Trop2 binders and conjugates thereof

Abstract

TROP2 binders and variants thereof are described. In a specific embodiment, the TROP2 binders that are antibodies that preferentially bind high-expressing TROP2 cells over low-expressing TROP2 cells and conjugates thereof comprising the TROP2 binders conjugated to a payload are described.

Description

Abstract This paper describes TROP2 binding molecules and their variants. In specific embodiments, the present invention discloses a class of anti-TROP2 antibodies that preferentially bind to TROP2-high expressing cells rather than low-expressing cells, and also discloses conjugates prepared by coupling such binding molecules with a payload.

Claims

WHAT IS CLAIMED:

1. An antibody drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof that specifically binds to human TROP2 conjugated to a linker- monomethylauristatin E (linker-MMAE) payload, wherein the antibody comprises two heavy chains, each heavy chain comprising a variable domain and a constant domain, the variable domain comprising a complementarity determining region (CDR) Hl , a CDRH2, and a CDRH3, and two light chains, each light chain comprising a variable domain and a constant domain, the vanable domain comprising a CDRL1, a CDRL2, and a CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3. respectively, comprise the amino acid sequence of NYGMN (SEQ ID NO: 4). WINTYTGEPTYTDDFKG (SEQ ID NO: 5). GGFGSSYWYFDV (SEQ ID NO: 6), KASQDVSIAVA (SEQ ID NO: 7), SASDRYT (SEQ ID NO: 10), and QQHYITPLT (SEQ ID NO: 9).

2. The ADC of claim L wherein the antibody or antigen-binding fragment thereof displays reduced binding to low TROP2-expressing cells compared to high TROP2-expressing cells and has reduced hydrophobicity compared to Sacituzumab as determined by hydrophobic interaction chromatography (HIC),3. The ADC of claim 1, wherein the antibody or antigen-binding fragment thereof is humanized.

4. The ADC of claim 1, wherein the antigen binding fragment of the antibody is a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

5. The ADC of claim 1, wherein the heavy chain variable domain comprises the ammo acid sequence of SEQ ID NO; 1 or 14 and the light chain variable domain comprises the ammo acid sequence of SEQ ID NO: 3 or 16.

6. lire ADC of claim 5, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 1 and the light chain variable domain comprises the ammo acid sequence of SEQ ID NO: 3 or the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 14 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 16.

7. The .ADC of claim 1, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 13 or 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 1 , 17. or 18.

8. Hie ADC of claim 7, wherein the antibody comprises(a) a light chain comprising the amino acid sequence of SEQ ID NO: 13 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 11;(b) a light chain comprising the amino acid sequence of SEQ ID NO: 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 17; or(c) a light chain comprising the amino acid sequence of SEQ ID NO: 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 18.

9. The ADC of claim 1, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 13 or 22 and a heavy’ chain comprising the ammo acid sequence of SEQ ID NO: 58, 59, or 60.

10. The ADC of claim 9, wherein the antibody’ comprises(a) a light chain comprising the amino acid sequence of SEQ ID NO: 13 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 58;(b) a light chain comprising the ammo acid sequence of SEQ ID NO: 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 59; or(c) a light chain comprising the ammo acid sequence of SEQ ID NO: 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 60.1 1. The ADC of claim 1, wherein the antibody further comprises a cysteine or a non- canonical amino acid amino acid substitution at one or more position(s) selected from the group consisting of: positions 152, 1.53, 171 , 172, 173. and 375 of the constant domain of the heavychain and positions 165 and 168 of the constant domain of the light chain, wherein the position numbering of the heavy chain constant domain is according to Eu numbering and the position numbering of the light chain constant domain is according to sequential numbering of the whole light chain sequence.

12. The ADC of claim 11. wherein the antibody comprises a cysteine or a non- canonical ammo acid amino acid substitution at position 375 of the constant domain of the heavy chain.

13. The ADC of claim 12, wherein the antibody comprises a heavy chain comprising the ammo acid sequence of SEQ ID NO: 19, 20. 61, or 6214. The ADC of any one of claims 11 to 13, wherein the linker-MMAE pay load is conjugated to the cysteine or noncanonical amino acid.

15. The ADC of claim 1, wherein the antibody comprises a cysteine residue in which the thiol (SH) group thereof is conjugated to a linker-MMAE payload comprising the formula:MP-AA-PABC-MMAE.CM2P-AA-PABC-MMAE:CM3P-AA-PABC-MMAE:

16. The ADC of claim 1, wherein the ADC comprises the formula:wherein Ab is an anti-TROP2 antibody; and p, is an integer from 1 to 8. wherein S is from the side chain of a cysteine residue of the antibody.

