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 comprising the sequence given in SEQ ID NO:33, wherein

SEQ ID NO: 33 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

TVDKSTSTAY MELSSLRSED TAVYYCAA GW NFDY 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; and

X 70 is I or L;

and

a light chain variable domain comprising the sequence given in SEQ ID NO:34, wherein

SEQ ID NO: 34 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 YNSYPLT 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; and

X 103 is K or M.

2. An antibody or antigen-binding portion thereof as claimed in claim 1 , wherein in SEQ ID NO:33 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 and X 70 is I.

3. An antibody or antigen-binding portion thereof as claimed in claim 1 , wherein in SEQ ID NO:33 X 9 is A, X 11 is V, X 24 is A, X 38 is R, or K, X 41 is P, X 55 is N, X 68 is V and X 70 is I.

4. An antibody or antigen-binding portion thereof as claimed in claim 1 , wherein in SEQ ID NO:34 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.

5. An antibody or antigen-binding portion thereof as claimed in claim 1 , wherein in SEQ ID NO:34 X 3 is Q, X 10 is T, X 63 is S, X 80 is P, X 85 is V, X 87 is Y and X 103 is K.

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

7. A vector comprising the polynucleotide as claimed in claim 6 .

8. A host cell comprising a vector as claimed in claim 7 .

9. An antibody conjugate comprising an antibody or antigen-binding portion thereof as claimed in claim 1 and a payload.

10. An antibody conjugate as claimed in claim 9 , 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.

11. A conjugate as claimed in claim 10 , in which W′ is a keto group —CO—.

12. A conjugate as claimed in claim 10 , in which the bonding portion has the formula:

13. A conjugate as claimed in claim 9 , which has the general formula:

(((D q -Lk 1 ) r -P 1 ) p -Lk 2 -Lk 3 ) e -Ab (III)

in which D represents the payload;

q represents an integer from 1 to 10;

Lk 1 represents a linker;

r represents an integer from 1 to 10;

P 1 represents a bond or a c-valent group —P 2 —NH— where c is from 2 to 11 and P 2 is a group containing at least one ethylene unit —CH 2 —CH 2 — or ethylene glycol unit —O—CH 2 —CH 2 —;

p represents an integer from 1 to 10;

Lk 2 represents a bond or a d-valent linker where d is from 2 to 11 and which consists of from 1 to 9 aspartate and/or glutamate residues;

Lk 3 represents a linker of the general formula:

—CO-Ph—Y—Z— (AII) in which Ph is an optionally substituted phenyl group; Y represents a CO group or a CH,OH group; and Z represents a group of formula:

in which each of A and B represents a C 1-4 alkylene or alkenylene group;

Ab represents an antibody or antigen-binding portion thereof as claimed in claim 1 , being bonded to Lk 3 via two sulfur atoms derived from a disulfide bond in the antibody or antigen-binding portion thereof; and

e represents an integer from 1 to s where s is the number of disulfide bonds present in the antibody or antigen-binding portion thereof prior to conjugating to Lk 3 .

14. A conjugate as claimed in claim 9 , in which the payload is or includes an auristatin or a maytansinoid.

15. A conjugate as claimed in claim 9 , which includes from 1 to 20 molecules of a therapeutic agent.

16. A conjugate as claimed in claim 9 , which includes a radioisotope.

17. A conjugate as claimed in claim 9 , 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, or a nanoparticle.

18. A method of diagnosing or treating a cancer 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 treat or prevent the disease or condition.

19. A method using an antibody or an antigen-binding portion thereof as claimed in claim 1 said method comprising:

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

(b) detecting the presence of the complex.

20. A method of diagnosing or treating a cancer mediated by PSMA or characterised by increased expression of PSMA comprising administering an antibody conjugate as claimed in claim 13 to a subject in need thereof in an amount effective to treat or prevent the disease or condition.

21. A method using an antibody conjugate as claimed in claim 9 , said method comprising:

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

(b) detecting the presence of the complex.

22. The method of claim 18 , wherein the cancer is prostate cancer.

23. The method of claim 18 , wherein the cancer is bladder cancer, pancreatic, lung cancer kidney cancer, sarcoma, liver cancer, breast cancer, brain cancer, colon cancer, testicular cancer, or melanoma.

24. The method of claim 18 , 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.

25. A polynucleotide encoding an antibody or antigen-binding portion thereof as claimed in claim 5 .

26. An antibody conjugate comprising an antibody or antigen-binding portion thereof as claimed in claim 5 and a payload.

27. The conjugate as claimed in claim 16 , 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.

28. An antibody or antigen-binding portion thereof as claimed in claim 1 , wherein the heavy chain variable domain comprises the sequence

(SEQ ID NO: 13)

EVQLVQSGAE VKKPGASVKV SCKASGYTFT EYTIHWVRQA 

PGKGLEWIGN INPNNGGTTY NQKFEDRVTI TVDKSTSTAY 

MELSSLRSED TAVYYCAAGW NFDYWGQGTT VTVSS;

and

the light chain variable domain comprises the sequence

(SEQ ID NO: 18)

DIQMTQSPST LSASVGDRVT ITCKASQDVG TAVDWYQQKP 

GQAPKLLIYW ASTRHTGVPD RFSGSGSGTD FTLTISRLQP 

EDFAVYYCQQ YNSYPLTFGQ GTKVDIK.

29. An antibody conjugate comprising the antibody or antigen-binding portion thereof as claimed in claim 28 , 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.

30. A polynucleotide encoding an antibody or antigen-binding portion thereof as claimed in claim 3 .

31. An antibody conjugate comprising an antibody or antigen-binding portion thereof as claimed in claim 3 and a payload.