The EphA2 receptor is found at high levels in tumors and low levels in normal tissue and high EphA2 expression in biopsies is a predictor of poor outcome in patients. Drug discovery groups have therefore sought to develop EphA2-based therapies using small molecule, peptide, and nanoparticle-based approaches (1-3). However, until now only EphA2-targeting antibody-drug conjugates (ADC) have entered clinical development. For example, MEDI-547 is an EphA2-targeting ADC that displayed encouraging antitumor activity in preclinical models and progressed to phase I clinical testing in man. Here we describe the development of BT5528, a bicyclic peptide ("Bicycle") conjugated to the auristatin derivative maleimidocaproyl-monomethyl auristatin E to generate the Bicycle toxin conjugate BT5528. The report compares and contrasts the Pharmacokinetics (PK) characteristics of antibody and Bicycle-based targeting systems and discusses how the PK and payload characteristics of different delivery systems impact the efficacy-toxicity trade off which is key to the development of successful cancer therapies. We show that BT5528 gives rise to rapid update into tumors and fast renal elimination followed by persistent toxin levels in tumors without prolonged exposure of parent drug in the vasculature. This fast in, fast out kinetics gave rise to more favorable toxicology findings in rats and monkeys than were observed with MEDI-547 in preclinical and clinical studies.Graphical Abstract: http://mct.aacrjournals.org/content/molcanther/19/7/1385/F1.large.jpg.
©2020 American Association for Cancer Research.