Antigen Specific T Cell tolerance by Anti CD3 Antibodies

抗 CD3 抗体的抗原特异性 T 细胞耐受

• 批准号: 8120238
• 负责人: CLAUDIO ANASETTI
• 金额: $ 36.54万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-25 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120238
• 关键词: Acute Graft Versus Host Disease; Agonist; Alloantigen; Allogenic; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; CD3 Antigens; Cell Death; Cell Differentiation process; Cell Transplantation; Cells; Clinical; Clinical Trials; Collaborations; Complex; Cytomegalovirus; Development; Doctor of Medicine; Fc Receptor; Grant; Health; Hematopoietic; Hematopoietic Stem Cell Transplantation; Human; Human Herpesvirus 4; Immune; Immune system; Immunity; Immunosuppression; Infectious Agent; Ligands; Mediating; Monoclonal Antibodies; Monoclonal Antibody HuM291; Mus; Organ Transplantation; Patients; Pattern; Peripheral; Play; Prevention; Principal Investigator; Procedures; Proteins; Receptor Signaling; Recruitment Activity; Refractory; Regimen; Regulatory T-Lymphocyte; Role; Safety; Signal Transduction; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Agents; Transplantation; Transplantation Tolerance; Tumor Antigens; Viral; Visilizumab; WT1 gene; anergy; animal data; design; disorder prevention; graft vs host disease; improved; man; patient safety; prevent; programs; prototype; receptor binding; response

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.

描述（由申请人提供）：尽管有最好的免疫抑制方案，但同种异体供体造血干细胞移植后可能会出现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。最近在了解外周T细胞耐受机制方面取得的进展，使得验证通过选择性消耗同种异体反应性T细胞，T细胞受体（TCR）部分激动剂配体可以预防人类GVHD的假设成为可能。移植耐受是由特异性同种异体抗原触发的外周T细胞激活诱导细胞死亡（AICD）促进的，TCR信号是诱导抗原特异性耐受不可或缺的。TCR参与可诱导T细胞增殖和分化或AICD。CD3单克隆抗体（mAb）是与TCR复合物相关的单态链，模拟抗原并诱导TCR信号传导和T细胞活化。Fc受体（FcR）结合的抗cd3单克隆抗体招募抗原呈递细胞（APC），并提供完整的激动剂信号，促进T细胞增殖和效应功能，不依赖抗原。相反，非fcr结合的抗cd3单克隆抗体诱导部分激动剂TCR信号传导模式，在初始T细胞中引起能量，在抗原激活的循环T细胞中引起AICD。在小鼠中，我们发现非fr结合的抗cd3单克隆抗体诱导识别受体同种异体抗原的供体T细胞选择性耗尽，从而通过MHC差异阻止GVHD，并保留对第三方抗原特异性的T细胞。与j.t so合作，我们设计了一种“人源化”的非fr结合抗cd3单抗，visilizumab，它向TCR提供部分激动剂信号。Visilizumab在诱导活化的、循环的人T细胞AICD方面比其他抗cd3单抗更有效。我们在人体试验中的初步结果表明，visilizumab可以在一些严重急性GVHD患者中诱导完全的临床反应，这些患者对常规免疫抑制剂难以耐受。我们建议研究visilizumab在HLA不相容供者造血细胞移植（HCT）后预防GVHD的疗效，并评估其免疫抑制作用是否对同种抗原具有选择性。我们将追求以下具体目标：目的1：确定人源化非fr结合抗cd3单抗visilizumab在预防hla不相容供者t -造血细胞移植后严重GVHD的安全性和有效性。目的2：研究visilizumab治疗是否会消耗同种异体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WT1的免疫。公共卫生相关性：开发预防GVHD的有效方案将提高移植后患者的安全性和生存率，并将该手术的使用范围扩大到更多的患者。GVHD预防的进展有可能推动器官移植和自身免疫性疾病治疗领域的发展。抗cd3单克隆抗体代表了一类新的治疗药物的原型，这些药物通过诱导T细胞的失活激活和死亡来抑制免疫系统。使抗cd3单克隆抗体比其他药物更独特和更有吸引力的是快速和不可逆地实现免疫耐受的潜力。证明非fcr结合的抗cd3单克隆抗体是预测患者安全性的关键。