Abstract LB127: A first-in-class bispecific ADC targeting FORL1 and MUC1 exhibits promising anti-tumor activity in a FOLR1low xenograft model

Abstract Folate receptor alpha (FOLR1) is specifically overexpressed in malignant tumors of epithelial origin, including ovarian, lung and breast cancers. While antibody-drug conjugate (ADC) therapies targeting FOLR1 have shown promise in clinical trials, there is still a large proportion of patients, particularly those with low FOLR1 expression, who do not respond, indicating new therapeutic strategies are needed. MUC1 is another tumor-associated antigen that is likewise overexpressed in epithelial ovarian cancer, breast cancer, and NSCLC, among other cancers; analysis of ovarian PDX tumors by immunohistochemistry (IHC) suggests that FOLR1 and MUC1 are both highly expressed in this cancer type. We therefore hypothesized that dual targeting of FOLR1 and MUC1 could provide therapeutic benefit in ovarian cancer as well as a broad range of tumors. We generated a FOLR1 x MUC1 bispecific antibody (bsAb) from anti-FOLR1 and anti-MUC1 monoclonal antibodies that were produced using RenLite® fully human common light chain mice. These parental monoclonal antibodies recognize both human and cynomolgus monkey antigens. Anti-FOLR1 antibodies were highly specific for FOLR1, as they did not recognize other FOLR family members. The anti-MUC1 antibody was previously confirmed to target MUC1-C, the juxtamembrane domain of MUC1, ensuring tumor cell recognition regardless of MUC1 cleavage. Assessment of the novel FORL1 x MUC1 bsAb indicates binding to several ovarian, breast and NSCLC cell lines, and shows enhanced internalization in MDA-MB-468 and T47D cell lines when compared to parental antibodies. Subsequently, the FORL1 x MUC1 bsAb was conjugated to vcMMAE with a DAR of 4, to generate a bispecific ADC, BCG023. BCG023 exhibited superior tumor growth inhibition compared to benchmark ADCs conjugated with the same payload and DAR in a low FOLR1-expressing NSCLC PDX model. These data suggest that targeting FOLR1 and MUC1 with a bispecific ADC is a promising therapeutic strategy for the treatment of ovarian and other tumors. Citation Format: Yifu Zhang, Chengzhang Shang, Chaoshe Guo, Yi Yang. A first-in-class bispecific ADC targeting FORL1 and MUC1 exhibits promising anti-tumor activity in a FOLR1low xenograft model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB127.