Combining anti-ERBB3 antibodies specific for domain I and domain III enhances the anti-tumor activity over the individual monoclonal antibodies.
BACKGROUND
Inappropriate signaling through the epidermal growth factor receptor family (EGFR1/ERBB1, ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4) of receptor tyrosine kinases leads to unregulated activation of multiple downstream signaling pathways that are linked to cancer formation and progression. In particular, ERBB3 plays a critical role in linking ERBB signaling to the phosphoinositide 3-kinase and Akt signaling pathway and increased levels of ERBB3-dependent signaling is also increasingly recognized as a mechanism for acquired resistance to ERBB-targeted therapies.


METHODS
We had previously reported the isolation of a panel of anti-ERBB3 single-chain Fv antibodies through use of phage-display technology. In the current study scFv specific for domain I (F4) and domain III (A5) were converted into human IgG1 formats and analyzed for efficacy.


RESULTS
Treatment of cells with an oligoclonal mixture of the A5/F4 IgGs appeared more effective at blocking both ligand-induced and ligand-independent signaling through ERBB3 than either single IgG alone. This correlated with improved ability to inhibit the cell growth both as a single agent and in combination with other ERBB-targeted therapies. Treatment of NCI-N87 tumor xenografts with the A5/F4 oligoclonal led to a statistically significant decrease in tumor growth rate that was further enhanced in combination with trastuzumab.


CONCLUSIONS
These results suggest that an oligoclonal antibody mixture may be a more effective approach to downregulate ERBB3-dependent signaling.
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America.
Jimson W
JW
D'Souza
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America.
Smitha
S
Reddy
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America.
Lisa E
LE
Goldsmith
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America.
Irina
I
Shchaveleva
Department of Anesthesia and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.
James D
JD
Marks
Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, United States of America.
Samuel
S
Litwin
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America.
Matthew K
MK
Robinson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D061505:Cell Surface Display Techniques; D057809:HEK293 Cells; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008819:Mice, Nude; D009369:Neoplasms / Q000628:therapy; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D057127:Single-Chain Antibodies; D020893:Receptor, ErbB-3