Antibodies to carcinoembryonic antigen (CEA), methods of making same, and uses thereof
The present invention relates to antigen binding molecules (ABMs). In particular embodiments, the present invention relates to recombinant monoclonal antibodies, including chimeric, primatized or humanized antibodies or variants thereof specific for cell surface or membrane bound human CEA. In addition, the present invention relates to nucleic acid molecules encoding such ABMs, and vectors and host cells comprising such nucleic acid molecules. The invention further relates to methods for producing the ABMs of the invention, and to methods of using these ABMs in treatment of disease. In addition, the present invention relates to ABMs with modified glycosylation having improved therapeutic properties, including antibodies with increased Fc receptor binding and increased effector function.
1. An antigen binding molecule (ABM) comprising a humanized, affinity-matured antigen binding domain as compared to the murine monoclonal antibody PR1A3, wherein said antigen binding domain specifically binds membrane-bound human carcinoembryonic antigen (CEA) and binds the same epitope as, or is capable of competing for binding with, the murine monoclonal antibody PR1A3, and, wherein said antigen binding domain comprises a heavy chain variable region comprising the complementarity determining regions (CDRs):
SEQ ID NO: 2,
SEQ ID NO: 15, and
SEQ ID NO:25; and
wherein said antigen binding domain comprises a light chain variable region comprising the CDRs:
SEQ ID NO:45,
SEQ ID NO:55, and
SEQ ID NO:56.
2. The ABM of claim 1 , wherein said antigen binding domain comprises a heavy chain variable region comprising the sequence of SEQ ID NO:107, and a light chain variable region comprising the sequence of SEQ ID NO:108.
3. The ABM of claim 1 , wherein said ABM comprises at least one framework region from a human germline immunoglobulin gene.
4. The ABM of claim 3 , wherein said ABM comprises heavy chain framework regions FR1-3 of SEQ ID NO:102 and light chain framework regions FR1-3 of SEQ ID NO:106.
5. The ABM of claim 1 , wherein said ABM comprises an Fc region.
6. The ABM of claim 5 , wherein said Fc region is a human IgG Fc region.
7. The ABM of claim 5 , wherein said Fc region is a glycoengineered Fc region.
8. The ABM of claim 7 , wherein said ABM has at least one increased effector function compared to the murine monoclonal antibody PR1A3.
9. The ABM of claim 1 , wherein said ABM is an antibody or fragment thereof selected from the group consisting of: a whole antibody, an scFv fragment, an Fv fragment, an F(ab′)2 fragment, a minibody, a diabody, a triabody, and a tetrabody.
10. The ABM of claim 1 , wherein said ABM increases maximum survival time in a mouse xenograft tumor model by at least from about 10 to about 120 days compared to murine monoclonal antibody PR1A3.
11. The ABM of claim 1 , wherein said ABM is at least from about 10-fold to about 1000-fold more potent at inducing ADCC at a given concentration compared to the murine PR1A3 antibody.
12. An isolated antibody that specifically binds to membrane-bound CEA with a monovalent K D of no more than about 100 nM, said antibody comprising the heavy chain variable region of SEQ ID NO:107 and the light chain variable region of SEQ ID NO:108, wherein said antibody has increased ADCC compared to the murine PR1A3 antibody.
13. An isolated anti-CEA antibody comprising a heavy chain variable region comprising:
SEQ ID NO:2,
SEQ ID NO:15, and
SEQ ID NO:25; and
a light chain variable region comprising:
SEQ ID NO:45,
SEQ ID NO:55, and
SEQ ID NO:56.
14. The isolated antibody of claim 13 wherein the antibody comprises the heavy chain variable region sequence of SEQ ID NO: 107.
15. The isolated antibody of claim 13 wherein the antibody comprises the light chain variable region sequence of SEQ ID NO: 108.
16. The isolated antibody of claim 13 wherein the antibody comprises the heavy chain variable region sequence of SEQ ID NO: 107 and the light chain variable region sequence of SEQ ID NO: 108.
17. The isolated anti-CEA antibody of claim 13 , wherein said antibody comprises at least one framework region from a human germline immunoglobulin gene.
18. The isolated anti-CEA antibody of claim 17 , wherein said antibody comprises heavy chain framework regions FR1-3 of SEQ ID NO:102 and light chain framework regions FR1-3 of SEQ ID NO:106.
19. The isolated anti-CEA antibody of claim 13 , wherein said antibody comprises an Fc region.
20. The isolated anti-CEA antibody of claim 19 , wherein said Fc region is a human IgG Fc region.
21. The isolated anti-CEA antibody of claim 19 , wherein said Fc region is a glycoengineered Fc region.
22. The isolated anti-CEA antibody of claim 21 , wherein said antibody has at least one increased effector function compared to the murine monoclonal antibody PR1A3.
23. The isolated anti-CEA antibody of claim 13 , wherein said antibody is an antibody or fragment thereof selected from the group consisting of: a whole antibody, an scFv fragment, an Fv fragment, an F(ab′)2 fragment, a minibody, a diabody, a triabody, and a tetrabody.
24. The isolated anti-CEA antibody of claim 13 , wherein said antibody increases maximum survival time in a mouse xenograft tumor model by at least from about 10 to about 120 days compared to murine monoclonal antibody PR1A3.
25. The isolated anti-CEA antibody of claim 13 , wherein said antibody is at least from about 10-fold to about 1000-fold more potent at inducing ADCC at a given concentration compared to the murine PRIA3 antibody.