Anti-HER2 x HER2 Bi-Specific Overview

ZW25 is an engineered bi-specific Azymetric™ antibody that targets two different epitopes (bi-paratopic targeting) of the HER2 protein, which is overexpressed on the surface of some cancerous cells. While several HER2-directed therapies are currently marketed, their usage is limited to patients with high HER2 expression levels (gene amplified or HER2 3+ by IHC). Compared to such therapies, ZW25 shows enhanced activity as a result of multiple mechanisms of action, and preclinical data supports the potential clinical utility of ZW25 for patients expressing lower levels of HER2 that are not eligible for other HER2-targeted therapies.

We are therefore developing ZW25 as a best-in-class HER2-targeting antibody for a variety of indications characterized by HER2 overexpression including breast, gastric, ovarian, colorectal, and non-small cell lung cancers. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for ZW25 for the treatment of ovarian cancer. Phase 1 clinical trial for ZW25 was initiated in September 2016.

ZW25 can potentially mediate its therapeutic effect on low HER2-expressing tumors by the bi-paratopic targeting of HER2 resulting in:

  • Enhanced effector function-mediated cytotoxicity including ADCC, CDC and ADCP as a result of increased binding/decoration of the tumor cells by ZW25. Enhanced phagocytosis and presentation of HER2 antigen may also lead to increased immune targeting of the tumors;

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

  • Increased ZW25-mediated HER2 internalization, which reduces HER2-mediated signaling and results in tumor growth inhibition and apoptosis.