Preclinical characterization of HSC00189, a novel bispecific ADC targeting cadherin-6 (CDH6) and folate receptor alpha (FOLR1) for the treatment of ovarian cancer

As monospecific antibody-drug conjugates (ADCs) enter front-line therapeutics and benefit numerous cancer patients, natural or acquired resistance, as well as individual-population heterogeneity in ADC target expression, are compromising monospecific ADC efficacy. Bispecific ADCs hold promise for overcoming these hurdles. Cadherin-6 (CDH6) is a type I transmembrane protein overexpressed in several tumor types with limited expression in normal tissues. Similarly, folate receptor alpha (FRalpha; FOLR1) is a cell surface protein upregulated in tumors and a clinically validated ADC target for the treatment of ovarian cancer. Co-expression analysis demonstrated that CDH6 and FRalpha are heterogeneously expressed in ovarian tumors, either within the same tumor or across tumors, underpinning the rationale for developing CDH6/FOLR1 bispecific ADCs. HSC00189 is an ADC consisting of an anti-CDH6/anti-FOLR1 bispecific antibody and a topoisomerase I inhibitor (TOP1i) payload. It can be internalized by cells expressing CDH6 or FOLR1, exhibiting broad cytotoxic coverage against cancer cell lines and organoids that is superior to that of monospecific ADCs. Furthermore, HSK51892, the payload of HSC00189, exhibits superior bystander killing efficacy compared to DXd. In addition, HSC00189 demonstrates robust in vivo antitumor efficacy in patient-derived xenograft (PDX) models. Finally, HSC00189 possesses favorable pharmacokinetic (PK) and toxicological profiles, with a Highest Non-Severely Toxic Dose (HNSTD) of 50 mg/kg in a non-human primate (NHP) dose-ranging study.