Abstract

A Novel Biparatopic Approach to Target Cancer Cells

John Li, Senior Scientist, MedImmune

Current HER2-targeted drugs are ineffective in killing cancer cells expressing relatively low levels of HER2. Therefore, more than 60% of breast cancer patients are ineligible for HER2-targeted therapies because of lack of HER2 overexpression and the vast majority of eligible patients who initially respond to the treatment will eventually relapse. MedImmune is developing a novel targeting antibody-drug conjugate (ADC) to address this unmet medical need. We show that a bivalent biparatopic antibody targeting two distinct non-overlapping epitopes on a breast tumor antigen was able to induce receptor clustering on the tumor cell surface, which in turn facilitated receptor internalization and promoted lysosomal trafficking and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic antibody delivered a greater quantity of cytotoxin into the targeted cancer cells. As a result, it demonstrated superior anti-tumor activity over Kadcyla® (T-DM1) in HER2-overexpressing (HER2-positive) tumor models. It also induced complete tumor regression in a HER2-positive tumor model that had developed acquired resistance to T-DM1 through chronic exposure. Lastly, we demonstrated tumor regressions in PDX breast cancer models with low levels of HER2 expression that represented patients ineligible for the current approved HER2 targeted therapies. Overall, our findings underscore the potential use of this novel targeted ADC to treat a large patient population that is ineligible for or relapsed/refractory to current HER2-targeted therapies, and thus warrant investigation in the clinic.