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）：尽管有最佳的免疫抑制方案，但移植同种异体供体的造血干细胞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中发挥着核心作用。了解外周 T 细胞耐受机制的最新进展使得检验以下假设变得可行：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 细胞来预防人类 GVHD。特定同种异体抗原引发的外周 T 细胞活化诱导细胞死亡 (AICD) 促进了移植耐受，而 TCR 信号对于诱导抗原特异性耐受是不可或缺的。 TCR 参与可以诱导 T 细胞增殖和分化或 AICD。 CD3（与 TCR 复合物相关的单态链）的单克隆抗体 (mAb) 模拟抗原并诱导 TCR 信号传导和 T 细胞激活。 Fc 受体 (FcR) 结合抗 CD3 mAb 招募抗原呈递细胞 (APC) 并传递完全激动剂信号，促进 T 细胞增殖和效应功能，而与抗原无关。相比之下，非 FcR 结合抗 CD3 mAb 诱导部分激动剂 TCR 信号传导模式，导致初始 T 细胞无反应性和抗原激活的循环 T 细胞中的 AICD。在小鼠中，我们发现非 FcR 结合的抗 CD3 mAb 会选择性地消耗识别受体同种抗原的供体 T 细胞，从而防止 MHC 差异性的 GVHD，并保留对第三方抗原具有特异性的 T 细胞。我们与 J. Tso 合作，设计了一种“人源化”非 FcR 结合抗 CD3 mAb，visilizumab，它向 TCR 传递部分激动剂信号。 Visilizumab 在诱导激活的循环人类 T 细胞的 AICD 方面比其他抗 CD3 mAb 更有效。我们的人体试验初步结果表明，visilizumab 可以在一些对传统免疫抑制剂耐药的严重急性 GVHD 患者中诱导完全临床反应。我们在此建议研究visilizumab预防HLA不相容供体造血细胞移植（HCT）后GVHD的功效，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： 目标 1：确定人源化非 FcR 结合抗 CD3 mAb visilizumab 在预防 HLA 不相容供体的 T 充足造血细胞移植物移植后发生严重 GVHD 方面的安全性和有效性。目标 2：研究 Visilizumab 疗法是否会耗尽同种异体反应性 T 细胞库，同时保留对第三方同种抗原、巨细胞病毒 (CMV) 和 Epstein-Barr 病毒 (EBV) 以及肿瘤相关抗原 WT1 的免疫力。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患者。 GVHD 预防方面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 mAb 代表了一类新型治疗剂的原型，该治疗剂通过诱导无效激活和 T 细胞死亡来抑制免疫系统。抗 CD3 mAb 的独特性和比其他药物更有吸引力的原因在于其具有快速且不可逆地实现免疫耐受的潜力。证明非 FcR 结合抗 CD3 mAb 可以保留病毒和肿瘤相关抗原特异性的 T 细胞，这是预测患者安全的关键。