RRC ID 51971
Author Sellmann C, Doerner A, Knuehl C, Rasche N, Sood V, Krah S, Rhiel L, Messemer A, Wesolowski J, Schuette M, Becker S, Toleikis L, Kolmar H, Hock B.
Title Balancing Selectivity and Efficacy of Bispecific Epidermal Growth Factor Receptor (EGFR) × c-MET Antibodies and Antibody-Drug Conjugates.
Journal J Biol Chem
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.
Volume 291(48)
Pages 25106-25119
Published 2016-11-25
DOI 10.1074/jbc.M116.753491
PII M116.753491
PMID 27694443
PMC PMC5122778
MeSH A549 Cells Antibodies, Bispecific / immunology* Antibodies, Bispecific / therapeutic use ErbB Receptors / immunology* Hep G2 Cells Humans Immunotoxins / immunology* Immunotoxins / therapeutic use Neoplasms / drug therapy Neoplasms / immunology Proto-Oncogene Proteins c-met / immunology*
IF 4.106
Times Cited 15
Resource
Human and Animal Cells KP4(RCB1005)