Preclinical activity of MCLA-128, an ADCC enhanced bispecific IgG1 antibody targeting the HER2:HER3 heterodimer.

560 Background: Amplification and dimerization of HER2 promotes growth and survival of malignant cells. Tumor responses to available therapeutic agents targeting HER2 are variable. Re-activation of the potent HER2:HER3 signaling dimer by up-regulation of the HER3 ligand heregulin (HRG) has recently been identified as an important resistance mechanism. Treatment of patients with tumors expressing HER2 could be improved with agents that specifically target and potently inhibit the HER2:HER3 heterodimer. Methods: Inhibition of HRG mediated cell growth and invasiveness was assessed by proliferation inhibition and high content imaging. ADCC activity was measured by standard PBMC assays and reporter cell lines. The trastuzumab-resistant, HER2 amplified JIMT-1 xenograft model was used to assess in vivo activity. Activation status of HER dimers was determined by specific phosphorylation readouts. Results: MCLA-128 is a human common light chain bispecific antibody targeting HER2 and HER3 selected from > 500 bispec...