Antibodies against epidermal growth factor receptor (EGFR) and uses thereof
Anti-EGFR antibodies, therapeutic compositions comprising combinations of anti-EGFR antibodies, as well as methods for using such antibodies and compositions to treat EGFR-related disorders (e.g., cancers), are disclosed.
1. A composition comprising a trio of anti-EGFR antibodies comprising a first monoclonal antibody, a second monoclonal antibody and a third monoclonal antibody, wherein (i) the first antibody is or binds to the same epitope as, antibody ca (comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 29, 30 and 34, respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 48, 45 and 49, respectively); (ii) the second antibody is or binds to the same epitope as, antibody cd (comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 29, 30 and 31, respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 53, 54 and 55, respectively); and (iii) the third antibody is or binds to the same epitope as, antibody ch (comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 23, 24 and 26, respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 39, 40 and 42, respectively).
2. A composition comprising a trio of antibodies of claim 1 wherein each antibody of the trio is an IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, or IgE.
3. The composition of claim 1 , wherein each of the antibodies comprised by the composition binds to EGFR with a K D of 10 7 to 10 12 M −1 .
4. The composition of claim 1 , wherein the composition exhibits at least one of the following properties:
(a) inhibition of AKT phosphorylation or ERK phosphorylation, as measured in a cell-based in vitro assay;
(b) inhibition of the growth of tumor cells expressing EGFR in vitro;
(c) inhibition of the growth of tumor cells expressing EGFR in a xenograft model in vivo;
(d) inhibition of ligand binding to EGFR extracellular domain in vitro;
(e) inhibition of EGFR dimerization in vitro; or
(f) downregulation of EGFR on cell surfaces in vitro.
5. The composition of claim 4 , wherein the inhibition or downregulation is additive or synergistic as compared to a preparation comprising an individual antibody comprised by the composition in an amount (in moles) equivalent to the total amount (in moles) of combined antibodies in the composition.
6. A kit comprising the composition of claim in a container.
7. A monoclonal antibody of claim 1 , wherein the antibody is selected from the group consisting of a bispecific antibody, immunoconjugate, Fab, Fab′2, and ScFv.
8. A method of using the composition of claim 1 for the treatment of a human subject having a cancer associated with EGFR dependent signaling, the method comprising administering the composition to the subject in an amount sufficient to produce a therapeutic effect.
9. The method of claim 8 , wherein the treatment of the cancer is treatment by combination therapy with an additional anti-cancer agent.
10. The method of claim 9 wherein the additional anti-cancer agent comprises a topoisomerase inhibitor.
11. A method of using a composition of claim 2 for the treatment of a human subject having a cancer associated with EGFR dependent signaling, the method comprising administering the composition to the subject as combination therapy with an additional anti-cancer agent.
12. The method of claim 11 , wherein the additional anti-cancer agent comprises a topoisomerase inhibitor.