Anti-PSMA antibodies, uses thereof and conjugates thereof

1. An antibody or antigen-binding portion thereof which binds to PSMA and comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the sequences:

(SEQ ID NO: 33)

CDR1: EYTIH

(SEQ ID NO: 34)

CDR2: NINPNX 1 GGTTYNQKFED; and

(SEQ ID NO: 35)

CDR3: X 2-5 DY

wherein

X 1 is N or Q, and

X 2-5 is YWLF (SEQ ID NO: 39), GWTF (SEQ ID NO: 40) or AWTM (SEQ ID NO: 41), and wherein

if X 2-5 is GWTF (SEQ ID NO: 40) or AWTM (SEQ ID NO: 41), the amino acid residue at position H94 in the heavy chain variable region, based on Kabat numbering, is G; and

if X 2-5 is YWLF (SEQ ID NO: 39), the amino acid residue at position H94 in the heavy chain variable region, based on Kabat numbering, is A; and

wherein the light chain variable domain comprises the sequences:

(SEQ ID NO: 36)

CDR1: KASQDVGTAVD

(SEQ ID NO: 37)

CDR2: WASTRHT; and

(SEQ ID NO: 38)

CDR3: QQX 1-5 LT

wherein X 1-5 is FTRYP or YNAYS.

2. An antibody or antigen-binding portion thereof as claimed in claim 1 , which comprises a heavy chain variable domain comprising the sequence given in SEQ ID NO:29, wherein

SEQ ID NO: 29 is:

EVQLVQSGAE VKKPGASVKV SCKASGYTFT  EYTIH WVRQA

PGKGLEWIG N   INPNNGGTTY NQKFED RVTI TVDKSTSTAY

MELSSLRSED TAVYYCAX 98 X 99-102 DY WGQGTT VTVSS

wherein:

X 98-102 is AYWLF (SEQ ID NO: 42), GGWTF (SEQ ID NO: 43), or GAWTM (SEQ ID NO: 44),

whereby the heavy chain variable domain comprises up to 12 amino acid sequence modification(s) at any of positions 1-30, 36-49, 67-97 and 105-115 of SEQ ID NO: 29.

3. An antibody or antigen-binding portion thereof as claimed in claim 1 , which comprises a heavy chain variable domain comprising the sequence given in SEQ ID NO:30, wherein

SEQ ID NO: 30 is:

EVQLVQSGX 9 E X 11 KKPGASVKV SCKX 24 SGYTFT  EYTIH WVX 38 QA

X 41 GKGLEWIG N   INPNX 55 GGTTY NQKFED RX 68 TX 70  TVDKSTSTA

YMELSSX 86 RSED TAVYYCAX 98 X 99 X 100  X 101 X 102  DY WGQGTT

VTVSS

wherein:

X 9 is A or P

X 11 is V or L

X 24 is A or T

X 38 is R or K

X 41 is P or H

X 55 is N or Q

X 68 is V or A

X 70 is I or L,

X 86 is L or P, and

X 98-102 is AYWLF (SEQ ID NO: 42), GGWTF (SEQ ID NO: 43), or GAWTM (SEQ ID NO: 44),

whereby the heavy chain variable domain comprises up to 3 amino acid sequence modification(s) between positions 1-30, 36-49, 67-98 and 105-115 of SEQ ID NO: 30.

4. An antibody or antigen-binding portion thereof as claimed in claim 3 , wherein in SEQ ID NO:30 X 9 is A, X 11 is V, X 24 is A or T, X 38 is R or K, X 41 is P, X 55 is N or Q, X 68 is V or A, X 70 is I and X 86 is L or P.

