Structural Biology-Informed Optimization of Antibody-Drug Conjugates for Ovarian Cancer with an Emphasis on Minimizing Toxicity
Abstract
Hypothesis and Rationale: In contrast to other solid tumor malignancies such as breast and bladder cancer, there are no FDA-approved antibody-drug conjugates (ADC) for the treatment of ovarian cancer (OvCa). Despite decades of research, ADCs for ovarian cancer have been hobbled by lack of clinically meaningful efficacy and toxicity. OvCa has had few new therapy approvals in the past 20 years and immunotherapy has had limited efficacy in OvCa, likely because OvCa reflects a state of insufficient or inadequate target antigens. The epitope CA-125 or MUC16 is present in 95% of high-grade serous ovarian cancer (HGSOC) and is related to worse clinical outcomes. The overexpressed MUC16 protein is generally found anchored on cell surface and undergoes proteolytic cleavage over time into two independent fragments. A cleaved portion (Shed form) bearing the CA-125 antigen, is released into the blood circulation and can serve as a serum biomarker for diagnosing or monitoring response to therapy. However, there is a membrane tethered retained portion, herein termed the ectodomain, or MUC16ecto, that could be targeted by ADC. ADC against the shed CA-125 have been developed; however, because these antibodies bind to the circulating CA-125 that is not attached to the tumor, there have been limited efficacy and increased toxicity. The antibody we propose for development in this proposal binds portion of MUC16 that is retained on the tumor (MUC16ecto). This approach improves effectiveness and minimizes toxicity. Using the structure of the retained portion of MUC16 (MUC16ecto) that we have solved in our group, we will optimize the binding properties of the antibodies we use for ADC development in the first aim, and we will rigorously test our best candidates for specificity and toxicity in our second aim. At the completion of this project, we will have designed and evaluated ADC that can be used to treat high-grade serous ovarian cancer. Our lead candidates will have been rigorously evaluated for both toxicity, efficacy, and mechanisms of resistance. Once we have concluded all the preclinical experiments outlined in this proposal, our ADC will be ready for evaluation in clinical trials. Areas of Emphasis: This proposal covers multiple components that are critical to the mission of the DOD OCRP award. In the first aim, this proposed work will harness fundamental structural and molecular biology principles to design a novel precision-medicine strategy for patients with ovarian cancer; in the second aim, we will validate these therapeutic ADC with an eye on clinical development as the next step. The potential impact of the proposed research on the health and well-being of all women impacted by this disease. Women with ovarian cancer who have relapsed will eventually develop multidrug-resistant disease. Harnessing ADC to treat these cancers is a potential solution to this problem because these drugs can home to the tumor directly and deliver cytotoxic compounds directly to the tumor. This approach minimizes systemic side effects and, because different payloads can be attached to these ADC, if the cancer progresses on the first ADC, a second ADC with a different tumor toxin can be used.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310241
Entities
People
- Oladapo Yeku
Organizations
- Massachusetts General Hospital
- United States Army