEQ ID NO: 827.

32. The system of any one of claims 28-31 , wherein the first transmembrane domain comprises a Notch 1 transmembrane domain.

33. The system of any one of claims 28-32, wherein the transmembrane domain comprises the sequence as set forth in SEQ ID NO: 828.

34. The system of any one of claims 28-33, wherein the intracellular domain comprises an HNFla / p65 domain or a Gal4 / VP64 domain.

35. The system of claim 34, wherein the intracellular domain comprises the sequence as set forth in SEQ ID NO: 830, 831, or 832.

36. The system of any one of claims 28-34, wherein the priming receptor comprises a stop- transfer-sequence or juxtamembrane domain between the first transmembrane domain and the intracellular domain.

37. The system of claim 36, wherein the stop-transfer-sequence or juxtamembrane domain comprises the sequence as set forth in SEQ ID NO: 829.

38. The system of any one of claims 1-37, wherein the priming receptor comprises a sequence as set forth in SEQ ID NO: 1158, 1160, or 1162.

39. The system of any one of claims 1 to 36, wherein the CAR comprises, from N-terminus to C-terminus, a. a second antigen-binding domain; b. a second transmembrane domain; c. an intracellular co-stimulatory domain; and d. an intracellular activation domain.

40. The system of any one of claims 1-39, wherein the CAR comprises a second hinge domain.

41. The system of claim 40, wherein the second hinge domain comprises a CD8a or truncated CD8a hinge domain.

42. The system of claim 41, wherein the second hinge domain comprises a sequence as set forth in SEQ ID NO: 821.

43. The system of any one of claims 39-42, wherein the second transmembrane domain comprises a CD8a transmembrane domain.

44. The system of claim 43, wherein the second transmembrane domain comprises a sequence as set forth in SEQ ID NO: 822.

45. The system of any one of claims 39-44, wherein the intracellular co-stimulatory domain comprises a 4- IBB domain.

46. The system of claim 45, wherein the intracellular co-stimulatory domain comprises a sequence as set forth in SEQ ID NO: 823.

47. The system of any one of claims 39-46, wherein the intracellular activation domain comprises a CD3^ domain.

48. The system of claim 47, wherein the intracellular activation domain comprises a sequence as set forth in SEQ ID NO: 824.

49. The system of any one of claims 1-48, wherein the CAR comprises a sequence as set forth in SEQ ID NOs: 1164 or 1166.

50. The system of any one of claims 1-49, wherein the priming receptor and the CAR are capable of binding to a same target cell if the target cell expresses SLC34A2 and TMPRSS4.

51. The system of any one of claims 12-50, wherein the at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to human FAS, human TGFBR2 and / or human PTPN2 are at least 16, 17, 18, 19, 20, 21, or 22 nucleotides in length.

52. The system of any one of claims 12-51, wherein the at least one or more nucleic acid sequences are a short hairpin RNA (shRNA), a small interfering RNA (siRNA), a double stranded RNA (dsRNA), or an antisense oligonucleotide.

53. The system of claim 52, wherein the at least one or more nucleic acid sequences are shRNA.

54. The system of any one of claims 12-53, wherein the at least one or more nucleic acids comprises a sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 967-970.

55. The system of any one of claims 12-54, wherein the at least one or more nucleic acid sequence complementary to a nucleic acid encoding human FAS comprises a sequence as set forth in SEQ ID NO: 967.

56. The system of any one of claims 12-55, wherein the at least one or more nucleic acid reduces expression of FAS in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

57. The system of any one of claims 12-56, wherein the at least one or more nucleic acid sequence complementary to a nucleic acid encoding human TGFBR2 comprises a sequence as set forth in SEQ ID NOs: 969 or 970.

58. The system of any one of claims 12-57, wherein the at least one or more nucleic acid reduces expression of TGFBR2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

59. The system of any one of claims 12-58, wherein the system comprises at least two nucleic acid sequences complementary to a nucleic acid encoding human TGFBR2 comprising the sequences as set forth in SEQ ID NOs: 969 and 970.

