Antigen Specific T Cell tolerance by Anti CD3 Antibodies

描述（由申请人提供）：尽管采用了最佳的免疫抑制方案，但同种异体供体的造血干细胞移植后仍可能发生严重的移植物抗宿主病（GVHD）。实验动物数据和临床试验结果表明，T细胞在GVHD中起着核心作用。外周T细胞耐受机制的最新进展使得可以验证T细胞受体（TCR）部分激动剂配体通过选择性耗竭同种异体反应性T细胞可以预防人类GVHD的假设。移植耐受是由特异性同种异体抗原引发的外周血T细胞活化诱导的细胞死亡（AICD）促进的，而TCR信号对于诱导抗原特异性耐受是必不可少的。TCR接合可以诱导T细胞增殖和分化或AICD。针对CD 3（与TCR复合物相关的单态性链）的单克隆抗体（mAb）模拟抗原并诱导TCR信号传导和T细胞活化。Fc受体（FcR）结合抗CD 3 mAb募集抗原呈递细胞（APC）并递送完全激动剂信号，促进T细胞增殖和效应子功能，不依赖于抗原。相反，非FcR结合抗CD 3 mAb诱导部分激动剂TCR信号传导模式，导致初始T细胞中的无反应性和抗原活化的循环T细胞中的AICD。在小鼠中，我们发现非FcR结合的抗CD 3单克隆抗体诱导识别受体同种异体抗原的供体T细胞的选择性耗竭，从而防止跨MHC差异的GVHD，并保留对第三方抗原特异性的T细胞。与J. Tso合作，我们设计了一种“人源化”非FcR结合抗CD 3 mAb，即Alcurizumab，它向TCR提供部分激动剂信号。Visilizumab在诱导活化的循环人T细胞的AICD方面比其他抗CD 3 mAb更有效。我们在人体试验中的初步结果表明，阿曲利珠单抗可以在一些患有严重急性GVHD的患者中诱导完全的临床应答，这些患者对常规免疫抑制剂难以治疗。我们建议在这里研究阿曲利珠单抗在预防HLA不相容供体造血细胞移植（HCT）后GVHD的疗效，并评估其免疫抑制作用是否对同种异体抗原具有选择性。我们将追求以下具体目标：目标1：确定人源化非FcR结合抗CD 3 mAb阿曲利珠单抗在预防来自HLA不相容供体的T-完全造血细胞移植物移植后严重GVHD中的安全性和有效性。目标二：研究阿曲利珠单抗治疗是否耗尽同种异体反应性T细胞池，同时保留对第三方同种异体抗原、巨细胞病毒（CMV）和EB病毒（EBV）以及肿瘤相关抗原WT 1的免疫力。公共卫生相关性：开发有效的方案预防GVHD将提高移植后患者的安全性和存活率，并将该程序的使用扩展到更多的患者。GVHD预防的进展具有推进器官移植和自身免疫性疾病治疗领域的潜力。抗CD 3单克隆抗体代表了一类新的治疗剂的原型，其通过诱导流产活化和T细胞死亡来抑制免疫系统。抗CD 3单克隆抗体的独特性和比其他药物更有吸引力的是快速和不可逆地实现免疫耐受的潜力。显示非FcR结合抗CD 3 mAb备用对病毒和肿瘤相关抗原特异性的T细胞是预测患者安全性的关键。

DESCRIPTION (provided by applicant): Transplantation of hematopoietic stem cells from an allogeneic donor can be followed by serious graft-versus-host disease (GVHD) despite the best available regimen for immune suppression. Experimental animal data and results of clinical trials have demonstrated that T cells play a central role in GVHD. Recent advances in understanding the mechanisms of peripheral T cell tolerance have made it feasible to test the hypothesis that GVHD can be prevented in man by T cell receptor (TCR) partial agonist ligands through the selective depletion of alloreactive T cells. Transplantation tolerance is facilitated by activation-induced cell death (AICD) of peripheral T cells triggered by the specific alloantigens, and TCR signals are indispensable for induction of antigen-specific tolerance. TCR engagement can induce either T cell proliferation and differentiation or AICD. Monoclonal antibodies (mAb) to CD3, a monomorphic chain associated to the TCR complex, mimic antigen and induce TCR signaling and T cell activation. Fc receptor (FcR)-binding anti-CD3 mAbs recruit antigen-presenting cells (APC) and deliver full agonist signals that promote T cell proliferation and effector functions, independent of antigen. In contrast, non-FcR-binding anti-CD3 mAbs induce a partial agonist TCR signaling pattern causing anergy in naive T cells and AICD in antigen-activated, cycling T cells. In mice, we found that non-FcR-binding anti-CD3 mAbs induce selective depletion of donor T cells that recognize recipient alloantigens thereby preventing GVHD across MHC disparities, and spare T cell specific to third party antigens. In collaboration with J. Tso, we designed a `humanized' non-FcR-binding anti-CD3 mAb, visilizumab, which delivers a partial agonist signal to the TCR. Visilizumab is more effective than other anti-CD3 mAbs in inducing AICD of activated, cycling human T cells. Our preliminary results in human trials show that visilizumab can induce complete clinical responses in some patients with severe acute GVHD, refractory to conventional immune suppressive agents. We propose here to study efficacy of visilizumab in the prevention of GVHD after hematopoietic cell transplantation (HCT) from HLA incompatible donors, and assess whether its immune suppressive effects are selective for alloantigens. We will pursue the following specific aims: Aim 1: Determine the safety and efficacy of humanized non-FcR-binding anti-CD3 mAb visilizumab in preventing severe GVHD after transplantation of T-replete hematopoietic cell grafts from HLA-incompatible donors. Aim 2: Investigate whether visilizumab therapy depletes the alloreactive T cell pool, while sparing immunity to third party alloantigens, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), and tumor- associated antigen WT1. PUBLIC HEALTH RELEVANCE: The development of effective regimens for the prevention of GVHD will improve patient safety and survival after transplantation, and extend the use of this procedure to a larger number of patients. Progress in the prevention of GVHD has the potential for advancing the fields of organ transplantation and therapy for autoimmune disorders. Anti-CD3 mAbs represent the prototype of a new class of therapeutic agents that suppress the immune system by inducing an abortive activation and T cell death. What makes anti-CD3 mAbs unique and more attractive than other agents is the potential for achieving immunological tolerance rapidly and irreversibly. Showing that non-FcR-binding anti-CD3 mAbs spare T cells specific for viral and tumor-associated antigens is key to predict patient safety.