17. The ADC of claim 1, wherein the ADC comprisesthe formula:w herein Ab is an anti-TROP2 antibody comprising heavy chain engineered cysteine residues or light chain engineered cysteine residues, wherein the anti-TROP2 antibody comprising the engineered cysteine residues is (A) selected from the group consisting of:(a) aTROP2 (HC:Sac-E152C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 64 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(b) &TROP2 (HC: Sac-El 53C) (LC:Sac-Y53D) two heavy chains having the amino acid sequence set forth in SEQ ID No: 65 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(c) aTR0P2 (HC:Sac-E171C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 66 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(d) aTROP2 (HC:Sac-E172C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 67 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(e) aTROP2 (HC:Sac-E173C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 68 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(f) aTROP2 (HC:Sac-S375C) (LC:Sac-Y53D) comprising two heavy chains hating the amino acid sequence set forth in SEQ ID No: 69 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(g) aTROP2 (HC:Sac-YTE-E152C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 71 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(h) aTROP2 (HC:Sac-YTE-E153C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 72 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(i) aTROP2 (HC:Sac-YTE-E171C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 73 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(j) aTROP2 (HC:Sac-YTE-E172C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 74 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(k) O.TROP2 (HC:Sac-YTE-E173C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 75 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(l) aTROP2 (HC:Sac-YTE-S375C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 76 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(m) O.TROP2 (HC:Sac) (LC:Sac-Y53D-E165C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 58 and two light chains having the amino acid sequence set forth in SEQ ID NO: 50;(n) aTR0P2 (HC:Sac) (LC:Sac-Y53D-E168C) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 58 and two light chains having the amino acid sequence set forth in SEQ ID NO: 51 ;(o) aTROP2 (HC:Sac-YTE) (LC:Sac-Y53D-E165C) comprising two heavy chains having the amino acid sequence set forth in SEQ1ID No: 63 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 50;(p) aTROP2 (HC:Sac-YTE) (LC:Sac-Y53D-E168C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 63 and two light chains having the amino acid sequence set forth in SEQ ID NO: 51 ;(q) aTROP2 (HC:BSM-S375C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 83 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21;(r) aTROP2 (HC1BSM-E152C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 78 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 2.2;(s) aTROP2 (HC:BSM-E153C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 79 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(t) aTROP2 (HC:BSM-E171C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 80 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22;(u) aTROP2 (HC:BSM-E172C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 81 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(v) aTROP2 (HC:BSM-E173C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 82 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(w') al ROP2 (HC:BSM-S375C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 83 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22;(x) aTROP2 (HC:BSM) (LC:BSM-Y53D-E165C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 59 and two light chains having the amino acid sequence set forth in SEQ ID NO: 54;(y) aTR0P2 (HC:BSM) (LC:BSM-Y53D~E168C) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 59 and two light chains having the amino acid sequence set forth in SEQ ID NO: 55;(z) aTROP2 (HC:BSM-YTE) (LC:BSM-Y53D-E165C) comprising two heavy chains having the amino acid sequence set forth in SEQ1ID No: 60 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 54;(aa) aTROP2 (HC;BSM-YTE) (LC:BSM-Y53D-E168C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 58 and two light chains having the amino acid sequence set forth in SEQ ID NO: 57;(bb) aTROP2 (HC:BSM-YTE-E152C) (LC:BSM-Y53D) comprising two heavychains having the ammo acid sequence set forth in SEQ ID No: 85 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(cc) a.TROP2 (HC:BSM-YTE-E153C) (LC:BSM-Y53D) comprising two heavychains having the amino acid sequence set forth in SEQ ID No: 86 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(dd) aTROP2 (HC;BSM-YTE-E171C) (LC:BSM-Y53D) comprising two heavychains having the amino acid sequence set forth in SEQ ID No: 87 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22;(ee) aTROP2 (HC:BSM-YTE-E172C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 88 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(ft) aTROP2 (HC:BSM-YTE-E173C) (LC:BSM-Y53D) comprising two heavychains having the amino acid sequence set forth in SEQ ID No: 89 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22; and(gg) aTROP2 (HC:BSM-YTE-S375C) (LC:BSM-Y53D) comprising two heavychains having the ammo acid sequence set forth in SEQ ID No: 90 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22; wherein S is from the side chain of the engineered cysteine residue; and, wherein p is an integer selected from 1 or 2; or (B) selected from the group consisting of:(a) aTROP2 (HC:Sac-E152C-S375C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 70 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(b) aTROP2 (HC:Sac-YTE-E152C-S375C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 77 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(c) aTROP2 (HC:BSM-E152C-S375C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 84 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22; and(d) aTROP2 (HC:BSM-YTE-E152C-S375C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 91 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22; wherein S is from the side chain of the engineered cysteine residue; and, wherein p is an integer selected from 1, 2, 3, or 4.

