Unlocking EphA2: The Efficacy and Safety of BT5528 in Solid Tumor Models

The abstract discusses the development of a new class of cancer therapeutics known as Bicycle Toxin Conjugates (BTCs), which are designed to target the EphA2 protein, commonly overexpressed in solid tumors and linked to poor patient outcomes. Unlike previous approaches, such as the antibody drug conjugate MEDI-547 which was discontinued due to severe adverse events like bleeding toxicity, BTCs consist of a small bicyclic peptide that binds specifically to EphA2 and is linked to a toxin payload through a cleavable linker. This design allows for advantages like rapid tumor penetration and clearance.

BT5528 was identified as a promising candidate among over 75 BTCs evaluated for its in vivo efficacy and tolerability. It has demonstrated significant antitumor effects in various EphA2-expressing xenograft models, including complete tumor regression at certain dosages. Notably, BT5528 induced rapid and complete regression even in large tumors, such as NSCLC PDX models grown to over 1000mm3.

A critical aspect of the study is the safety profile of BT5528. Unlike MEDI-547, which showed effects on the coagulation system leading to bleeding events, BT5528 did not exhibit evidence of Disseminated Intravascular Coagulation (DIC) or other coagulation-related issues in toxicology studies involving rats and non-human primates. There were no abnormal changes in platelet levels, D-Dimer, APTT, or liver enzymes.

The abstract concludes that BTCs, exemplified by BT5528, exhibit potent antitumor activity without the severe toxicities associated with previous EphA2-targeting approaches. IND-enabling studies for BT5528 are currently in progress.

The research was presented by Gavin Bennett, Philip Huxley, and colleagues at the American Association for Cancer Research Annual Meeting in 2018.