Lead Optimization and Evaluation of Anti-SN38 Payload Binding Selectivity Enhancers

Cancer is a major cause of morbidity and mortality in the US, with 1.8 million cases and 600 thousand cancer deaths projected for 2020. Substantial progress in cancer treatment has been made in the past two decades, largely through the development of highly targeted therapies, including development of antibody-drug conjugates (ADCs). ADCs employ monoclonal antibodies with specificity for tumor-associated antigens to increase the efficiency and selectivity of the delivery of anti-cancer toxins (i.e., payloads) to cancer cells. Although this approach has proven to be successful, with 8 anti-cancer ADCs approved for use in the US (brentuximab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, and sacituzumab govitecan), ADC therapies are often associated with substantial off-target toxicity, narrow therapeutic windows, and high failure rates in clinical testing. Consideration of the FDA-approved ADCs shows that these agents often allow a modest extension in average survival time, but they very rarely cure a patient from their cancer. The development of adverse events prevents the administration of ADC at dosages that are necessary to achieve tumor eradication. This project pursues a new strategy to increase the tumor-selectivity of antibody-directed delivery of anti-cancer drugs. In our approach, payload-binding antibody fragments, termed payload-binding selectivity enhancers (PBSE), are co-administered with ADCs to decrease the exposure of healthy tissues to payload agents, thereby reducing the development of off-target toxicity, increasing the tolerable dose of ADCs, and increasing ADC efficacy. The strategy is based on the recognition that off-site ADC toxicity is primarily attributed to the released (“free”) payload molecule, and also on the hypothesis that PBSE may be employed to prevent cellular entry of free payload molecules in non-targeted cells (by preventing diffusion across plasma membranes) without altering entry of ADCs into targeted cells (which proceeds via receptor mediated endocytosis). Work on this project focuses on lead optimization for newly developed anti-SN38 PBSE, which are expected to increase the safety and efficacy of SN38 ADC, including sacituzumab govitecan. The project will develop optimized derivatives of our lead anti-SN38 PBSE, evaluate the PBSE constructs for plasma, tissue, and tumor disposition, and conduct assessments of safety and efficacy in mice bearing human breast cancer xenografts. In sum, work proposed in this Phase 1 project will enable the identification of an optimized lead anti-SN38 PBSE, which will then advance through IND-enabling preclinical investigations.Narrative This project develops anti-SN38 antibody fragments for use as an adjunctive therapy to decrease the toxicity of antibody-SN38 conjugates. The strategy introduced in this proposal, and the optimized anti-SN38 agent to be developed, may be expected to increase the safety and efficacy of SN38 antibody-drug conjugates, including sacituzumab govitecan. It is anticipated that anti-SN38 and sacituzumab govitecan will be used as a combination therapy to treat patients with metastatic triple-negative breast cancer, which is associated with very poor prognosis.