60. The system of any one of claims 12-59, wherein the at least one or more nucleic acid sequence complementary to human PTPN2 comprises a sequence set forth in SEQ ID NO: 968.

61. The system of claim 60, wherein the at least one or more nucleic acid reduces expression of PTPN2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

62. The system of any one of claims 12-61, wherein the at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to human FAS, human TGFBR2, and human PTPN2 comprises a sequence as set forth in SEQ ID NO: 1252 or 972.

63. The system of any one of claims 12-62, wherein the at least one or more nucleic acid sequence complementary to a nucleic acid encoding human FAS reduces expression of FAS inthe immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid, the at least one or more nucleic acid sequence(s) complementary to a nucleic acid encoding human TGFBR2 reduces expression of TGFBR2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid, and the at least one or more nucleic acid sequence complementary to a nucleic acid encoding human PTPN2 reduces expression of PTPN2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

64. The system of any one of claims 1-63, wherein the system is encoded by: a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1238; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1239; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1240; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1241; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1242; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7257 of SEQ ID NO: 1120; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7239 of SEQ ID NO: 1121; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7621 of SEQ ID NO: 1122; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7636 of SEQ ID NO: 1123; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7621 of SEQ ID NO: 1124; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122; a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123; or a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124.

65. The system of any one of claims 1-50, wherein the system is encoded by a nucleic acid comprising a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 1120, 1121, 1122, 1123, 1124, 1238, 1239, 1240, 1241, or 1242.

66. The system of claims 50-61, wherein the target cell is a human cell.

67. The system of claims 50-66, wherein the target cell is a cancer cell expressing TMPRSS4 on its cell surface.

68. The system of claims 50-67, wherein the target cell is a cancer cell expressing SLC34A2 and TMPRSS4 on its cell surface.

69. The system of claim 67 or 68, wherein the cancer cell is a solid cancer cell or a liquid cancer cell.

70. The system of any one of claims 67-69, wherein the cancer cell is a lung cell, optionally wherein the cancer cell is a non-small cell lung cancer (NSCLC) cell, ovarian cancer, cervical cancer, endometrial cancer, uterine cancer, pancreatic cancer, esophageal cancer, head and neck squamous cell cancer, thyroid cancer, bladder cancer, breast cancer, cholangiocarcinoma cancer, colon cancer, rectal cancer, kidney cancer, renal cell carcinoma, prostate cancer, stomach cancer, or gastric cancer.

71. One or more nucleic acids comprising at least one nucleic acid fragment comprising a nucleotide sequence encoding the system of one of claims 1-70.

72. The nucleic acid(s) of claim 71, comprising a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1238; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1239; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1240; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1241; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1242; at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7257 of SEQ ID NO: 1120; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7239 of SEQ ID NO: 1121; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7621 of SEQ ID NO: 1122; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 481-7636 of SEQ ID NO: 1123; or a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% identity to a sequence comprising nucleotides 481-7621 of SEQ ID NO: 1124; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1120; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1121; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1122, a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1123, a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 1124; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121; a sequencewith at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122; a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123; or a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124.

73. The nucleic acid(s) of claim 71 , wherein the nucleic acid comprises a sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 1120, 1121, 1122, 1123, 1124, 1238, 1239, 1240, 1241 or 1242.

74. One or more nucleic acid(s), wherein the one or more nucleic acid(s) encode: a. a first chimeric polypeptide comprising a priming receptor comprising a first antigen-binding domain that specifically binds to human Solute Carrier Family 34 Member 2 (SLC34A2); b. a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising a second antigen-binding domain that specifically binds to human Transmembrane protease, serine 4 (TMPRSS4).

75. The nucleic acid(s) of claim 74, comprising at least one nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of: a. a nucleic acid encoding human Fas Cell Surface Death Receptor (FAS) comprising the sequence set forth in SEQ ID NO: 964; and / or b. a nucleic acid encoding human Transforming Growth factor (TGF)-P Receptor 2 (TGFBR2) comprising the sequence set forth in SEQ ID NO: 965; and / or c. a nucleic acid encoding Phosphatase Non-Receptor Type 2 (PTPN2) comprising the sequence set forth in SEQ ID NO: 966.

