PROJECT SUMMARY/ABSTRACT Ovarian cancer is the most lethal gynecologic cancer with limited therapeutic options. Targeted cancer therapeutics, such as antibody-drug conjugates (ADCs), are a promising new therapeutic class that has recently overcome this limitation with the approval of mirvetuximab soravtansine. ADCs provide targeted delivery of cytotoxic payloads by conjugating them to antibodies directed against tumor-selective targets. Potential clinical benefits of ADCs, however, is limited as they are dependent on target expression. Mirvetuximab soravtansine is currently restricted to an ovarian cancer patient sub-population that expresses high levels of the ADC target, FOLR1, which is estimated to be less than 30% of all ovarian cancer cases. Novel targets and ADC therapeutics are therefore required to increase clinical responses and expand treatment options to a broader patient population. Using our proprietary IMPACT tumor microenvironment platform, we have identified a novel tumor-selective target that is overexpressed in ovarian cancer with a known immunosuppressive role. These characteristics suggest that this target is an intriguing ADC target as there may be an added benefit of blocking its immunosuppressive function. In pursuit of this potential, we completed a rigorous antibody campaign that resulted in a fully human lead antibody against this target that retains the necessary characteristics for ADC development. ADCs generated with our lead antibody and two different clinically validated payloads demonstrated remarkable tumor control in an in vivo proof-of-concept study and was superior to that of the standard-of-care chemotherapeutic, carboplatin. The purpose of the current proposal is to facilitate development our ADC by refining the ovarian cancer target population and determine the optimal payload and preclinical dose. Completion of this Phase 1 SBIR proposal will support our goal of advancing this ADC program to IND-enabling studies, with the eventual goal of clinical testing for the treatment of ovarian cancer.