EGFR binding Fc domain-drug conjugates: stable and highly potent cytotoxic molecules mediate selective cell killing
Author:
Jäger Sebastian12, Dickgiesser Stephan1, Tonillo Jason1, Hecht Stefan1, Kolmar Harald2, Schröter Christian1
Affiliation:
1. ADCs & Targeted NBE Therapeutics, Merck KGaA , Frankfurter Str. 250 , D-64293 Darmstadt , Germany 2. Institute for Organic Chemistry and Biochemistry , Technical University of Darmstadt , Alarich-Weiss-Str. 4 , D-64287 Darmstadt , Germany
Abstract
Abstract
The exposition of cancer cells to cytotoxic doses of payload is fundamental for the therapeutic efficacy of antibody drug conjugates (ADCs) in solid cancers. To maximize payload exposure, tissue penetration can be increased by utilizing smaller-sized drug conjugates which distribute deeper into the tumor. Our group recently explored small human epidermal growth factor receptor 2 (HER2) targeting Fc antigen binding fragments (Fcabs) for ADC applications in a feasibility study. Here, we expand this concept using epidermal growth factor receptor (EGFR) targeting Fcabs for the generation of site-specific auristatin-based drug conjugates. In contrast to HER2-targeting Fcabs, we identified novel conjugation sites in the EGFR-targeting Fcab scaffold that allowed for higher DAR enzymatic conjugation. We demonstrate feasibility of resultant EGFR-targeting Fcab-drug conjugates that retain binding to half-life prolonging neonatal Fc receptor (FcRn) and EGFR and show high serum stability as well as target receptor mediated cell killing at sub-nanomolar concentrations. Our results emphasize the applicability of the Fcab format for the generation of drug conjugates designed for increased penetration of solid tumors and potential FcRn-driven antibody-like pharmacokinetics.
Publisher
Walter de Gruyter GmbH
Subject
Clinical Biochemistry,Molecular Biology,Biochemistry
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