76. One or more nucleic acids, wherein the one or more nucleic acids encode: a. a first chimeric polypeptide comprising a priming receptor comprising a first antigen-binding domain that specifically binds to human Solute Carrier Family 34 Member 2 (SLC34A2);b. a second chimeric polypeptide comprising a chimeric antigen receptor (CAR) comprising a second antigen-binding domain that specifically binds to human Transmembrane protease, serine 4 (TMPRSS4); and c. at least one nucleic acid sequence at least 15 nucleotides in length complementary to a portion thereof of: i. a nucleic acid encoding human Fas Cell Surface Death Receptor (FAS) comprising the sequence set forth in SEQ ID NO: 964; and / or ii. a nucleic acid encoding human Transforming Growth factor (TGF)-P Receptor 2 (TGFBR2) comprising the sequence set forth in SEQ ID NO: 965; and / or iii. a nucleic acid encoding human Protein Tyrosine Phosphatase NonReceptor Type 2 (PTPN2) comprising the sequence set forth in SEQ ID NO: 966.

77. The nucleic acid(s) of any one of claims 74-76, wherein the first antigen-binding domain comprises a heavy chain comprising a first variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 1001, 1009, or 1015, and a first variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequences set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1002, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1003, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1004, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1008; or b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1010, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1011, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1012, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1006, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1007, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1014; orc. CDR-H1 comprises the sequence set forth in SEQ ID NO: 1016, CDR-H2 comprises the sequence set forth in SEQ ID NO: 1017, CDR-H3 comprises the sequence set forth in SEQ ID NO: 1018, CDR-L1 comprises the sequence set forth in SEQ ID NO: 1020, CDR-L2 comprises the sequence set forth in SEQ ID NO: 1021, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 1022.

78. The nucleic acid(s) of any one of claims 74-77, wherein the first VH chain sequence comprises the VH sequence set forth in SEQ ID NOs: 1001, 1009, or 1015.

79. The nucleic acid(s) of any one of claims 74-78, wherein the second VL comprises the sequence set forth in SEQ ID NOs: 1005, 1013, 1125, or 1019.

80. The nucleic acid(s) of any one of claims 74-78, wherein the first antigen-binding domain comprises the sequence set forth in SEQ ID NOs: 1107, 1108, or 1109.

81. The nucleic acid(s) of any one of claims 74-80, wherein the second antigen-binding domain comprises a second variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, of the VH sequences set forth in SEQ ID NOs: 319 or 326, and a second variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, of the VL sequence set forth in SEQ ID NOs: 320 or 327, optionally wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 321, CDR-H2 comprises the sequence set forth in SEQ ID NO: 322, CDR-H3 comprises the sequence set forth in SEQ ID NO: 323, CDR-L1 comprises the sequence set forth in SEQ ID NO: 324, CDR-L2 comprises the sequence set forth in SEQ ID NO: 325, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 16; and b. CDR-H1 comprises the sequence set forth in SEQ ID NO: 193, CDR-H2 comprises the sequence set forth in SEQ ID NO: 80, CDR-H3 comprises the sequence set forth in SEQ ID NO: 328, CDR-L1 comprises the sequence set forth in SEQ ID NO: 329, CDR-L2 comprises the sequence set forth in SEQ ID NO: 330, and CDR-L3 comprises the sequence set forth in SEQ ID NO: 331.

82. The nucleic acid(s) of any one of claims 74-81, wherein the second VH comprises the sequence as set forth in SEQ ID NO: 319 or 326.

83. The nucleic acid(s) of any one of claims 74-82, wherein the second VE comprises the sequence set forth in SEQ ID NOs: 320 or 327.

84. The nucleic acid(s) of any one of claims 74-83, wherein the second antigen binding domain comprises the sequence set forth in SEQ ID NO: 551 or 552.

85. The nucleic acid(s) of any one of claims 76-84, wherein the at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to human FAS, human TGFBR2 and / or human PTPN2 are at least 16, 17, 18, 19, 20, 21, or 22 nucleotides in length.