18. The ADC of claim 1 , wherein the ADC comprises the formula:wherein Ab is an anti-TR0P2 antibody comprising heavy chain engineered cysteine residues or light chain engineered cysteine residues, wherein the anti-TROP2 antibody comprising the engineered cysteine residues is (A) selected from the group consisting of:(a) aTROP2 (HC:Sac-E152C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 24 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(b) aTROP2 (HC : Sac-El 53C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 25 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(c) aTROP2 (HC:Sac-E171C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 26 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(d) aTROP2 (HC:Sac-E172C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 27 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(e) aTROP2 (HC:Sac-E173C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 28 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(f) aTROP2 (HC:Sac-S375C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 29 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(g) O.TROP2 (HC:Sac-YTE-E152C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 31 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(h) aTR0P2 (HC:Sac-YTE-E153C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 32 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(i) aTROP2 (HC:Sac-YTE-E171C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 33 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13:(j) aTROP2 (HC:Sac-YTE-E172C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 34 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(k) C.TROP2 (HC:Sac-YTE-EI73C) (LC:Sac-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 35 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(l) aTROP2 (HC:Sac-YTE-S375C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 36 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(m) aTROP2 (HC:Sac) (LC:Sac-Y53D-E165C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 11 and two light chains having the amino acid sequence set forth in SEQ ID NO: 52;(n) aTROP2 (HC:Sac) (LC:Sac-Y53D-E168C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 11 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 53;(o) aTROP2 (HC:Sac-YTE) (LC:Sac-Y53D-E165C) comprising two heavychains having the amino acid sequence set forth in SEQ ID No: 23 and two light chains having the amino acid sequence set forth in SEQ ID NO: 52;(p) O.TROP2 (HC:Sac-YTE) (LC:Sac-Y53D-E168C) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 23 and two light chains having the amino acid sequence set forth in SEQ ID NO: 53;(q) aTROP2 (HC:BSM-S375C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 19 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 21;(r) aTROP2 (HC:BSM-E152C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 38 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(s) aTR0P2 (HC:BSM-E153C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 39 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(t) aTROP2 (HC:BSM-E171C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 40 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(u) a TROP2 (HC:BSM-EI 72C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 41 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22;(vj (XTR0P2 (HC:BSM-EI 73C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 42 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(w) U.TROP2 (HC:BSM-S375C) (LC:BSM-Y53D) composing two heavy chains having the ammo acid sequence set forth in SEQ ID No: 19 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 2.2;(x) aTROP2 (HC:BSM) (LC:BSM-Y53D-E168C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 17 and two light chains having the amino acid sequence set forth in SEQ ID NO: 55;(y) aTROP2 (HC:BSM-YTE) (LC:BSM-Y53D-E165C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 18 and two light chains having the amino acid sequence set forth in SEQ ID NO: 54;(z) aTROP2 (HC:BSM-YTE) (LC:BSM-Y53D-E168C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 18 and two light chains having the amino acid sequence set forth in SEQ ID NO: 55;(aa) aTROP2 (HC:BSM-YTE-E152C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 44 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(bb) aTROP2 (HC:BSM-YTE-E153C) (LC1BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 45 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(cc) aTROP2 (HC:BSM-YTE-EI71C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 46 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22;(dd) aTROP2 (HC:BSM-YTE-E172C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 47 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22;(ee) aTROP2 (HC:BSM-YTE-E173C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 48 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22; and(ft) aTROP2 (HC:BSM-YTE-S375C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 20 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22; wherein S is from the side chain of the engineered cysteine residue; and, wherein p is an integer selected from 1 or 2; or (B) selected from the group consisting of:(a) aTROP2 (HC:Sac-E152C-S375C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 30 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 13;(b) aTROP2 (HC:Sac-YTE-E152C-S375C) (LC:Sac-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 37 and two light chains having the amino acid sequence set forth in SEQ ID NO: 13;(c) aTROP2 (HC:BSM-E152C-S375C) (LC:BSM-Y53D) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 43 and two light chains having the amino acid sequence set forth in SEQ ID NO: 22; and(d) aTROP2 (HC:BSM-YTE-E152C-S375C) (LC:BSM-Y53D) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 49 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22; wherein S is from the side chain of the engineered cysteine residue; and, wherein p is an integer selected from 1 , 2, 3, or 4.

19. The ADC of ciaim 1, wherein the ADC comprises the formula:wherein Ab is an anti-Trop2 antibody comprising two heavy chains having the amino acid sequence set forth in SEQ ID NO: 20 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 22; wherein p is 1 or 2; and wherein S is from the side chain of an engineered cysteine residue at position 375 of the constant domain of the heavy chain, the position as defined according to Eu numbering.

