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

项目总结 移植物抗宿主病(GvHD)是造血干细胞移植(HSCT)的主要并发症， 尽管普遍使用了预防措施，但仍在患者中造成显著的发病率和死亡率。当前的方法 预防GvHD依赖于免疫抑制药物，包括他克莫司(TAC)或环孢素A(CsA)加用 甲氨蝶呤(MTX)用于预防，具有严重的副作用，损害T细胞重建，减少移植物抗宿主病。 抗肿瘤(GVT)效应。Triursus Treateutics，Inc.开发了一种单抗(MAb)技术 目的：治疗造血干细胞移植患者的移植物抗宿主病。我们的主要候选药物在维持GVT的同时预防急性GvHD 对小鼠造血干细胞移植模型的影响。在此SBIR Fast-Track应用程序中，我们的目标是进一步开发领先的候选者 并完成临床前安全性和有效性研究。在第一阶段，我们将开发人源化单抗，并 在人源化小鼠GvHD中测试与未经治疗或免疫抑制药物治疗的对照的疗效 模特。在第二阶段，我们将在HSCT/GvHD的非人类灵长类动物模型中测试我们的人源化mAb的安全性和 与免疫抑制药物治疗的对照组进行疗效比较。我们还将推进药品 通过建立主细胞库、标准化制造、执行 支持IND的活动，并核实拟议的发展计划是否为监管机构所接受。 在这个项目完成后，我们希望有一种人性化的mAb来预防GvHD并全面改善 单独或与标准护理药物之一联合使用时，生存期和GvHD评分， 他克莫司，用于GvHD模型。我们还将拥有该药物的安全性和有效性概况，这将为我们的计划提供依据 用于人体临床研究。该项目是将我们治疗GvHD的单抗药物从 从长椅到床边。

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.