86. The nucleic acid(s) of any one of claims 76-85, wherein the at least one nucleic acid sequences are a short hairpin RNA (shRNA), a small interfering RNA (siRNA), a double stranded RNA (dsRNA), or an antisense oligonucleotide.

87. The nucleic acid(s) of claim 86, wherein the at least one nucleic acid sequences are shRNA.

88. The nucleic acid(s) of any one of claims 76-87, wherein the at least one or more nucleic acids comprises a sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence as set forth in SEQ ID NO: 967.

89. The nucleic acid(s) of any one of claims 76-88, wherein the at least one or more nucleic acid reduces expression of FAS in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

90. The nucleic acid(s) of any one of claims 76-87, wherein the at least one or more nucleic acid comprises a sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 969 and / or 970.

91. The nucleic acid(s) of any one of claims 76-87 or 90, wherein the at least one or more nucleic acid reduces expression of TGFBR2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

92. The nucleic acid(s) of any one of claims 76-91, comprising at least one nucleic acid sequence at least 15 nucleotides in length complementary to a nucleic acid encoding human PTPN2 comprising the sequence set forth in SEQ ID NO: 966.

93. The nucleic acid(s) of claim 92, wherein the nucleic acid sequence complementary to human PTPN2 comprises a sequence as set forth in SEQ ID NO: 968.

94. The nucleic acid(s) of claim 93, wherein the at least one or more nucleic acid reduces expression of PTPN2 in the immune cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a control cell that does not comprise the nucleic acid.

95. The nucleic acid(s) of any one of claims 76-94, wherein the at least one or more nucleic acids comprising a nucleic acid sequence at least 15 nucleotides in length complementary to human FAS, human TGFBR2, and human PTPN2 comprises a sequence as set forth in SEQ ID NO: 1252 or 972.

96. The nucleic acid(s) of any one of claims 74-95, wherein the at least one or more nucleic acid sequence is encoded in at least one intron region of the nucleic acid.

97. One or more nucleic acids comprising the nucleic acid(s) of any one of claims 74-96.

98. The nucleic acid(s) of any one of claims 71-97, wherein the nucleic acid comprises two or more nucleic acid fragments.

99. The nucleic acid(s) of any one of claims 71-98, wherein the nucleic acid comprises an inducible promoter operably linked to the nucleotide sequence encoding the CAR, wherein the inducible promoter drives the inducible expression of the CAR.

100. The nucleic acid(s) of any one of claims 71-99, wherein the nucleic acid comprises a constitutive promoter operably linked to the nucleotide sequence encoding the priming receptor, wherein the constitutive promoter drives constitutive expression of the priming receptor.

101. The nucleic acid(s) of any one of claims 71-100, wherein the nucleic acid comprises an inducible promoter element operably linked to the nucleotide sequence encoding the chimeric antigen receptor and a constitutive promoter operably linked to the nucleotide sequence encoding the priming receptor.

102. The nucleic acid(s) of any one of claims 71-101, wherein the constitutive promoter is an EFla promoter.

103. The nucleic acid(s) of claim 102, wherein the constitutive promoter comprises a sequence as set forth in SEQ ID NO: 991.

104. The nucleic acid(s) of any one of claims 71-103, wherein the inducible promoter comprises a YB-TATA promoter sequence and one or more Hepatocyte Nuclear Factor la (HNFla) response element(s).

105. The nucleic acid(s) of claim 104, wherein the YB-TATA promoter sequence comprises a sequence as set forth in SEQ ID NO: 1246.

106. The nucleic acid(s) of claim 104, wherein the one or more Hepatocyte Nuclear Factor la (HNFla) response element(s) comprises a sequence as set forth in SEQ ID NO: 1245.

107. The nucleic acid(s) of any one of claims 71-106, wherein the inducible promoter comprises a sequence as set forth in SEQ ID NO: 992.

108. The nucleic acid(s) of any one of claim 71-107, wherein the nucleic acid comprises, in a 5’ to 3’ direction, a. the constitutive promoter; b. the nucleotide sequence encoding priming receptor; c. the inducible promoter element; and d. the nucleotide sequence encoding chimeric antigen receptor.