20. The ADC of claim 1, wherein the ADC comprises the formula:wherein Ab is an anti-TROP2 antibody; wherein p is 1 or 2, and wherein S is from the side chain of an engineered cysteine residue at position 375 of the constant domain of the heavy chain, the position as defined according to Eu numbering.

21. A composition comprising the ADC of any one of claims 1 to 20 and a pharmaceutically acceptable carrier.The composition of claim 21. wherein the predominant ADC species in the composition comprises (i) antibodies in which the heavy chain C -terminus lacks a lysine residue:(ii) antibodies in which the heavy chain N-terminus is glutamine, glutamic acid, or pyroglutamate; or, (iii) antibodies in which the heavy chain C-terminus lacks a lysine residue and the heavy chain N-terminus is glutamine, glutamic acid, or pyroglutamate.

23. .A method for treating a cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the ADC of any one of claims 1 to20 or the composition of claim 21 or claim 22 to treat the cancer, wherein the cancer is a cancer that overexpresses TROP2.

24. The method of claim 23, wherein the cancer is selected from the group consisting of breast cancer (e.g.. triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary’ bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-sniall cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

25. Use of an ADC of any one of claims 1 to 20 or the composition of of claim 2.1 or22 for the manufacture of a medicament for treatment of a cancer that overexpresses TR0P2.

26. The use of claim 25, wherein the cancer is selected from the group consisting of breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), coion cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

27. The ADC of any one of claims 1 to 20 or the composition of claim 21 or claim 22 for treatment of a cancer that overexpresses TROP2.

28. The ADC of claim 27, wherein the cancer is selected from the group consisting of breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic, cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

29. A combination therapy for treating cancer comprising the ADC of any one of claims Ito 20 or the composition of claim 21 or claim 22 and a therapeutic agent, wherein the cancer is a cancer that overexpresses TROP2.

30. The combination therapy of claim 29, wherein the therapeutic agent is a chemotherapy agent or a therapeutic antibody.

31. The combination therapy of claim 30, wherein the therapeutic antibody’ is a checkpoint inhibitor.32 The combination therapy of claim 31, wherein the therapeutic antibody is an anti- PD1 antibody or an anti-PD-Ll antibody.

33. The combination therapy of ciaim 29, wherein the cancer is selected from the group consisting of breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer. non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CM J. Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

34. An antibody -drug conjugate (ADC) comprising an antibody that specifically binds to human TROP2 conjugated to a linker-monomethylauristatin E (linker-MMAE) payload, wherein the antibody comprises two heavy chains, each heavy chain comprising a variable domain and a constant domain, the variable domain comprising the ammo acid sequence of SEQ ID NO: 14, and two light chains, each light chain comprising a variable domain and a constant domain, the variable domain comprising the amino acid sequence of SEQ ID NO: 15.

35. The ADC of claim 34, wherein the antibody displays reduced hydrophobicity compared to Sacituzuniab as determined by hydrophobic interaction chromatography (HIC).

36. The ADC of claim 34, wherein the antibody further comprises a cysteine or a non-canonical amino acid amino acid substitution at one or more position(s) selected from the group consisting of: positions 152, 153, 171, 172, 173, and 375 of the constant domain of the heavy chain and positions 165 and 168 of the constant domain of the light chain, wherein the position numbering of the heavy chain constant domain is according to Eu numbering and the position numbering of the light chain constant domain is according to sequential numbering of the whole light chain sequence.

37. The ADC of claim 36, wherein the antibody comprises a cysteine or a non- canonical ammo acid amino acid substitution at position 375 of the constant domain of the heavy chain.

38. The ADC of claim 34, wherein the antibody comprises a heavy chain comprising the ammo acid sequence of SEQ ID NO: 17, 18, 19, 20, 59, 60, or 61 and a light chain comprising the amino acid sequence of SEQ ID NO: 21.

39. The ADC of claim 36, wherein the linker-MMAE payload is conjugated to the cysteine or noncanonical amino acid.

40. The ADC of claim 34, wherein the antibody comprises a cysteine residue in which the thiol (SH) group thereof is conjugated to a linker-MMAE pay load comprising the formula:MP-AA-PABC-MMAE:CM3P-AA-PABC-MMAE:

41. Hie ADC of claim 34, wherein the ADC comprises the formula:wherein Ab is the antibody: and p, is an integer from 1 to 8, wherein S is from the side chain of a cysteine residue of the antibody.

