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：
10618872
负责人：
M. AMIN ARNAOUT
金额：
$ 20.44万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618872
关键词：
Acute Address Allografting Anti-CD40 Binding Cell physiology Cells Cercopithecidae Chimerism Clinical Clinical Trials Coagulation Process Complement Complication Cyclization Dendritic Cells FOXP3 gene Family suidae Galactosyltransferases Genes Genetic Engineering Glycolipids Glycoproteins Graft Survival Heterophile Antigens Human ITGAM gene Immune Immunologic Receptors In Vitro Inflammatory Integrins Ischemia Kidney Kidney Transplantation Knock-out Leukocytes Life Ligand Binding Ligands Link Macaca fascicularis Macrophage 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 Reperfusion Therapy Signal Transduction Surface System T-Lymphocyte T-Lymphocyte Subsets TNFRSF5 gene TNFSF5 gene Testing Thromboembolism Thrombosis Transplantation Xenograft Model Xenograft procedure clinical development clinical translation cytokine effectiveness evaluation galactosyl-(1-3)galactose genetic regulatory protein improved kidney allograft kidney xenograft man monocyte mouse model natural antibodies neutrophil nonhuman primate preservation prevent receptor receptor binding response thrombotic thrombotic complications transgene expression

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.

项目概要/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基因编辑的猪器官异种移植物在非人灵长类动物（NHP）受体中的存活率。然而，危及生命的与使用抗 CD154 相关的血栓栓塞并发症阻碍了其批准用于人类。通过阻断 CD40（经典的 CD154 受体）来避免这种并发症的尝试却相反地受到了阻碍比促进 NHP 接受者的耐受诱导。最近的一项研究表明，阻断第二个 CD154 受体整合素 CD11b 显着提高了抗 CD40 延长小鼠同种异体移植物存活的功效。尽管小鼠模型对于开发概念验证很重要，但是否结合起来仍有待确定研究表明，CD40 和 CD11b 的阻断可以延长 NHP 受者异种移植物的存活时间对于指导临床转化至关重要。在初步研究中，我们表明，具有独特特性的抗 CD11b mAb 作用机制不仅可以阻止多配体与 CD11b 结合，还可以阻断直接和间接的 NHP T 细胞异体反应并延长 NHP 受者肾同种异体移植物的存活时间。此次探索的主要目的 R21是为了检验这个mAb与抗CD40结合更安全、等效甚至更安全的假设在我们建立的基因编辑猪转 NHP 中，比抗 CD154 更有效地延长肾异种移植物的存活异种移植模型。这项研究的第二个目标是评估这种联合封锁对治疗 NHP 中 T 细胞亚群的计数和功能。如果成功的话，这些研究可能会提供基础延长肾异种移植物的存活率，从而解决紧迫但未得到满足的医疗需求。