Glypican 3 antibodies and conjugates thereof

1. An antibody that specifically binds to the human Glypican-3 (GPC3) protein wherein the antibody comprises a heavy chain variable region comprising complementarity-determining regions (CDRs) comprising the amino acid sequences of the heavy chain variable region CDRs set forth in SEQ ID NO: 1, and a light chain variable region comprising CDRs comprising the amino acid sequences of the light chain variable region CDRs set forth in SEQ ID NO: 2.

2. The antibody of claim 1 that is a humanized, or chimeric antibody.

3. The antibody of claim 1 , wherein the following variable region frameworks positions are occupied as specified: H24 is occupied by V or A, H38 is occupied by Q, R or K, H48 is occupied by M or I, H66 is occupied by R or K, H67 is occupied by V or A, H69 is occupied by L, H71 is occupied by A, H73 is occupied by K or T, H93 is occupied by G or A, H94 is occupied by R and the following amino acid residues of the light chain are present: L45 is occupied by R or K, L46 is occupied by L or R, L105 is occupied by E or V, L106 is occupied by I or M; numbering is via the Kabat numbering system.

4. The antibody of claim 1 , wherein the following variable region frameworks positions are occupied as specified: H24 is occupied by V, H38 is occupied by Q, H48 is occupied by M, H66 is occupied by R, H67 is occupied by V, H69 is occupied by L, H71 is occupied by A, H73 is occupied by K, H93 is occupied by G, H94 is occupied by R; numbering is via the Kabat numbering system.

5. The antibody of claim 1 , wherein the following variable region frameworks positions are occupied as specified: L45 is occupied by R, L46 is occupied by L, L105 is occupied by E, L106 is occupied by I; numbering is via the Kabat numbering system.

6. The antibody of claim 1 that is HALA, HALB, HALC, HBLA, HBLB, HBLC, HBLD, HBLE, HBLB-Q, HBLB-V, HCLA, HCLB, HCLC, HDLA, HDLB and HDLC.

7. The antibody of claim 1 wherein the heavy chain variable region is fused to a heavy chain constant region and the light chain variable region is fused to a light chain constant region.

8. The antibody of claim 7 , wherein the heavy chain constant region is a mutant form of a natural human constant region which has reduced binding to an Fc gamma receptor relative to the natural human constant region.

9. The antibody of claim 7 , wherein the heavy chain constant region is of IgG1 isotype.

10. The antibody of claim 7 , wherein the heavy chain constant region has the amino acid sequence comprising SEQ ID NO:5 or SEQ ID NO:6 and the light chain constant region has the amino acid sequence comprising SEQ ID NO:7.

11. The antibody of claim 1 , wherein the antibody is conjugated to a cytotoxic or cytostatic agent.

12. The antibody of claim 11 wherein the conjugated cytotoxic agent is a tubulysin.

13. The antibody of claim 11 wherein the conjugated cytotoxic agent is a conjugated tubulysin having the structure of:

wherein the conjugated tubulysin is in salt form, in particular pharmaceutically acceptable salt form, or a solvate thereof, and wherein the wavy line indicates the site at which the tubulysin is conjugated to the antibody;

R 2A is —C(═O)R 2B wherein R 2B is methyl, ethyl, propyl, iso-propyl, 2-methyl-prop-1-yl, 2,2-dimethyl-prop-1-yl, or vinyl, or R 2A is methyl, ethyl, propyl, iso-propyl, prop-2-en-1-yl or 2-methyl-prop-2-en-1-yl; and

R 7B is —H or —OH.

14. The antibody of claim 11 wherein the conjugated cytotoxic agent is a conjugated tubulysin having the structure of:

wherein the conjugated tubulysin is in salt from, in particular in pharmaceutically acceptable salt form, or a solvate thereof, and wherein the wavy line indicates the site at which the tubulysin is conjugated to the antibody.

15. The antibody of claim 11 wherein the conjugated cytotoxic agent is a conjugated tubulysin having the structure of:

wherein the conjugated tubulysin is in salt form, in particular in pharmaceutically acceptable salt form, or a solvate thereof, and wherein the wavy line indicates the site at which the tubulysin is conjugated to the antibody.

16. A pharmaceutical composition comprising the antibody of claim 1 ; and a pharmaceutically acceptable carrier.

17. A method of treating a patient having a cancer that expresses GPC3, comprising administering to the patient an effective regimen of the composition of claim 16 .

18. The method of claim 17 , wherein the cancer is a hepatocellular carcinoma (HCC), a lung carcinoma, Wilms tumor (nephroblastoma), an ovarian clear cell carcinoma, a colorectal carcinoma, or a sarcoma.

19. The method of claim 17 , wherein the cancer is HCC.

20. The antibody of claim 1 , wherein the three heavy chain variable region CDRs are as set forth in SEQ ID NOs: 10, 11, and 12, and the three light chain variable region CDRs are as set forth in SEQ ID NOs: 13, 14, and 15.

21. The antibody of claim 1 , wherein the heavy chain variable region comprises the sequence set forth in SEQ ID NO: 1, and the light chain variable region comprises the sequence set forth in SEQ ID NO: 2.