42. The ADC of claim 34, wherein the ADC comprisesthe formula:wherein Ab is the antibody, wherein the antibody comprises a heavy chain engineered cysteine residues or light chain engineered cysteine residues, wherein the antibody comprising the engineered cysteine residues is: (A) selected from the group consisting of:(a) aTROP2 (HC:BSM-E152C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 78 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21;(b) a,TROP2 (HC:BSM-E153C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 79 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ;(c) aTR0P2 (HC1BSM-E171C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 80 and two tight chains having the amino acid sequence set forth in SEQ ID NO: 21;(d) aTROP2 (HC:BSM-E172C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 81 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ;(e) aTROP2 (HC:BSM-E173C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 82 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ;(I) aTROP2 (HC:BSM) (LC:BSM-E165C) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 59 and two light chains having the amino acid sequence set forth in SEQ ID NO: 52;(g) aTROP2 (HC:BSM) (LC:BSM-E168C) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 59 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 53;(h) aTROP2 (HC:BSM-YTE) (LC:BSM-E165C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 60 and two light chains having the amino acid sequence set forth in SEQ ID NO: 52;(i) aTROP2 (HC:BSM-YTE) (LC:BSM-EI68C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 60 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 53;(j) aTROP2 (HC:BSM-YTE-E152C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 85 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ;(k) aTROP2 (HC:BSM-YTE-E153C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 86 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ;(l) aTROP2 (HC:BSM-YTE-E171C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 87 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 21 ;(m) O.TROP2 (HC:BSM-YTE-E172C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 88 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21;(n) aTROP2 (HC:BSM-YTE-E173C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 89 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ; and(o) aTROP2 (HC:BSM-YTE-S375C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 90 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ; wherein S is from the side chain of the engineered cysteine residue; and. wherein p is an integer selected from 1, 2, 3, or 4; or (B) selected from the group consisting of:(a) «TROP2 (HC:BSM-E152C-S375C) (LC.BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 84 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21; and(b) O.TROP2 (HC:BSM-YTE-E152C-S375C) (LC:BSM) comprising two heavychains having the ammo acid sequence set forth in SEQ ID No: 91 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 21; and wherein S is from the side chain of the engineered cysteine residue; and, wherein p is an integer selected from 1, 2, 3, or 4.

43. The ADC of claim 34. wherein the ADC comprises the formula:wherein Ab is the antibody, wherein the antibody comprises a heavy chain engineered cysteine residues or light chain engineered cysteine residues, wherein the antibody comprising the engineered cysteine residues is: (A) selected from the group consisting of:(a) aTR0P2 (HC:BSM-E152C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 38 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ;(b) C.TROP2 (HC:BSM-E153C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 39 and two light chains having the amino acid sequence set forth m SEQ ID NO: 21;(c) aTROP2 (HC:BSM-EI71C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 40 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 21;(d) aTROP2 (HC:BSM-E172C) (LC'.BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 41 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ;(e) aTROP2 (HC:BSM-E173C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 42 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21;(I) aTROP2 (HC:BSM) (LC:BSM-E165C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 17 and two light chains having the amino acid sequence set forth in SEQ ID NO: 52;(g) aTROP2 (HC:BSM) (LC:BSM-E168C) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 1 7 and two light chains having the amino acid sequence set forth in SEQ ID NO: 53;(h) aTR0P2 (HC:BSM-YTE) (LC:BSM-E165C) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 18 and two light chains having the amino acid sequence set forth in SEQ ID NO: 52;(i) aTROP2 (HC1BSM-YTE) (LC1BSM-E168C) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 18 and two light chains having the amino acid sequence set forth in SEQ ID NO: 53;(j) aTROP2 (HC:BSM-YTE-E152C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 44 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 21 ;(k) (XTROP2 (HC:BSM-YTE-E153C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 45 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21;0) aTROP2 (HC:BSM-YTE-E171C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 46 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 2.1 ;(m) aTROP2 (HC:BSM-YTE-E172C) (LC1BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 47 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21;(n) a,TROP2 (HC:BSM-YTE-EI73C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 48 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 21; and(o) aTROP2 (HC:BSM-YTE-S375C) (LC:BSM) comprising two heavy chains having the ammo acid sequence set forth in SEQ ID No: 20 and two light chains having the amino acid sequence set forth in SEQ ID NO: 21 ; wherein S is from the side chain of the engineered cysteine residue; and, wherein p is an integer selected from 1 or 2; or (B) selected from the group consisting of:(a.) aTROP2 (HC.BSM-E152C-S375C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 43 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 21; and(b) aTROP2 (HC:BSM-YTE-E152C-S375C) (LC:BSM) comprising two heavy chains having the amino acid sequence set forth in SEQ ID No: 49 and two light chains having the ammo acid sequence set forth in SEQ ID NO: 21;wherein S is from the side chain of the engineered cysteine residue; and, wherein p is an integer selected from 1, 2, 3, or 4.

