Balancing Selectivity and Efficacy of Bispecific Epidermal Growth Factor Receptor (EGFR) × c-MET Antibodies and Antibody-Drug Conjugates
| Autor: | Mark Schuette, John S. Wesolowski, Harald Kolmar, Vanita D. Sood, Christine Knuehl, Bjoern Hock, Annika Messemer, Lars Toleikis, Simon Krah, Achim Doerner, Nicolas Rasche, Laura Rhiel, Carolin Sellmann, Stefan Becker |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
C-Met Immunology Biology Pharmacology Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Antigen Immunotoxin Neoplasms Antibodies Bispecific Potency Humans Epidermal growth factor receptor Receptor Cytotoxicity Molecular Biology Immunotoxins Cell Biology Hep G2 Cells Proto-Oncogene Proteins c-met ErbB Receptors 030104 developmental biology chemistry A549 Cells 030220 oncology & carcinogenesis biology.protein Antibody |
| Zdroj: | The Journal of biological chemistry. 291(48) |
| ISSN: | 1083-351X |
| Popis: | Bispecific antibodies (bsAbs) and antibody-drug conjugates (ADCs) have already demonstrated benefits for the treatment of cancer in several clinical studies, showing improved drug selectivity and efficacy. In particular, simultaneous targeting of prominent cancer antigens, such as EGF receptor (EGFR) and c-MET, by bsAbs has raised increasing interest for potentially circumventing receptor cross-talk and c-MET-mediated acquired resistance during anti-EGFR monotherapy. In this study, we combined the selectivity of EGFR × c-MET bsAbs with the potency of cytotoxic agents via bispecific antibody-toxin conjugation. Affinity-attenuated bispecific EGFR × c-MET antibody-drug conjugates demonstrated high in vitro selectivity toward tumor cells overexpressing both antigens and potent anti-tumor efficacy. Due to basal EGFR expression in the skin, ADCs targeting EGFR in general warrant early safety assessments. Reduction in EGFR affinity led to decreased toxicity in keratinocytes. Thus, the combination of bsAb affinity engineering with the concept of toxin conjugation may be a viable route to improve the safety profile of ADCs targeting ubiquitously expressed antigens. |
| Databáze: | OpenAIRE |
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