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.
Public Health Relevance Statement: PROJECT NARRATIVE 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. Triursus Therapeutics, Inc. has developed a monoclonal antibody (mAb) technology that prevents GvHD in murine HSCT models. This project will further develop the lead mAb drug candidate and complete the preclinical safety and efficacy studies to move forward with human clinical studies and commercialization.
Project Terms: Acute Graft Versus Host Disease; Adverse effects; Allogenic; Apoptosis; Area; ARHGEF5 gene; Automobile Driving; base; bench to bedside; Binding; Biological Markers; Blood Cell Count; Capital; Caring; cell bank; Cell Culture Techniques; Cell Surface Receptors; Cells; Clinical; Clinical Research; Clinical Trials; Collaborations; commercialization; comparative efficacy; Complication; Creatine; Cyclosporine; cytokine; Data; Development; Development Plans; Diarrhea; Disease model; Dose; drug candidate; efficacy study; efficacy testing; Funding; Goals; Graft Survival; graft vs host disease; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histopathology; Human; humanized monoclonal antibodies; humanized mouse; IgG2; Immune; immune reconstitution; Impairment; improved; In Vitro; in vitro testing; in vivo; Incidence; Inflammation; Inflammatory Response; interest; Lead; lead candidate; Life; Macaca; Maintenance; Measures; Mediating; Medical; meetings; Methods; Methotrexate; Modeling; Monoclonal Antibodies; Morbidity - disease rate; mortality; Mus; nonhuman primate; novel; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phagocytosis; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 2 testing; Phosphatidylserines; Physicians; preclinical safety; preconditioning; prevent; Prevention; Prophylactic treatment; Protocols documentation; Reporting; Rivers; Safety; safety study; Severities; side effect; Signal Pathway; Small Business Innovation Research Grant; Standardization; Surface; T cell reconstitution; Tacrolimus; TC1 Cell; Technology; Testing; Therapeutic; therapeutic effectiveness; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; Toxicology; Translating; transplant model; Transplant Recipients; transplantation medicine; Treatment Efficacy; Variant; Xenograft procedure