109. The nucleic acid(s) of any one of claim 71-107, wherein the nucleic acid comprises, in a 5’ to 3’ direction, a. the inducible promoter element; b. the nucleotide sequence encoding chimeric antigen receptor; c. the constitutive promoter; and d. the nucleotide sequence encoding priming receptor.

110. The nucleic acid(s) of any one of claims 75-107, wherein the nucleic acid comprises, in a 5’ to 3’ direction,a. a first constitutive promoter; b. the nucleotide sequence encoding the priming receptor; c. optionally, a second constitutive promoter; d. the nucleotide sequence encoding the at least one nucleic acid complementary to human FAS, human TGFBR2, and / or human PTPN2; e. the inducible promoter element; and f. the optional nucleotide sequence encoding the chimeric antigen receptor.

111. The nucleic acid(s) of any one of claim 75-107, wherein the nucleic acid comprises, in a 5’ to 3’ direction, a. a first constitutive promoter; b. the nucleotide sequence encoding the priming receptor; c. optionally, a second constitutive promoter; d. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; e. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; f. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; g. the inducible promoter element; and h. the nucleotide sequence encoding the chimeric antigen receptor.

112. The nucleic acid(s) of any one of claim 75-107, wherein the nucleic acid comprises, in a 5’ to 3’ direction, a. the inducible promoter; b. the nucleotide sequence encoding the chimeric antigen receptor; c. a first constitutive promoter; d. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; e. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; f. the nucleotide sequence encoding the first nucleic acid complementary to human FAS and / or the nucleotide sequence encoding the second nucleic acid complementary to human TGFBR2 and / or the nucleotide sequence encoding the third nucleic acid complementary to human PTPN2; g. optionally, a second constitutive promoter; and h. the nucleotide sequence encoding the priming receptor.

113. The nucleic acid(s) of any one of claim 71-112, wherein the nucleic acid comprises a 5’ homology directed repair arm and a 3 ’ homology directed repair arm, both of which are complementary to an insertion site in a host cell chromosome.

114. The nucleic acid(s) of any one of claims 71-113, wherein the nucleic acid comprises a woodchuck hepatitis virus post-translational regulatory element (WPRE).

115. The nucleic acid(s) of claim 114, wherein the WPRE is at the 3’ end of the nucleotide sequence encoding chimeric antigen receptor and at the 5 ’ end of the nucleotide sequence encoding priming receptor or wherein the WPRE is at the 3’ end of the nucleotide sequenceencoding priming receptor and at the 5 ’ end of the nucleotide sequence encoding chimeric antigen receptor.

116. The nucleic acid(s) of any one of claims 71-114, wherein the nucleic acid comprises synthetic polyA signal, an SV40 poly A signal, a human growth hormone (GH) polyA signal, or a bovine growth hormone (bGH) polyA signal.

117. The nucleic acid(s) of any one of claims 71 to 116, wherein the nucleic acid is incorporated into an expression cassette or a vector for viral or non-viral delivery to a cell.

118. The nucleic acid(s) of claim 117, wherein the vector is for non-viral delivery and is, e.g., a non-viral vector.

119. A vector comprising the nucleic acid of any one of claims 71-118.

120. The vector of claim 119, wherein the 5’ and 3’ ends of the nucleic acid comprise nucleotide sequences that are homologous to genomic sequences flanking an insertion site in a genome of a primary cell.

121. The vector of claim 120, wherein the insertion site is located at a genomic safe harbor (GSH) locus.

122. The vector of claim 121, wherein the GSH locus is a GS94 locus (chrl 1: 128340000- 128350000).

123. The vector of claim 122, wherein the nucleotide sequences that are homologous to genomic sequences flanking the GS94 locus insertion site comprise nucleotides 24-473 and 7258-7707 of SEQ ID NO: 1120; nucleotides 24-473 and 7240-7689 of SEQ ID NO: 1121; nucleotides 24-473 and 7622-8071 of SEQ ID NO: 1122; nucleotides 24-473 and 7637-8086 of SEQ ID NO: 1123; or nucleotides 24-473 and 7622-8071 of SEQ ID NO: 1124.

