Monoclonal antibodies against glypican-3
View Patent ↗The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to Glypican-3 with high affinity. Nucleic acid molecules encoding Glypican-3 antibodies, expression vectors, host cells and methods for expressing the Glypican-3 antibodies are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the Glypican-3 antibodies are also provided. Methods for detecting Glypican-3, as well as methods for treating various Glypican-3-related conditions, including hepatocellular cancer, are disclosed.
1. An isolated monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody is selected from the group consisting of:
(i) an antibody, or antigen binding portion thereof, comprising:
a) a heavy chain variable region CDR1 comprising SEQ ID NO:1;
b) a heavy chain variable region CDR2 comprising SEQ ID NO:4;
c) a heavy chain variable region CDR3 comprising SEQ ID NO:7;
d) a light chain variable region CDR1 comprising SEQ ID NO:10;
e) a light chain variable region CDR2 comprising SEQ ID NO:13; and
f) a light chain variable region CDR3 comprising SEQ ID NO:16;
(ii) an antibody, or antigen binding portion thereof, comprising:
a) a heavy chain variable region CDR1 comprising SEQ ID NO:2;
b) a heavy chain variable region CDR2 comprising SEQ ID NO:5;
c) a heavy chain variable region CDR3 comprising SEQ ID NO:8;
d) a light chain variable region CDR1 comprising SEQ ID NO:11;
e) a light chain variable region CDR2 comprising SEQ ID NO:14; and
f) a light chain variable region CDR3 comprising SEQ ID NO:17; and
(iii) an antibody, or antigen binding portion thereof, comprising:
a) a heavy chain variable region CDR1 comprising SEQ ID NO:3;
b) a heavy chain variable region CDR2 comprising SEQ ID NO:6;
c) a heavy chain variable region CDR3 comprising SEQ ID NO:9;
d) a light chain variable region CDR1 comprising SEQ ID NO:12;
e) a light chain variable region CDR2 comprising SEQ ID NO:15; and
f) a light chain variable region CDR3 comprising SEQ ID NO:18,
wherein the antibody, or antigen-binding portion thereof, binds to human Glypican-3.
2. An isolated monoclonal antibody, or antigen binding portion thereof, selected from the group consisting of:
a) an antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:22;
b) an antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:20 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23; and
c) an antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:24,
wherein the antibody, or antigen-binding portion thereof, binds to human Glypican-3.
3. An immunoconjugate comprising the antibody, or antigen-binding portion thereof, of claim 1 or 2 , linked to a therapeutic agent.
4. A composition comprising the antibody, or antigen binding portion thereof, of claim 1 or 2 and a pharmaceutically acceptable carrier.
5. A method of inhibiting growth of tumor cells expressing Glypican-3, comprising contacting the cells with the antibody, or antigen-binding portion thereof, of claim 1 , or 2 , in an amount effective to inhibit growth of the tumor cells.
6. The method of claim 5 , wherein the tumor cells are from liver tissue.
7. The method of claim 5 , wherein the antibody, or antigen-binding portion thereof, is an immunoconjugate.
8. An isolated human monoclonal antibody, or antigen binding portion thereof, which competes for binding to Glypican-3 with the antibody of claim 2 .
9. The antibody, or antigen-binding portion thereof, of claim 1 or 2 , wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of a human antibody, a chimeric antibody, and a humanized antibody.
10. The antibody, or antigen-binding portion thereof, of claim 1 , comprising:
a) a heavy chain variable region CDR1 comprising SEQ ID NO:1;
b) a heavy chain variable region CDR2 comprising SEQ ID NO:4;
c) a heavy chain variable region CDR3 comprising SEQ ID NO:7;
d) a light chain variable region CDR1 comprising SEQ ID NO:10;
e) a light chain variable region CDR2 comprising SEQ ID NO:13; and
f) a light chain variable region CDR3 comprising SEQ ID NO:16.
11. The antibody, or antigen-binding portion thereof, of claim 1 , comprising:
a) a heavy chain variable region CDR1 comprising SEQ ID NO:2;
b) a heavy chain variable region CDR2 comprising SEQ ID NO:5;
c) a heavy chain variable region CDR3 comprising SEQ ID NO:8;
d) a light chain variable region CDR1 comprising SEQ ID NO:11;
e) a light chain variable region CDR2 comprising SEQ ID NO:14; and
f) a light chain variable region CDR3 comprising SEQ ID NO:17.
12. The antibody, or antigen-binding portion thereof, of claim 1 , comprising:
a) a heavy chain variable region CDR1 comprising SEQ ID NO:3;
b) a heavy chain variable region CDR2 comprising SEQ ID NO:6;
c) a heavy chain variable region CDR3 comprising SEQ ID NO:9;
d) a light chain variable region CDR1 comprising SEQ ID NO:12;
e) a light chain variable region CDR2 comprising SEQ ID NO:15; and
f) a light chain variable region CDR3 comprising SEQ ID NO:18.
13. The antibody, or antigen-binding portion thereof, of claim 2 , comprising the amino acid sequence of SEQ ID NO:19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:22.
14. The antibody, or antigen-binding portion thereof, of claim 2 , comprising the amino acid sequence of SEQ ID NO:20 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23.
15. The antibody, or antigen-binding portion thereof, of claim 2 , comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:24.
16. The antibody, or antigen-binding portion thereof, of claim 1 or 2 , which is a full-length antibody of an IgG1 isotype.
17. The antibody, or antigen-binding portion thereof, of claim 1 or 2 , which is a full-length antibody of an IgG4 isotype.
18. The antibody, or antigen-binding portion thereof, of claim 1 or 2 , wherein the antibody is a hypofucosylated antibody.
19. The immunoconjugate of claim 3 , wherein the therapeutic agent is a cytotoxin or a radioactive isotope.
20. A composition comprising the immunoconjugate of claim 3 and a pharmaceutically acceptable carrier.
21. The method of claim 5 , wherein the tumor is hepatocellular carcinoma (HCC).