BT5528 (EphA2 Program)
Currently being evaluated in a Company-sponsored Phase I/II clinical trial
BT5528 targets EphA2 (or Ephrin type-A receptor 2), a member of the Ephrin superfamily of receptor tyrosine kinases, which regulates cell migration, adhesion, proliferation and differentiation during development. EphA2 is overexpressed in difficult to treat cancers, and expression of this kinase correlates with malignant progression and poor prognosis.
The molecule is composed of our EphA2 targeting Bicycle®, a valine-citrulline (val-cit) cleavable linker and a monomethyl auristatin E (MMAE) cytotoxin payload.
Bicycle’s EphA2 toxin conjugates have demonstrated promising target-dependent activity in preclinical models, including both cell- and patient-derived xenografts that are resistant to current treatments.
BT5528 is currently being evaluated in a Company-sponsored Phase I/II clinical trial as a potential monotherapy and in combination with nivolumab. Most patients enrolled into the study are being pre-screened according to tumor type and their EphA2 IHC status is recorded for future assessment as a potential predictor for efficacy of BT5528.
Examples of high EphA2 expressing tumors
Non-small cell lung cancer
Triple negative breast cancer
EphA2 is an attractive target for cytotoxin delivery previously pursued by other companies as an antibody drug conjugate (ADC) target. Despite encouraging preclinical activity, these ADCs produced significant safety concerns, including liver toxicity and a disseminated intravascular coagulation in several species and in humans. Development of these ADCs was ultimately terminated. We believe EphA2 remains an attractive target for our Bicycle Toxin Conjugates® due to the potential of Bicycles to overcome the safety concerns observed with ADCs. In our preclinical pharmacokinetics and toxicokinetic studies, we observed BT5528 exhibits a short half-life, rapid renal elimination, and volume of distribution that allows it to distribute to the tissues.