124. The vector of claim 122 or 123, wherein the nucleotide sequences that are homologous to genomic sequences flanking the GS94 locus insertion site comprise SEQ ID NOs: 1235 and 1236.

125. The vector of claim 122 or 123, comprising homology regions to the gRNA of the RNP complex used for inserting the nucleic acid into the genome of a cell.

126. The vector of claim 125, wherein the sequences of the gRNA homology regions comprise SEQ ID NOs: 932 and 1237.

127. An isolated cell comprising: a. the system of any one of claims 1 to 70; b. at least one nucleic acid of any one of claims 71 to 118; and / or c. the vector of any one of claims 119-126.

128. The isolated cell of claim 124, wherein the cell is an immune cell.

129. An isolated immune cell comprising: a. the system of any one of claims 1 to 70; b. at least one nucleic acid of any one of claims 71 to 118; and / or c. the vector of any one of claims 119-126.

130. The isolated cell of claim 128 or 129, wherein the immune cell is a primary human immune cell.

131. The isolated cell of any one of claims 128-130, wherein the primary immune cell is a natural killer (NK) cell, a T cell, a CD8+ T cell, a CD4+ T cell, a primary T cell, or a T cell progenitor.

132. The isolated cell of any one of claims 128-131, wherein the primary immune cell is a primary T cell.

133. The isolated cell of any one of claims 128-132, wherein the primary immune cell is a primary human T cell.

134. A population of isolated cells comprising a plurality of cells or immune cells of any one of claims 124-133.

135. A pharmaceutical composition comprising the isolated cells or immune cell of any one of claims 124 to 133 or the population of isolated cells of claim 134, and a pharmaceutically acceptable excipient.

136. A pharmaceutical composition comprising the nucleic acid of any one of claims 71-118 or the vector of any one of claims 119-126, and a pharmaceutically acceptable excipient.

137. A method of editing a cell, comprising inserting the nucleic acid of any one of claims 71 to 118 into a genome of the cell.

138. The method of claim 137, wherein the nucleic acid is inserted into a genomic safe harbor (GSH) locus.

139. The method of claim 138, wherein the GSH locus is a GS94 locus (chrl 1 : 128340000- 128350000).

140. A method of killing a target cell in a subject comprising administering the immune cell or population of immune cells of any one of claims 127-134 to the subject, wherein the immune cell kills the target cell and / or triggers cytolysis of the target cell.

141. A method of inhibiting a target cell in a subject comprising administering the immune cell or population of immune cells of any one of claims 127-134 to the subject, wherein the immune cell inhibits the target cell.

142. The method of claim 140 or 141, wherein the target cell expresses human TMRPSS4 or human TMPRSS4 and human SCL34A2.

143. The method of any one of claims 140-142, wherein the target cell is a cancer cell.

144. A method of treating a disease in a human subject comprising administering the cells or immune cell or population of cells or immune cells of any one of claims 127-134 or the pharmaceutical composition of claims 135 or 136 to the subject.

145. The method of claim 144, wherein the disease is cancer.

146. A method of treating cancer in a human subject, comprising administering the immune cell or population of immune cells of any one of claims 127-134 or the pharmaceutical composition of claims 135 or 136 to the subject, wherein the immune cells are primary immune cells obtained from the subject.

147. The method of any one of claims 143, 145, or 146, wherein the cancer cells express human TMRPSS4 or human TMPRSS4 and human SCL34A2 on the cell membrane.

148. A method of treating a disease in a subject comprising: a. determining or having determined the presence of human SLC34A2-positive (SLC34A2+) cells in a cancer sample obtained from the subject; and / orb. determining or having determined the presence of human TMPRSS4-positive (TMPRSS4+) cells in a cancer sample obtained from the subject; and c. administering the cell or immune cell of any one of claims 127-134 or the pharmaceutical composition of claims 135 or 136 to the subject.

