Anti-HER2 x HER2 Bispecific Overview

ZW25 is Zymeworks’ lead product candidate currently being evaluated in an adaptive Phase 1 clinical trial in the United States, based on Zymeworks’ Azymetric platform. It is a bispecific antibody that can simultaneously bind two non-overlapping epitopes, known as biparatopic binding, of HER2 resulting in dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and enhanced effector function. These combined mechanisms of action have led to significant anti-tumor activity in preclinical models of breast cancer. Zymeworks is developing ZW25 as a best-in-class HER2-targeting antibody intended as a treatment option for patients with any solid tumor that expresses HER2. 

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.