Anti-HER2 x HER2 ADC Overview

ZW33 is an engineered bi-specific antibody that delivers a cytotoxic payload to cancers cells by binding to two different epitopes (bi-paratopic targeting) of the overexpressed HER2 protein on the cell surface. ZW33 is based on the same antibody framework as ZW25 and leverages the same mechanisms of action including enhanced effector function, increased signaling blockade, and enhanced HER2 internalization. Based on the increased extent of internalization, we further engineered the antibody to include a cytotoxic payload for added anti-tumor efficacy. The pre-clinical data supports the clinical utility of ZW33 for patients with late-stage tumors expressing lower levels of HER2 and who are resistant/refractory to HER2-targeted treatments.

We are developing ZW33 as a best-in-class HER2-targeting ADC for a variety of indications characterized by HER2 overexpression including breast and ovarian cancers. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for ZW33 for the treatment of ovarian cancer. IND filing for ZW33 is anticipated in early 2017.

ZW33 can potentially mediate its therapeutic effect on low HER2-expressing tumors by the bi-paratopic targeting of HER2 resulting in:

  • Enhanced toxin-mediated cytotoxicity and tumor growth inhibition due to increased HER2-mediated ADC internalization;

  • Increased ZW33-mediated HER2 internalization, which reduces HER2-mediated signaling and results in tumor growth inhibition and apoptosis;

  • Enhanced effector function-mediated cytotoxicity including ADCC, CDC and ADCP as a result of increased binding/decoration of the tumor cells by ZW33. Enhanced phagocytosis and presentation of HER2 antigen may also lead to increased immune targeting of the tumors; and

  • Increased blockade of ligand-dependent and ligand-independent tumor growth.