Improving Tumor Penetration of Antibodies and Antibody–Drug Conjugates: Taking Away the Barriers for Trojan Horses

Abstract The high affinity of an antibody can result in restricted tumor penetration and heterogenous tumor distribution, with preferential binding of the antibody to tumor cells localized around tumor vasculature. This so-called “binding site barrier” effect limits the efficacy of antibody-based therapies like antibody–drug conjugates (ADC). In this issue, Bordeau and colleagues introduce an original approach to overcome this barrier through transient competitive inhibition of antibody–antigen binding. By coadministration of an anti-idiotypic anti-trastuzumab domain antibody as a competitive inhibitor, increased tumor penetration of trastuzumab as well as enhanced efficacy of the ADC ado-trastuzumab emtansine were observed in tumor-bearing mice See related article by Bordeau et al., p. 4145