TIM-1 blocking mAbs for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation patients

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PROJECT SUMMARY Graft-versus-host disease (GvHD) is the major complication of hematopoietic stem cell transplantation (HSCT), causing significant morbidity and mortality in patients despite the universal use of prophylaxis. Current methods of preventing GvHD rely on immunosuppressive drugs including tacrolimus (TAC) or cyclosporine (CSA) plus methotrexate (MTX) for prophylaxis, which have serious side effects, impair T cell reconstitution, and reduce graft- versus-tumor (GvT) effects. Triursus Therapeutics, Inc. has developed a monoclonal antibody (mAb) technology to treat GvHD in HSCT patients. Our lead candidate drug protects against acute GvHD while maintaining GvT effect in murine HSCT models. In this SBIR Fast-Track application, our goal is to further develop the lead candidate drug and complete the preclinical safety and efficacy studies. In Phase I, we will develop a humanized mAb and test the efficacy compared to untreated or immunosuppressive drug-treated control in the humanized mouse GvHD model. In Phase II, we will test our humanized mAb in a non-human primate model of HSCT/GvHD for safety and efficacy compared to immunosuppressive drug-treated controls. We will also advance the pharmaceutical development of our drug candidate by establishing a master cell bank, standardizing manufacturing, performing IND-enabling activities, and verifying that the proposed development plans are acceptable to regulatory agencies. At the completion of this project, we expect to have a humanized mAb that prevents GvHD and improves overall survival & GvHD scores when administered alone or in combination with one of the standards of care drugs, tacrolimus, in GvHD models. We will also have the safety and efficacy profile of the drug that will inform our plans for a human clinical study. This project is an important step forward in translating our mAb drug for GvHD from the bench to bedside.