44. The ADC of claim 34, wherein the ADC comprises the formulacysteine residue of the antibody.

45. A composition comprising the ADC of any one of claims 34 to 44 and a pharmaceutically acceptable carrier.

46. The composition of claim 45, wherein the predominant ADC species in the composition comprises (i) antibodies in which the heavy chain C-terminus lacks a lysine residue; (ii) antibodies in which the heavy chain N-terminus is glutamine, glutamic acid, or pyroglutamate; or, (iii) antibodies in which the heavy chain C-terminus lacks a lysine residue and the heavy chain N-terminus is glutamine, glutamic acid, or pyroglutamate.

47. A method for treating a cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the ADC of any one ofclaims 34 to 44 or the composition of claim 45 or claim 46 to treat the cancer, wherein the cancer is a cancer that overexpresses TROP2.

48. The method of claim 47, wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary' bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), coion cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

49. Use of an ADC of any one of claims 34 to 44 or the composition of claim 45 or claim 46 for the manufacture of a medicament for the treatment of a cancer that overexpresses TROP250. The use of claim 49, wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL). Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary' bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC). squamous ceil cancer of head and neck (SCCHN), coion cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer51. The ADC of any one of claims 34 to44 or the composition of claim 45 or claim 46 for the treatment of a cancer that overexpresses TROP2.

52. The ADC of claim 51, wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer. ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinaiy bladder cancer, glioma, oral cancer, gastric cancer, renalcancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer53. A combination therapy for treating cancer comprising the ADC of any one of claims 34 to 44 or the composition of claim 45 or claim 46 and a therapeutic agent, wherein the cancer is a cancer that overexpresses TROP254. The combination therapy of claim 53 wherein the therapeutic agent is a chemotherapy agent or a therapeutic antibody.

55. The combination therapy of claim 54, wherein the therapeutic antibody is a checkpoint inhibitor.

56. The combination therapy of claim 55. wherein the therapeutic antibody is an anti- PD1 antibody or an anti-PD-Ll antibody .

57. The combination therapy of claim 53. wherein the cancer is selected from the group consisting of: breast cancer (e.g.. triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary' bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

58. An antibody or antigen binding fragment thereof that specifically binds to human TROP2, comprising: a heavy chain variable domain comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable domain comprising a CDRL1, a CDRL2, and a CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequence NYGMN (SEQ ID NO: 4), W1NTYTGEPTYTDDFKG (SEQ ID NO: 5).GGFGSSY VVYFDV (SEQ ID NO: 6). KASQDVS1AVA (SEQ ID NO: 7). SASDRYT (SEQ ID NO: 10), and QQHYITPLT (SEQ ID NO: 9)59. The antibody or antigen binding fragment thereof of claim 58, wherein the antibody or antigen binding fragment thereof displays reduced binding to low TROP2-expressing cells compared to high TROP2-expressing cells and has reduced hydrophobicity compared to Sacituzumab as determined by hydrophobic interaction chromatography (HIC).

60. The antibody or antigen binding fragment thereof of claim 58 or claim 59, wherein the antibody or antigen-binding fragment thereof is humanized.61 . The antibody or antigen binding fragment thereof of any one of claims 58 to 60, wherein the antigen binding fragment is a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

62. The antibody or antigen binding fragment thereof of any one of claims 58 to 61, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 1 or 14 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 3 or 16.

63. The antibody or antigen binding fragment thereof of claim 62, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 1 and the light chain variable domain comprises the ammo acid sequence of SEQ ID NO: 3 or the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 14 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 1664. The antibody or antigen binding fragment thereof of claim 58, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 13 or 22 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 11, 17, or 18.

65. The antibody or antigen binding fragment thereof of claim 64, wherein the antibody comprises:(a) a light chain comprising the amino acid sequence of SEO ID NO: 13 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 11:(b) a light chain comprising the ammo acid sequence of SEQ ID NO: 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 17; or(c) a light chain comprising the amino acid sequence of SEQ ID NO: 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 18.

66. Hie antibody or antigen binding fragment thereof of claim 58, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 13 or 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 58, 59, or 60.

67. The antibody or antigen binding fragment thereof of claim 66, wherein the antibody comprises:(a) a light chain comprising the amino acid sequence of SEQ ID NO: 13 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 58;(b) a light chain comprising the ammo acid sequence of SEQ ID NO: 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 59; or(c) a light chain comprising the amino acid sequence of SEQ ID NO: 22 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 60.

68. The antibody or antigen binding fragment thereof of claim 58, wherein the antibody further comprises a cysteine or anon-canonical amino acid amino acid substitution at one or more posilion(s) selected from the group consisting of positions 152, 153, 171, 172, 173, and 375 of the constant domain of the heavy chain and positions 165 and 168 of the constant domain of the light chain, wherein the position numbering of the heavy chain constant domain is according to Eu numbering and the position numbering of the light chain constant domain according to sequential numbering of the whole light chain sequence.