5. An antibody or antigen-binding portion thereof as claimed in claim 1 , which comprises a light chain variable domain comprising the sequence given in SEQ ID NO:31, wherein

SEQ ID NO: 31 is:

DIQMTQSPST LSASVGDRVT ITC KASQDVG TAVD WYQQKP

GQAPKLLIY W   ASTRHT GVPD RFSGSGSGTD FTLTISRLQP

EDFAVYYC QQ X 91-95 LT FGQ GTKVDIK

wherein

X 91-95 is FTRYP (SEQ ID NO: 45) or YNAYS (SEQ ID NO: 46),

whereby the light chain variable domain comprises up to 10 amino acid sequence modification(s) between positions 1-23, 35-49, 57-88 and 98-107 of SEQ ID NO: 31.

6. An antibody or antigen-binding portion thereof as claimed in claim 1 , which comprises a light chain variable domain comprising the sequence given in SEQ ID NO:32, wherein

SEQ ID NO: 32 is:

DIX 3 MTQSPSX 10  LSASVGDRVT ITC KASQDVG TAVD WYQQKP

GQAPKLLIY W   ASTRHT GVPD RFX 63 GSGSGTD FTLTISRLQX 80

EDFAX 85 YX 87 C QQ X 91-95 LT FGQ GTX 103 VDIK

wherein

X 3 is Q or V

X 10 is T or F

X 63 is S or T

X 80 is P or S

X 85 is V or D

X 87 is Y or F

X 91-95 is FTRYP (SEQ ID NO: 45) or YNAYS (SEQ ID NO: 46); and

X 103 is K or M,

whereby the light chain variable domain comprises up to 3 amino acid sequence modification(s) between positions 1-23, 35-49, 57-88 and 98-107 of SEQ ID NO: 32.

7. An antibody or antigen-binding portion thereof as claimed in claim 6 , wherein in SEQ ID NO:32 X 3 is Q or V, X 10 is T, X 63 is S or T, X 80 is P or S, X 85 is V or D, X 87 is Y or F and X 103 is K.

8. A polynucleotide encoding an antibody or antigen-binding portion thereof as claimed in claim 1 .

9. A vector comprising the polynucleotide as claimed in claim 8 .

10. A host cell comprising a vector as claimed in claim 9 .

11. An antibody conjugate comprising an antibody or antigen-binding portion thereof as claimed in claim 1 conjugated via a linker to a payload.

12. An antibody conjugate as claimed in claim 11 , in which the payload is bonded to the antibody or antigen-binding portion thereof via a bonding portion which has the general formula:

in which Pr represents said antibody or antigen-binding portion thereof, each Nu represents a nucleophile present in or attached to the antibody or antigen-binding portion thereof, each of A and B independently represents a C 1-4 alkylene or alkenylene chain, and W′ represents an electron withdrawing group or a group obtained by reduction of an electron withdrawing group.

13. A conjugate as claimed in claim 12 , in which W′ is a keto group —CO—.

14. A conjugate as claimed in claim 12 , in which the bonding portion has the formula:

15. A conjugate as claimed in claim 11 , in which the payload is or includes an auristatin or a maytansinoid.

16. A conjugate as claimed in claim 11 , which includes from 1 to 20 molecules of a therapeutic agent.

17. A conjugate as claimed in claim 11 , which includes a radioisotope.

18. A conjugate as claimed in claim 11 , in which the payload is or includes a detectable marker selected from the group consisting of at least one of a radioactive substance, a dye, a contrast agent, a fluorescent compound, a bioluminescent compound, an enzyme, an enhancing agent, and a nanoparticle.

19. A method of diagnosing or treating a disease or condition mediated by PSMA or characterised by increased expression of PSMA comprising administering an antibody or antigen-binding portion thereof as claimed in claim 1 , to a subject in need thereof in an amount effective to diagnose or treat the disease or condition.

20. A method for detecting in vitro or in vivo the presence of PSMA antigen in a test sample using an antibody or an antigen-binding portion thereof as claimed in claim 1 , said method comprising:

(a) contacting the sample with the antibody or the antigen-binding portion thereof under conditions that allow for formation of a complex between a PSMA antigen and the antibody or the antigen-binding portion thereof;

(b) detecting the presence of the complex.

