Antibodies against ErbB3 and uses thereof
The present invention provides a novel class of monoclonal antibodies which bind ErbB3 receptor and inhibits various ErbB3 functions. In a particular embodiment, the antibodies are capable of binding to ErbB3 and inhibiting ligand mediated phosphorylation of the receptor.
1. An antibody which:
is an isolated full length IgG monoclonal antibody,
binds to ErbB3 with a K D of about 4 nM as measured using a surface plasmon resonance assay or a cell binding assay using MALME-3M cells, and
comprises a heavy chain variable region sequence as set forth in SEQ ID NO:1 and a light chain variable region sequence as set forth in SEQ ID NO:2.
2. An antibody which:
is an isolated full length IgG monoclonal antibody,
binds to ErbB3 with a K D of about 4 nM as measured using a surface plasmon resonance assay or a cell binding assay using MALME-3M cells, and
comprises a heavy chain variable region CDR1 comprising SEQ ID NO:7; a heavy chain variable region CDR2 comprising SEQ ID NO:8; a heavy chain variable region CDR3 comprising SEQ ID NO:9; a light chain variable region CDR1 comprising SEQ ID NO:10; a light chain variable region CDR2 comprising SEQ ID NO:11; and a light chain variable region CDR3 comprising SEQ ID NO:12.
3. An antibody which:
is an isolated full length IgG monoclonal antibody,
binds to ErbB3,
downregulates the ErbB3 receptor in MALME-3M cells so that, levels of ErbB3 on the surfaces of the cells are decreased by at least 50%, and
comprises a heavy chain variable region sequence as set forth in SEQ ID NO:1 and a light chain variable region sequence as set forth in SEQ ID NO:2.
4. An antibody which:
is an isolated full length IgG monoclonal antibody,
binds to ErbB3,
downregulates the ErbB3 receptor in MALME-3M cells so that levels of ErbB3 on the surfaces of the cells are decreased by at least 50%, and
comprises a heavy chain variable region CDR1 comprising SEQ ID NO:7; a heavy chain variable region CDR2 comprising SEQ ID NO:8; a heavy chain variable region CDR3 comprising SEQ ID NO:9; a light chain variable region CDR1 comprising SEQ ID NO:10; a light chain variable region CDR2 comprising SEQ ID NO:11; and a light chain variable region CDR3 comprising SEQ ID NO:12.
5. An antibody which:
is an isolated full length IgG monoclonal antibody,
binds to ErbB3,
exhibits an IC50 for betacellulin mediated phosphorylation of ErbB3 that is from 5.32 −10 M to 1.32 −9 M in ADRr cells stimulated with betacellulin, and
comprises a heavy chain variable region sequence as set forth in SEQ ID NO:1 and a light chain variable region sequence as set forth in SEQ ID NO:2.
6. An antibody which:
is an isolated full length IgG monoclonal antibody,
binds to ErbB3,
exhibits an IC50 for betacellulin mediated phosphorylation of ErbB3 that is from 5.32 −10 M to 1.32 −9 M in ADRr cells stimulated with betacellulin, and
comprises a heavy chain variable region CDR1 comprising SEQ ID NO:7; a heavy chain variable region CDR2 comprising SEQ ID NO:8; a heavy chain variable region CDR3 comprising SEQ ID NO:9; a light chain variable region CDR1 comprising SEQ ID NO:10; a light chain variable region CDR2 comprising SEQ ID NO:11; and a light chain variable region CDR3 comprising SEQ ID NO:12.
7. An antibody which:
is an isolated full length IgG monoclonal antibody
binds to ErbB3,
at a concentration of 63 nM, causes a decrease in heregulin mediated phosphorylation of AKT of about 100% in MALME-3M cells, and
comprises a heavy chain variable region sequence as set forth in SEQ ID NO:1 and a light chain variable region sequence as set forth in SEQ ID NO:2.
8. An antibody which:
is an isolated full length IgG monoclonal antibody
binds to ErbB3,
at a concentration of 63 nM, causes a decrease in heregulin mediated phosphorylation of AKT of about 100% in MALME-3M cells, and
comprises a heavy chain variable region CDR1 comprising SEQ ID NO:7; a heavy chain variable region CDR2 comprising SEQ ID NO:8; a heavy chain variable region CDR3 comprising SEQ ID NO:9; a light chain variable region CDR1 comprising SEQ ID NO:10; a light chain variable region CDR2 comprising SEQ ID NO:11; and a light chain variable region CDR3 comprising SEQ ID NO:12.
9. The antibody of any one of claims 2 , 4 , 6 and 8 which, at a concentration of 10 −8 M, inhibits betacellulin mediated phosphorylation of ErbB3 by about 100% in ADRr cells.
10. The antibody of any one of claims 2 , 4 , 6 and 8 which is an IgG2 isotype antibody.
11. A composition comprising an antibody of claim 10 in a pharmaceutically acceptable carrier.
12. The composition of claim 11 wherein the carrier is suitable for injection or infusion.
13. The composition of claim 11 further comprising a second therapeutic agent.
14. The composition of claim 13 , wherein the second therapeutic agent is a second antibody.
15. The composition of claim 14 , wherein the second antibody is an anti-ErbB3 antibody.
16. The composition of claim 13 , wherein the second therapeutic agent is an anti-cancer agent.
17. The composition of claim 16 , wherein the anti-cancer agent is selected from the group consisting of an antibody, a small molecule, an antimetabolite, an alkylating agent, a topoisomerase inhibitor, a microtubule-targeting agent, a kinase inhibitor, a protein synthesis inhibitor, an immunotherapeutic, a hormone or analog thereof, a somatostatin analog, a glucocortocoid, an aromatase inhibitor, and an mTOR inhibitor.
18. The antibody of claim 10 which further exhibits one or more of the following properties:
i. inhibition of epiregulin-mediated signaling through ErbB3;
ii. inhibition of proliferation of cells expressing ErbB3;
iii. downregulation of ErbB3 on cell surfaces;
iv. inhibition of VEGF secretion of cells expressing ErbB3;
v. inhibition of the migration of cells expressing ErbB3;
vi. inhibition of spheroid growth of cells expressing ErbB3;
vii. inhibition of heregulin binding to ErbB3; and
viii. inhibition of formation of ErbB2/ErbB3 complexes.