69. Die antibody or antigen binding fragment thereof of claim 68. wherein the antibody comprises a cysteine or anon-canonical amino acid amino acid substitution at position 375 of the constant domain of the heavy chain.

70. Die antibody or antigen binding fragment thereof of claim 69. wherein the antibody comprises a heavy chain comprising the ammo acid sequence of SEQ ID NO:

19.

20. 61, or 62.The antibody or antigen binding fragment thereof of claim 58, wherein the antibody is conjugated to a pay load.

72. The antibody or antigen binding fragment thereof of claim 68. wherein the cysteine or noncanonical amino acid is conjugated to a payload.

73. The antibody or antigen binding fragment thereof of claim 71 or 72, wherein the payload is a therapeutic moiety, a detectable label, a radionuclide, or a protecting group.

74. lire antibody or antigen binding fragment thereof of claim 73, wh erein the therapeutic moiety is a cytotoxic moiety, an anti-inflammatory moiety, a peptide, a nucleic acid molecule, or a nucleic acid analog.

75. The antibody or antigen binding fragment thereof of claim 74, wherein the cytotoxic moiety is taxol, methotrexate, methopterin, dichloromethotrexate, 5-fluorouracil, 6- mercaptopurine, cytosine arabinoside, melphalan, leurosine, leurosideine. actinomycin, daunorubicin, doxorubicin, mitomycin C, mitomycin A. caminomycin, aminopterin, tallysomycin, podophyllotoxin. podophyilotoxin derivatives such as etoposide or etoposide phosphate, vinblastine, vincristine, vindesine, taxanes such as taxol, taxotere retinoic acid, butyric acid, N8-acetyl spermidine, camptothecin, calicheamicin, esperamicin, ene-diynes, duocarmycin A, duocarmycin SA, calicheamicin, camptothecin, hennasterlins, maytansinoid such as DM1 , DM2, DM3. DM4). aunstatms including monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), monomethylauristatin D (MMAD), 7-ethyl-10-hydro.xy- camptothecin (SN-38), anthracy cline, alkylcycline, and derivatives thereof.

76. Hie antibody or antigen binding fragment thereof of claim 74, wherein the cytotoxic moiety is an inhibitor of topoisomerase I, topoisomerase II, or microtubule polymerization.

77. A method for treating a cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the antibody or antigen binding fragment thereof of claim 58 or composition comprising the antibody or antigen bindingfragment thereof and a pharmaceutically acceptable earner to treat the cancer, wherein the cancer is a cancer that overexpresses TR0P2.

78. The method of claim 77, wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), coion cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

79. Use of the antibody or antigen binding fragment thereof of claim 58 for the manufacture of a medicament for the treatment of a cancer that overexpresses TROP2.

80. The use of claim 79, wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer. ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small ceil lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

81. The antibody or antigen binding fragment thereof of claim 58 for the treatment of a cancer that overexpresses TROP2.

82. The antibody or antigen binding fragment thereof of claim 81, wherein the cancer is selected from the group consisting of: breast cancer (e.g., tuple negative breast cancer), cen / ix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroidcancer, neuroendocrine, non-small cell lung cancer (NSCLC). squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

83. A combination therapy for treating cancer comprising the antibody or antigen binding fragment thereof of claim 58 and a therapeutic agent, wherein the cancer is a cancer that overexpresses TROP2,84. The combination therapy of claim 83, wherein the therapeutic agent is a chemotherapy agent or a therapeutic antibody.

85. The combination therapy of claim 84, wherein the therapeutic antibody is a checkpoint inhibitor.

86. The combination therapy of claim 84, wherein the therapeutic antibody is an anti- PD1 antibody or an anti-PD-Ll antibody.

87. The combination therapy of claim 83, wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin’s lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary' duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC). squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

88. An antibody or antigen binding fragment thereof that specifically binds to human TROP2 comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable domain comprising the ammo acid sequence of SEQ ID NO: 15.

89. Die antibody or antigen binding fragment thereof of claim 88. wherein the antibody or antigen-binding fragment thereof displays reduced hydrophobicity compared to Sacituzumab as determined by hydrophobic interaction chromatography (HIC).90 The antibody or antigen binding fragment thereof of claim 88 or claim 89, wherein the antigen binding fragment is a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

91. The antibody or antigen binding fragment thereof of any one of claims 88 to 90, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 21 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 17 or 18.

92. The antibody or antigen binding fragment thereof of any one of claims 88 to 90, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 21 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 59 or 60.

