Development of Bone-Targeting Antibodies for Ewing Sarcoma Using Genetic Code Expansion

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PROJECT SUMMARY/ABSTRACT Ewing sarcoma (ES) is the second most common pediatric bone cancer with peak incidence during the adolescent and young adult period. ES is an extremely aggressive malignancy with the current treatment regimen relying on a combinatorial approach of chemotherapy, radiotherapy, and/or surgery. 65%-75% of ES patients can be cured with the current treatment strategies, but at a risk of suffering signficant systemic side effects. These include high risks for infection secondary to immunosuppression from cytotoxic chemotherapy to long term effects that can lead to serious cardiac, learning deficits, reproductive capabilities and even second malignancies. Therefore, it is essential to develop more precise, effective therapeutic approaches to maximize patient outcomes while minimizing devastating side effects. Our long-term goals are to design new therapeutic strategies against bone cancer cells through a synergistic collaborative effort between labs at Rice University and the Baylor College of Medicine. The overall goal of this proposal is to develop bone-targeting precision therapeutic biologics for the treatment of ES. To achieve this goal, the first research direction will focus on the generation of bone-targeting antibodies for ES using an innovative genetic code expansion technology we have recently pioneered. Bisphosphonates are a class of negatively charged molecules able to selectively bind to mineralized, positively charged bone matrix. Site-specific conjugation of bisphosphonates to antibodies will deliver a high concentration of therapeutic antibodies to the bone and activated within the acidic tumor microenvironment for better therapeutic efficacy and reduce adverse side effects associated with systemic delivery. To demonstrate the enhanced therapeutic profile of these bone-targeting antibodies for the treatment of ES, we will study their effects on the survival and progression of ES using ES cells or patient-derived xenograft- derived primary ES cells. Our efforts in this project will yield a collection of bone-targeting antibodies and demonstrate their enhanced therapeutic profile on Ewing sarcoma. Considering the growing success of antibody therapy in the clinic, selective delivery of therapeutic antibodies to the bone microenvironment will provide a promising avenue for different bone-associated primary and metastatic malignancies.