149. The method of claims 143 or 145-148, wherein the cancer is a solid cancer or a liquid cancer.

150. The method of claims 143 or 145-149, wherein the cancer is non-small cell lung cancer (NSCLC), ovarian cancer, cervical cancer, endometrial cancer, uterine cancer, pancreatic cancer, esophageal cancer, head and neck squamous cell cancer, thyroid cancer, bladder cancer, breast cancer, cholangiocarcinoma cancer, colon cancer, rectal cancer, kidney cancer, renal cell carcinoma, prostate cancer, stomach cancer, or gastric cancer.

151. The method of any one of claims 140-150, wherein the administration of the immune cell to the subject enhances an immune response in the subject or kills, or induces cytolysis, of the cancer cells.

152. A method of modulating the activity of a cell or immune cell comprising: a. obtaining a cell or immune cell comprising b. the system of any one of claims 1-70; c. the nucleic acid of any one of claims 71-118; and / or d. the vector of any one of claims 119-126; and e. contacting the cell or immune cell with a target cell expressing SLC34A2 and TMPRSS4, wherein binding of the priming receptor to SLC34A2 on the target cell induces activation of the priming receptor and expression of the chimeric antigen receptor and wherein binding of the chimeric antigen receptor to TMPRSS4 on the target cell modulates the activity of the immune cell.

153. The method of claim 152 or 154, wherein the immune cell activity is cytolytic activity.

154. The method of claim 152, wherein the modulation of the immune cell activity comprises enhancing an immune response.

155. The method of claim 151 or 154, wherein the enhanced immune response is an adaptive immune response.

156. The method of claim 151 or 154, wherein the enhanced immune response is an innate immune response.

157. The method of any one of claims 151 or 154-156, wherein the enhanced immune response is an increased expression of at least one cytokine or chemokine.

158. The method of claim 157, wherein the cytokine is interferon-gamma (IFNy).

159. The method of any one of claims 140 -158, comprising administering an immunotherapy to the subject concurrently with the cell or immune cell or subsequently to the cell or immune cell.

160. A method of inducing expression of a chimeric antigen receptor with a priming receptor in a cell comprising: a. obtaining a cell or immune cell comprising i. the system of any one of claims 1-70; ii. the nucleic acid of any one of claims 71-118; and / or iii. the vector of any one of claims 119-126; and b. contacting the cell or immune cell with a cell expressing SLC34A2, wherein binding of the priming receptor to SLC34A2 on the cell induces activation of the priming receptor and expression of the chimeric antigen receptor.

161. A nucleic acid comprising a nucleic acid sequence that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NOs: 1120, 1121, 1122, 1123, 1124, 1238, 1239, 1240, 1241, or 1242, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24- 7707 of SEQ ID NO: 1120, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequencecomprising nucleotides 24-8086 of SEQ ID NO: 1123, or at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124; wherein the nucleic acid encodes a priming receptor comprising a first antigen binding domain that binds to SLC34A2 and a chimeric antigen receptor comprising a second antigen binding domain that binds to TMPRSS4.

162. The nucleic acid of claim 161, wherein any difference in the nucleotide sequence as compared to SEQ ID NOs: 1120, 1121, 1122, 1123, 1124, 1238, 1239, 1240, 1241, 1242, or a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120, a sequence comprising nucleotides 24-7689 of SEQ ID NO: 1121, a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122, a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123, or a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124 does not affect the activity of any of the elements provided in Table 19.

163. The nucleic acid of claim 161 or 162, comprising a sequence selected from the sequences as set forth in SEQ ID NOs: 1122, 1123, 1124, 1238, 1239, 1240, 1241, or 1242 or a sequence comprising nucleotides 24-7707 of SEQ ID NO: 1120, a sequence comprising nucleotides 24- 7689 of SEQ ID NO: 1121, a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1122, a sequence comprising nucleotides 24-8086 of SEQ ID NO: 1123, or a sequence comprising nucleotides 24-8071 of SEQ ID NO: 1124.

164. An isolated human cell comprising the nucleic acid of any one of claims 161-163.

165. The isolated human cell of claim 164, wherein the nucleic acid is inserted into a genomic safe harbor (GSH) locus of the cell.