21. A method of diagnosing or treating a disease or condition mediated by PSMA or characterised by increased expression of PSMA comprising administering an antibody conjugate as claimed in claim 11 , to a subject in need thereof in an amount effective to diagnose or treat the disease or condition.

22. A method for detecting in vitro or in vivo the presence of PSMA antigen in a test sample using an antibody conjugate as claimed in claim 11 , said method comprising:

(a) contacting the test sample with the antibody conjugate under conditions that allow for formation of a complex between a PSMA antigen and the antibody conjugate;

(b) detecting the presence of the complex.

23. The method of claim 19 , wherein the disease mediated by PSMA is cancer.

24. The method of claim 23 wherein the cancer is prostate cancer.

25. The method of claim 23 wherein the cancer is bladder cancer, pancreatic cancer, lung cancer, kidney cancer, sarcoma, liver cancer, breast cancer, brain cancer, colon cancer, testicular cancer, or melanoma.

26. The method of claim 23 , wherein the cancer is transitional cell carcinoma of the bladder, pancreatic duct carcinoma, non-small cell lung carcinoma, conventional renal cell carcinoma, soft tissue sarcoma, metastatic adenocarcinoma of the liver, breast carcinoma, glioblastoma multiforme, neuroendocrine carcinoma, colonic carcinoma, testicular embryonal carcinoma, or malignant melanoma.

27. An antibody conjugate comprising an antibody or antigen-binding portion thereof as claimed in claim 1 .

28. An antibody or antigen-binding portion thereof as claimed in claim 2 , which comprises a light chain variable domain comprising the sequence given in SEQ ID NO:31, wherein

SEQ ID NO: 31 is:

DIQMTQSPST LSASVGDRVT ITC KASQDVG TAVD WYQQKP 

GQAPKLLIY W ASTRHT GVPD RFSGSGSGTD FTLTISRLQP

EDFAVYYC QQ X 91-95 LT FGQ GTKVDIK

wherein

X 91-95 is FTRYP (SEQ ID NO: 45) or YNAYS (SEQ ID NO: 46),

whereby the light chain variable domain comprises up to 10 amino acid sequence modification(s) between positions 1-23, 35-49, 57-88 and 98-107 of SEQ ID NO: 31.

29. An antibody or antigen-binding portion thereof as claimed in claim 3 , which comprises a light chain variable domain comprising the sequence given in SEQ ID NO:32, wherein

SEQ ID NO: 32 is:

DIX 3 MTQSPSX 10  LSASVGDRVT ITC KASQDVG TAVD WYQQKP 

GQAPKLLIY W   ASTRHT GVPD RFX 63 GSGSGTD FTLTISRLQX 80  

EDFAX 85 YX 87 C QQ X 91-95 LT FGQ GTX 103 VDIK

wherein

X 3 is Q or V

X m is T or F

X 63 is S or T

X 80 is P or S

X 85 is V or D

X 87 is Y or F

X 91-95 is FTRYP (SEQ ID NO: 45) or YNAYS (SEQ ID NO: 46); and

X 103 is K or M

whereby the light chain variable domain comprises up to 3 amino acid sequence modification(s) between positions 1-23, 35-49, 57-88 and 98-107 of SEQ ID NO: 32.

30. An antibody or antigen-binding portion thereof as claimed in claim 29 , wherein in SEQ ID NO:32 X 3 is Q or V, X 10 is T, X 63 is S or T, X 80 is P or S, X 85 is V or D, X 87 is Y or F and X 103 is K.

31. A conjugate as claimed in claim 17 , wherein the radioisotope is selected from the group consisting of Iodine-131, Yttrium-90, Lutetium-177, Copper-67, Astatine-211, Lead-212/Bismuth-212, Actinium-225/Bismuth-213, and Thorium.