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

TIM-1 阻断单克隆抗体用于预防造血干细胞移植患者的移植物抗宿主病

• 批准号: 10079012
• 负责人: Kirk Essenmacher
• 金额: $ 39.97万
• 依托单位: TRIURSUS THERAPEUTICS INCORPORATED
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079012
• 关键词: ARHGEF5 gene; Acute Graft Versus Host Disease; Adverse effects; Allogenic; Apoptosis; Area; Automobile Driving; Binding; Biological Markers; Blood Cell Count; Capital; Caring; Cell Culture Techniques; Cell Surface Receptors; Cells; Clinical; Clinical Research; Clinical Trials; Collaborations; Complication; Creatine; Cyclosporine; Data; Development; Development Plans; Diarrhea; Disease model; Dose; Funding; Goals; Graft Survival; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histopathology; Human; IgG2; Immune; Impairment; In Vitro; Incidence; Inflammation; Inflammatory Response; Lead; Life; Macaca; Maintenance; Measures; Mediating; Medical; Methods; Methotrexate; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phagocytosis; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphatidylserines; Physicians; Prevention; Prophylactic treatment; Protocols documentation; Reporting; Rivers; Safety; Severities; Signal Pathway; Small Business Innovation Research Grant; Standardization; Surface; T cell reconstitution; TC1 Cell; Tacrolimus; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; Toxicology; Translating; Transplant Recipients; Treatment Efficacy; Variant; Xenograft procedure; base; bench to bedside; cell bank; commercialization; comparative efficacy; cytokine; drug candidate; efficacy study; efficacy testing; graft vs host disease; humanized monoclonal antibodies; humanized mouse; immune reconstitution; improved; in vitro testing; in vivo; interest; lead candidate; meetings; mortality; nonhuman primate; novel; phase 2 testing; preclinical safety; preconditioning; prevent; safety study; side effect; therapeutic effectiveness; transplant model; transplantation medicine

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.

项目摘要 移植物抗宿主病（GvHD）是造血干细胞移植（HSCT）的主要并发症， 尽管普遍使用预防，但仍导致患者显著的发病率和死亡率。的当前方法 预防GvHD依赖于免疫抑制药物，包括他克莫司（TAC）或环孢霉素（CSA）加 甲氨蝶呤（MTX）用于预防，具有严重的副作用，损害T细胞重建，并减少移植物的生成。 抗肿瘤（GvT）效应。Triursus Therapeutics，Inc.开发了单克隆抗体（mAb）技术 治疗HSCT患者的GvHD。我们的主要候选药物在维持GvT的同时保护急性GvHD 在小鼠HSCT模型中的作用。在这个SBIR快速通道应用程序中，我们的目标是进一步发展领导候选人 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mAb， 在人源化小鼠GvHD中测试与未处理或免疫抑制药物处理的对照相比的功效 模型在II期，我们将在HSCT/GvHD的非人灵长类动物模型中测试我们的人源化mAb的安全性， 与免疫抑制药物治疗的对照相比的功效。我们还将推进制药业 通过建立主细胞库，标准化生产， IND使能活动，并验证拟议的开发计划是否为监管机构所接受。 在这个项目完成后，我们希望有一个人源化的单克隆抗体，防止GvHD和改善整体 当单独施用或与标准护理药物之一组合施用时的存活率和GvHD评分， 他克莫司，在GvHD模型中。我们也将有药物的安全性和有效性概况，将告知我们的计划 用于人体临床研究该项目是将我们用于GvHD的mAb药物从 长凳到床边