93. The antibody or antigen binding fragment thereof of any one of claims 88 to 92, wherein the antibody further comprises a cysteine or anon-canonical amino acid amino acid substitution at one or more position(s) selected from the group consisting of positions 152, 153, 171, 172, 173, and 375 of the constant domain of the heavy chain and positions 165 and 168 of the constant domain of the light chain, wherein the position numbering of the heavy chain constant domain is according to Eu numbering and the position numbering of the light chain constant domain is according to sequential numbering of the whole light chain sequence.

94. The antibody or antigen binding fragment thereof of claim 93. wherein the antibody comprises a cysteine or a non-canonical amino acid amino acid substitution at position 375 of the constant domain of the heavy chain.

95. The antibody or antigen binding fragment thereof of claim 94. wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19, 20,61, or 62.

96. The antibody or antigen binding fragment thereof of claim 88, wherein the antibody is conjugated to a payload.

97. The antibody or antigen binding fragment thereof of claim 93, wherein the cysteine or noncanonical ammo acid is conjugated to a payload.98 The antibody or antigen binding fragment thereof of claim 96 or 97, wherein the payload is a therapeutic moiety, a detectable label a radionuclide, or a protecting group.

99. The antibody or antigen binding fragment thereof of claim 98. wherein the therapeutic moiety is a cytotoxic moiety, an anti-inflammatory moiety, a peptide, a nucleic acid molecule, or a nucleic acid analog.100 The antibody or antigen binding fragment thereof of claim 99. wherein the cytotoxic moiety is taxol, methotrexate, methopterin, dicbloromethotrexate, 5-fluorouracil, 6- mercaptopurine, cytosine arabinoside, melphalan, leurosine, leurosideine, actinomycin, daunorubicin, doxorubicin, mitomy cin C, mitomycin A, caminomycin, aminopterin, tallysomycin, podophyllotoxin, podophyllotoxin derivatives such as etoposide or etoposide phosphate, vinblastine, vincristine, vindesine, manes such as taxol. taxotere retinoic acid, butyric acid, N8-acetyl spermidine, camptothecin, calicheamicin, esperamicin, ene-diynes, duocarmycin A, duocarmycin SA, calicheamicin, camptothecin, hemiasterlins, maytansinoid such as DM1 , DM2, DM3, DM4), auristatins including monomethylauristatin E (MMAE), monomethylauristatin F (MMAF). monomethylauristatin D (MMAD), 7-ethyl-10-hydroxy- camptothecin (SN-38), anthracy cline, alkylcycline, and derivatives thereof.101 . The antibody or antigen binding fragment thereof of claim 99, wherein the cytotoxic moiety is an inhibitor of topoisomerase I, topoisomerase II, or microtubule polymerization inhibitor.

102. A method for treating a cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the antibody or antigen binding fragment thereof of claim 88 or composition comprising the antibody or antigen binding fragment thereof and a pharmaceutically acceptable carrier to treat the cancer, wherein the cancer is a cancer that overexpresses TROP2.103 The method of claim 102. wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma(CLL). Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non- small cell lung cancer (NSCLC). squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

104. Use of the antibody or antigen binding fragment thereof of claim 88 for the manufacture of a medicament for the treatment of a cancer that ox erexpresses TROP2.105 The use of claim 104, wherein the cancer is selected from the group consisting of breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary' bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC ), squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

106. The antibody or antigen binding fragment thereof of claim 88 for the treatment of a cancer that overexpresses TROP2.

107. The antibody or antigen binding fragment thereof of claim 106, wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer, non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC). squamous cell cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

108. A combination therapy for treating cancer comprising the antibody or antigen binding fragment thereof of claim 88 and a therapeutic agent, wherein the cancer is a cancer that overexpresses TROP2.

109. The combination therapy of claim 108. wherein the therapeutic agent is a chemotherapy agent or a therapeutic antibody.

110. The combination therapy of claim 109, wherein the therapeutic antibody is a checkpoint inhibitor.111 The combination therapy of claim 109, wherein the therapeutic antibody is an anti-PDl antibody or an anti-PD-Ll antibody.1 12. The combination therapy of claim 108. wherein the cancer is selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervix cancer, colorectal cancer, esophagus cancer, lung cancer. non-Hodgkin's lymphoma, chronic lymphocytic lymphoma (CLL), Raji Burkitt lymphoma, oral squamous cell cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, urinary bladder cancer, glioma, oral cancer, gastric cancer, renal cancer, salivary duct cancer, anaplastic thyroid cancer, neuroendocrine, non-small cell lung cancer (NSCLC), squamous ceil cancer of head and neck (SCCHN), colon cancer, sarcoma, esophageal cancer, cervical cancer, and uterine cancer.

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