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J Biol Chem. 2016 Nov 25;291(48):25106-25119. Epub 2016 Sep 30.

Balancing Selectivity and Efficacy of Bispecific Epidermal Growth Factor Receptor (EGFR) × c-MET Antibodies and Antibody-Drug Conjugates.

Author information

1
From the Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, D-64287 Darmstadt, Germany.
2
Protein Engineering and Antibody Technologies and.
3
Merck Research and Development, Merck KGaA, Frankfurter Strasse 250, D-64293 Darmstadt, Germany, and.
4
the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821.
5
From the Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, D-64287 Darmstadt, Germany, Kolmar@Biochemie-TUD.de.
6
Protein Engineering and Antibody Technologies and Bjoern.Hock@merckgroup.com.

Abstract

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.

KEYWORDS:

antibody engineering; anticancer drug; epidermal growth factor receptor (EGFR); sortase A; toxicity

PMID:
27694443
PMCID:
PMC5122778
DOI:
10.1074/jbc.M116.753491
[Indexed for MEDLINE]
Free PMC Article

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