A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity

The epidermal growth factor receptor (EGFR) and the type I insulin-like growth factor receptor (IGF-1R) are two cell surface receptor tyrosine kinases known to cooperate to promote tumor progression and drug resistance. Combined blockade of EGFR and IGF-1R has shown improved anti-tumor activity in p...

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Published in:	mAbs Vol. 3; no. 3; pp. 273 - 288
Main Authors:	Dong, Jianying, Sereno, Arlene, Aivazian, Dikran, Langley, Emma, Miller, Brian R., Snyder, William B, Chan, Eric, Cantele, Matt, Morena, Ronald, Joseph, Ingrid B.J.K., Boccia, Antonio, Virata, Cyrus, Gamez, James, Yco, Grace, Favis, Michael, Wu, Xiufeng, Graff, Christilyn P., Wang, Qin, Rohde, Ellen, Rennard, Rachel, Berquist, Lisa, Huang, Flora, Zhang, Ying, Gao, Sharon X., Ho, Steffan N., Demarest, Stephen J., Reff, Mitchell E., Hariharan, Kandasamy, Glaser, Scott M.
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 01-05-2011 Landes Bioscience
Subjects:	Animals Antibodies, Bispecific - immunology Antibodies, Bispecific - pharmacology Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacology Antibody Affinity - immunology Antibody Specificity - immunology Binding Biology Bioscience Blotting, Western Calcium Cancer Cell Cell Line, Tumor Cell Survival - drug effects Cell Survival - immunology CHO Cells Cricetinae Cricetulus Cycle Dose-Response Relationship, Drug ErbB Receptors - immunology ErbB Receptors - metabolism Humans Immunoglobulin G - immunology Landes Mice Mice, Nude Mice, SCID Neoplasms - drug therapy Neoplasms - immunology Neoplasms - pathology Organogenesis Phosphorylation - drug effects Proteins Receptor, IGF Type 1 - immunology Receptor, IGF Type 1 - metabolism Signal Transduction - drug effects Single-Chain Antibodies - immunology Single-Chain Antibodies - pharmacology Tumor Burden - drug effects Xenograft Model Antitumor Assays
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Summary:	The epidermal growth factor receptor (EGFR) and the type I insulin-like growth factor receptor (IGF-1R) are two cell surface receptor tyrosine kinases known to cooperate to promote tumor progression and drug resistance. Combined blockade of EGFR and IGF-1R has shown improved anti-tumor activity in preclinical models. Here, we report the characterization of a stable IgG-like bispecific antibody (BsAb) dual-targeting EGFR and IGF-1R that was developed for cancer therapy. The BsAb molecule (EI-04), constructed with a stability-engineered single chain variable fragment (scFv) against IGF-1R attached to the carboxyl-terminus of an IgG against EGFR, displays favorable biophysical properties for biopharmaceutical development. Biochemically, EI-04 bound to human EGFR and IGF-1R with sub nanomolar affinity, co-engaged the two receptors simultaneously, and blocked the binding of their respective ligands with similar potency compared to the parental monoclonal antibodies (mAbs). In tumor cells, EI-04 effectively inhibited EGFR and IGF-1R phosphorylation, and concurrently blocked downstream AKT and ERK activation, resulting in greater inhibition of tumor cell growth and cell cycle progression than the single mAbs. EI-04, likely due to its tetravalent bispecific format, exhibited high avidity binding to BxPC3 tumor cells co-expressing EGFR and IGF-1R, and consequently improved potency at inhibiting IGF-driven cell growth over the mAb combination. Importantly, EI-04 demonstrated enhanced in vivo anti-tumor efficacy over the parental mAbs in two xenograft models, and even over the mAb combination in the BxPC3 model. Our data support the clinical investigation of EI-04 as a superior cancer therapeutic in treating EGFR and IGF-1R pathway responsive tumors.
ISSN:	1942-0862 1942-0870
DOI:	10.4161/mabs.3.3.15188