A tumor-penetrating bicyclic peptide that delivers a toxic payload may have finally unlocked the therapeutic potential of targeting EphA2. According to phase I trial data, BT5528 yielded clinical responses in three patients with ovarian and urothelial cancers—without any of the toxicity issues that have plagued other EphA2-directed therapeutic candidates.

A tumor-penetrating bicyclic peptide that delivers a toxic payload may have finally unlocked the therapeutic potential of targeting EphA2, a regulator of cancer progression overexpressed in several tumor types.

According to phase I trial data presented at the virtual International Conference on Molecular Targets and Cancer Therapeutics held October 7–10, the peptide–drug conjugate BT5528 (Bicycle Therapeutics) yielded clinical responses against ovarian and urothelial cancers—with signs of more pronounced tumor shrinkage among those patient samples that expressed higher levels of EphA2. Critically, none of the 24 trial participants treated with BT5528 developed clotting abnormalities or peripheral neuropathy, side effects that have befallen other EphA2-directed therapeutic candidates.


BT5528 is a tumor-penetrating bicyclic peptide conjugated to the auristatin derivative MMAE. The agent binds to the EphA2 receptor on tumor cells; any unbound drug rapidly moves to the bladder for elimination. [Modified from Bennett G, Brown A, Mudd G, Huxley P, Van Rietschoten K, Pavan S, et al. MMAE delivery using the Bicycle toxin conjugate BT5528. Mol Cancer Ther 2020;19:1385–94.]

The findings showcase “the platform's ability to reach a target that to date has been unachievable using antibody-based approaches,” said Dominic Smethurst, MB, chief medical officer of Bicycle Therapeutics in Cambridge, UK.

It “does look like very promising response data with predictive biomarker linkage,” said Stefan Symeonides, MRCP, PhD, of the University of Edinburgh, UK, who was not involved in the research.

Despite more than 25 years of research linking EphA2 signaling to cancer, previous attempts to drug the molecular target have fallen flat. In early clinical testing, only one of 37 patients treated with DS-8895a (Daiichi Sankyo) responded to the monoclonal antibody, while antibody-directed agents designed to deliver toxic payloads—either a docetaxel prodrug in the case of MM-310 (Merrimack Pharmaceuticals) or an auristatin derivative with MEDI-547 (AstraZeneca)—produced unacceptable toxicities.

Scientists at Bicycle Therapeutics reasoned that their drug would be more tolerable because the relatively small size of bicyclic peptides—defined by their short polypeptide chains that form two rigid looping structures—would allow for rapid tumor penetration and fast kidney clearance without the prolonged bloodstream exposure typical of most antibody-based agents.

The researchers showed as much in preclinical experiments published last year (Mol Cancer Ther 2020;19:1385–94). Gavin Bennett, PhD, and his colleagues evaluated BT5528 against MEDI-547—both of which deliver the same payload, MMAE. In rodents and monkeys, Bicycle's peptide–toxin conjugate had more favorable pharmacokinetic and toxicology profiles compared with AstraZeneca's antibody–drug conjugate—and those findings have now been validated in humans.

According to first-in-human clinical data presented at the Molecular Targets meeting by Meredith McKean, MD, of Sarah Cannon Research Institute in Nashville, TN, BT5528 frequently caused low white blood cell counts and gastrointestinal disturbances, but these side effects generally proved manageable. (By comparison, treatment-related bleeding and coagulation events prompted the premature termination of earlier MEDI-547 trials.)

McKean also described two patients with urothelial cancer and one with ovarian cancer who experienced partial responses. Three more patients with ovarian cancer, all of whom had tumors with high EphA2 expression above a predetermined threshold, were classified as having stable disease. To McKean, these data indicate the potential for a “correlation between the target presence and efficacy.”

“However, this is very early data and will be reassessed after additional patients are treated on study,” she said. Further expansion cohort studies and combination therapy trials are planned or ongoing. –Elie Dolgin