166. The isolated human cell of claim 165, wherein the GSH locus is a GS94 locus (chrl 1 : 128340000-128350000).

167. The isolated human cell of any one of claims 164-166, comprising a sequence selected from the sequences set forth in SEQ ID Nos: 1238, 1239, 1240, 1241 and 1242.

168. An isolated human cell expressing a priming receptor comprising an antigen-binding domain that specifically binds to human SLC34A2 and a CAR comprising an antigen-binding domain that specifically binds to human TMPPRSS4, wherein binding of the priming receptor toSLC34A2 on the surface of a target cell and binding of the CAR to TMPRSS4 on the surface of a target cell induces lysis of the cell expressing TMPRSS4.

169. The cell of claim 168, where the cell expressing TMPRSS4 comprises SLC34A2 surface expression.

170. One or more nucleic acids comprising a nucleic acid sequence encoding a first cell surface receptor that specifically binds to human SLC34A2 and a nucleic acid sequence encoding a second cell surface receptor that specifically binds to human TMPRSS4, wherein binding of the first and second cell surface receptors to SLC34A2 and TMPRSS4 on the surface of one or more human cells, respectively, induces lysis of a human cell with TMPRSS4 on the surface.

171. The one or more nucleic acids of claim 170, wherein the first and the second cell surface receptor comprise the VH and VL of any of the SLC34A2 or TMPRSS4 antigen binding domains described herein, or their VH and VL CDRs.

172. A nucleic acid comprising a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1238, 1239, 1240, 1241, or 1242, which contains functional domains and wherein the activity of the functional domains is not altered relative to those in a nucleic acid consisting of SEQ ID NO: 1238, 1239, 1240, 1241, or 1242, respectively, or comprises silent substitutions, additions or deletions of nucleotides.

173. A nucleic acid comprising a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1120, 1121, 1122, 1123, or 1124, which contains functional domains and wherein the activity of the functional domains is not altered relative to those in a nucleic acid consisting of SEQ ID NO: 1120, 1121, 1122, 1123, or 1124 respectively, or comprises silent substitutions, additions or deletions of nucleotides.

174. A nucleic acid comprising SEQ ID NO: 1238, 1239, 1240, 1241, or 1242.

175. A nucleic acid comprising SEQ ID NO: 1120, 1121, 1122, 1123, or 1124.

176. The nucleic acid of claims 174 or 175, wherein the nucleic acid is a linear nucleic acid177. The nucleic acid of claims 174 or 175, wherein the nucleic acid is a circular nucleic acid178. The nucleic acid of any one of claims 174-177, comprising an additional 5' and / or 3' nucleotide sequence179. The nucleic acid of claim 178, wherein the additional 5' and / or 3' nucleotide sequence comprises from 1-100 nucleotides180. The nucleic acid of claims 178 or 179, wherein the additional 5' nucleotide sequence and the additional 3' nucleotide sequence each comprise a protelomerase binding sequence.

181. The nucleic acid of any one of claims 174-180, wherein the nucleic acid is a closed end DNA (ceDNA).

182. A cell comprising a nucleotide sequence comprising SEQ ID NO: 1238, 1239, 1240, 1241, or 1242 or a nucleotide sequence that differs therefrom in at most 50 nucleotides, wherein the differences are silent substitutions, additions or deletions.

183. A cell comprising a nucleotide sequence comprising SEQ ID NO: 1120, 1121, 1122,1123, or 1124 or a nucleotide sequence that differs therefrom in at most 50 nucleotides, wherein the differences are silent substitutions, additions or deletions.

184. The cell of claim 182 or 183, wherein the cell is a human cell.

185. The cell of claim 184, wherein the cell is a primary cell.

186. The cell of claim 185, wherein the cell is a T cell.

187. The cell of any one of claims 182-186, wherein the cell is manufactured from a cell obtained from a human subject.

188. The cell of any one of claims 182-187, which comprises at least one protein encoded by SEQ ID NO: 1120, 1121, 1122, 1123, or 1124 or SEQ ID NO: 1238, 1239, 1240, 1241, or 1242.

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