EphA2

Class

Bicycle Toxin Conjugate (peptide-MMAE conjugate)

Pathway

EphA2-binding bicyclic peptide delivers cytotoxin MMAE via cleavable linker to EphA2-expressing tumor cells

EphA2 is a receptor tyrosine kinase that is frequently overexpressed on the surface of tumor cells across several solid cancers, while being expressed at much lower levels on most normal adult tissues. This differential expression makes it a useful docking point for targeted therapies that seek to concentrate a cytotoxic payload within tumors rather than throughout the body. This mechanism uses a bicyclic peptide, a small synthetic molecule constrained into two loops that bind EphA2 with high affinity and selectivity, in place of the larger antibodies used in conventional antibody-drug conjugates. The peptide is chemically linked to monomethyl auristatin E (MMAE), a potent microtubule-disrupting agent, through a linker designed to remain stable in circulation but to be cleaved once the conjugate is taken up by EphA2-expressing cells. Release of MMAE inside the cell halts cell division and triggers cell death. Because the peptide scaffold is far smaller than an antibody, it can penetrate tumor tissue more readily and clears from the body more quickly, an approach being explored broadly in oncology as a way to combine tumor-selective targeting with potent cytotoxic killing while limiting systemic drug exposure.