1. 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.
- Author
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Dong J, Sereno A, Aivazian D, Langley E, Miller BR, Snyder WB, Chan E, Cantele M, Morena R, Joseph IB, Boccia A, Virata C, Gamez J, Yco G, Favis M, Wu X, Graff CP, Wang Q, Rohde E, Rennard R, Berquist L, Huang F, Zhang Y, Gao SX, Ho SN, Demarest SJ, Reff ME, Hariharan K, and Glaser SM
- Subjects
- Animals, Antibodies, Bispecific pharmacology, Antibodies, Monoclonal pharmacology, Antibody Affinity immunology, Antibody Specificity immunology, Blotting, Western, CHO Cells, Cell Line, Tumor, Cell Survival drug effects, Cell Survival immunology, Cricetinae, Cricetulus, Dose-Response Relationship, Drug, ErbB Receptors metabolism, Humans, Immunoglobulin G immunology, Mice, Mice, Nude, Mice, SCID, Neoplasms drug therapy, Neoplasms pathology, Phosphorylation drug effects, 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, Antibodies, Bispecific immunology, Antibodies, Monoclonal immunology, ErbB Receptors immunology, Neoplasms immunology, Receptor, IGF Type 1 immunology
- Abstract
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.
- Published
- 2011
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