Effects of combining anti-CD40 and anti-CD11b mAb107 on survival of pig kidney xenografts in cynomolgus monkeys

抗CD40和抗CD11b mAb107联合使用对食蟹猴猪肾异种移植物存活的影响

基本信息

批准号：
10425736
负责人：
M. AMIN ARNAOUT
金额：
$ 24.24万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-06 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425736
关键词：
Acute Address Allografting Anti-CD40 Binding Cell physiology Cells Cercopithecidae Chimerism Clinical Clinical Trials Coagulation Process Complement Complication Dendritic Cells FOXP3 gene Family suidae Galactose Galactosyltransferases Genes Genetic Engineering Glycolipids Glycoproteins Graft Survival Heterophile Antigens Human ITGAM gene Immune Immunologic Receptors In Vitro Inflammatory Integrins Kidney Kidney Transplantation Knock-out Leukocytes Life Ligands Link Macaca fascicularis Mediating Medical Modeling Monoclonal Antibodies Mus Natural Killer Cells Organ Organ Transplantation Outcome Papio Pathway interactions Peptides Physiological Pongidae Pre-Clinical Model Primates Production Rattus Receptor Activation Regimen Regulatory T-Lymphocyte Renal function Signal Transduction Surface System T-Lymphocyte T-Lymphocyte Subsets TNFRSF5 gene TNFSF5 gene Testing Thromboembolism Thrombosis Transgenic Organisms Transplantation Xenograft procedure base clinical development clinical translation cytokine effectiveness evaluation genetic regulatory protein improved kidney allograft kidney xenograft macrophage man monocyte mouse model natural antibodies neutrophil nonhuman primate preservation prevent receptor receptor binding response thrombotic thrombotic complications

Acute Address Allografting Anti-CD40 Binding Cell physiology Cells Cercopithecidae Chimerism Clinical Clinical Trials Coagulation Process Complement Complication Dendritic Cells FOXP3 gene Family suidae Galactose Galactosyltransferases Genes Genetic Engineering Glycolipids Glycoproteins Graft Survival Heterophile Antigens Human ITGAM gene Immune Immunologic Receptors In Vitro Inflammatory Integrins Kidney Kidney Transplantation Knock-out Leukocytes Life Ligands Link Macaca fascicularis Mediating Medical Modeling Monoclonal Antibodies Mus Natural Killer Cells Organ Organ Transplantation Outcome Papio Pathway interactions Peptides Physiological Pongidae Pre-Clinical Model Primates Production Rattus Receptor Activation Regimen Regulatory T-Lymphocyte Renal function Signal Transduction Surface System T-Lymphocyte T-Lymphocyte Subsets TNFRSF5 gene TNFSF5 gene Testing Thromboembolism Thrombosis Transgenic Organisms Transplantation Xenograft procedure base clinical development clinical translation cytokine effectiveness evaluation genetic regulatory protein improved kidney allograft kidney xenograft macrophage man monocyte mouse model natural antibodies neutrophil nonhuman primate preservation prevent receptor receptor binding response thrombotic thrombotic complications

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项目摘要

Project Summary/Abstract Disrupting the CD40-CD154 costimulatory pathway using an anti-CD154-based regimen has markedly improved gene-edited pig organ xenograft survival in nonhuman primate (NHP) recipients. However, the life-threatening thromboembolic complications associated with use of anti-CD154 have precluded its approval for human use. Attempts to avoid this complication by blocking CD40, the classic CD154 receptor, paradoxically impeded rather than promoted tolerance induction in NHP recipients. A recent study showed that blocking a second CD154 receptor, integrin CD11b, significantly increased efficacy of anti-CD40 in prolonging allograft survival in mice. Although mouse models are important for developing proof-of-concept, it remains to be determined if combined blockade of CD40 and CD11b can be extended to prolonging survival of xenografts in NHP recipients, studies that will be critical for guiding clinical translation. In preliminary studies, we show that an anti-CD11b mAb with a unique mechanism of action not only prevents multiligand binding to CD11b but also blocks direct and indirect NHP T cell alloresponses and prolongs survival of kidney allografts in NHP recipients. The main objective of this exploratory R21 is to test the hypothesis that combining this mAb with anti-CD40 is safer and equivalent to or even more effective than anti-CD154 in prolonging kidney xenograft survival in our established gene-edited pig-to-NHP xenotransplantation model. A second objective of this study is to evaluate the effect of this combined blockade on enumeration and function of T cell subsets in treated NHP. If successful, these studies may provide a basis for prolonging kidney xenograft survival, thus addressing a pressing yet unmet medical need.

项目摘要/摘要使用基于抗CD154的方案破坏CD40-CD154共刺激途径已显着改善非人类灵长类动物（NHP）受体中基因编辑的猪器官异种移植物存活。但是，威胁生命与使用抗CD154相关的血栓栓塞并发症已经排除了其对人类使用的批准。试图通过阻止CD40（经典CD154受体）矛盾地阻碍CD40来避免这种并发症比促进NHP接受者的耐受性诱导。最近的一项研究表明，阻止第二个CD154 受体，整联蛋白CD11b显着提高了抗CD40在延长小鼠同种异体移植存活中的疗效。尽管鼠标模型对于开发概念验证很重要，但如果合并，仍有待确定 CD40和CD11b的封锁可以扩展到NHP受体中异种移植物的延长生存，研究对于指导临床翻译至关重要。在初步研究中，我们显示了具有独特的抗CD11b mAb 作用机理不仅可以防止多元与CD11b结合，还可以阻止直接和间接的NHP T细胞同种酶和延长NHP受体中肾脏同种异体移植的生存。此探索的主要目标 R21是测试以下假设：将此MAB与抗CD40相结合更安全，相当于甚至更多在我们已建立的基因编辑的猪至NHP中，在延长肾脏异种移植物存活中比抗CD154有效异种移植模型。这项研究的第二个目标是评估这种联合封锁对 T细胞子集在处理过的NHP中的枚举和功能。如果成功，这些研究可能会为延长肾脏异种移植的生存，从而解决了紧迫而未满足的医疗需求。