A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor specificity

Abstract P-cadherin (pCAD) and LI-cadherin (CDH17) are cell surface proteins belonging to the cadherin superfamily that are both highly expressed in colorectal cancer. This co-expression profile presents a novel and attractive opportunity for a dual targeting approach using an antibody-drug conjugate (ADC). In this study, we used a unique avidity-driven in vitro screening approach to generate pCAD x CDH17 bispecific antibodies that selectively targets cells expressing both antigens over cells expressing only pCAD or only CDH17. Based off the in vitro results we selected a lead bispecific antibody to link to the cytotoxic payload MMAE to generate a pCAD x CDH17 bispecific MMAE ADC. In in vivo dual flank mouse models, we demonstrated antitumor activity of the bispecific ADC in tumors expressing both antigens, but not in tumors expressing only pCAD or only CDH17. Overall, the preclinical data presented here suggests that a pCAD x CDH17 bispecific MMAE ADC has the potential to provide clinical benefit to colorectal cancer patients.