Safe and effective anti CD154 antibodies for therapeutic intervention

用于治疗干预的安全有效的抗 CD154 抗体

• 批准号: 8609546
• 负责人: CHRISTOPHER M BURNS
• 金额: $ 96.27万
• 依托单位: IMMUNEXT, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609546
• 关键词: Ablation; Adopted; Adverse effects; Affect; Allogenic; Allograft Tolerance; Animals; Antibodies; Autoimmune Diseases; Autoimmunity; Binding; Calcineurin inhibitor; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Complement; Complement 1q; Complication; Data; Development; Disease; Disease model; Disease remission; Engineering; Evaluation; Event; Failure; Goals; Government; Graft Rejection; Graft Tolerance; Half-Life; Hematopoietic Stem Cell Transplantation; Human; Immune; Immunosuppressive Agents; Intervention; Laboratories; Lead; Licensing; Macaca fascicularis; Modeling; Modification; Monkeys; Multiple Sclerosis; Mus; Mutate; Mutation; Organ Transplantation; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Platelet aggregation; Program Development; Safety; Severe Adverse Event; Site; Site-Directed Mutagenesis; Small Business Innovation Research Grant; Solid; Steroids; Suspension substance; Suspensions; Systemic Lupus Erythematosus; TNFSF5 gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Thrombocytopenia; Toxic effect; Transplantation; Variant; Work; base; chronic graft versus host disease; graft vs host disease; improved; in vivo; interest; islet allograft; mortality; mutant; novel; novel strategies; novel therapeutics; phase 1 study; pre-clinical; programs; prophylactic; public health relevance; safety study; safety testing; standard of care; therapeutic target

DESCRIPTION (provided by applicant): In both animal proof of concept studies and preliminary clinical trials, there is ample data demonstrating the potential therapeutic benefits o CD154 blockade for treatment of GVHD, organ transplantation and autoimmune diseases. However, development of ¿CD154 as a therapeutic has been impeded by antibody toxicity observed in early clinical trials. GVHD is a complication of allogeneic Hematopoietic Stem Cell Transplantation (HSCT). GVHD remains a major cause of mortality in approximately 50% of patients who survive > 1 year post transplant. The standard of care is limited to drugs that need to be taken long term, work moderately well and are associated with significant side effects. There is therefore profound unmet need and significant potential for drugs that are safe and efficacious. Studies in GVHD have demonstrated that anti-CD154 acts as a prophylactic and is effective as a monotherapy as demonstrated in NHP where permanent allograft tolerance can be achieved using short courses of treatments comprised of ?CD154 alone. This strategy eliminates the use of steroids and calcineurin inhibitors both of which are associated with numerous side effects. ?CD154 thus has a competitive advantage as most other drugs in development will require some form of combination therapy with either steroids or calcineurin inhibitors. A similar opportunity for improved clinical outcomes due to effective induction of tolerance exists in recipients of solid organ transplants. Furthermore, virtually all autoimmune disease models can be effectively ameliorated with ?CD154 therapy, with long-term remission observed. We will target GVHD and chronic rejection associated with transplantation as our first clinical indication for commercial development. Existing studies strongly suggest that domains within the Fc region of the ?CD154 mAb contribute to its toxicity and therapeutic capacity. When toxicity was observed in the clinic and retrospectively in NHP, modifications were made to the antibody; while these modifications eliminated toxicity in NHP, the efficacy of ?CD154 as a tolerogenic antibody also was significantly reduced. As a result, development programs for ?CD154 as a therapeutic stalled. In Phase 1 studies we identified modifications that resulted in safe and efficacious versions of ¿CD154 as tested in murine models. The goal of this proposal is to build on those observations and generate variant forms of the ?human CD154 antibody that retain the beneficial tolerogenic effects of ?CD154 while greatly reducing or eliminating toxicity. Variant forms of the antibody will be evaluated for both safety and efficacy in NHP models. Successful proof of concept in NHP transplant models will be the basis for creating a novel therapeutic, which could have far-reaching impacts on the treatment of autoimmune diseases and organ transplantation.

描述（由申请人提供）：在动物概念验证研究和初步临床试验中，有充分的数据证明了CD 154阻断剂治疗GVHD、器官移植和自身免疫性疾病的潜在治疗益处。然而，CD 154作为治疗剂的发展受到早期临床试验中观察到的抗体毒性的阻碍。 GVHD是异基因造血干细胞移植（HSCT）的并发症。GVHD仍然是移植后存活> 1年的患者中约50%的死亡的主要原因。护理标准仅限于需要长期服用的药物，工作适度，并与显着的副作用有关。因此，对安全有效的药物存在着巨大的未满足需求和巨大的潜力。在GVHD的研究已经证明，抗CD 154作为一种预防和有效的单一疗法，在NHP中证明，永久性移植物耐受可以实现使用短期治疗组成的？CD 154单独使用。这种策略消除了类固醇和钙调磷酸酶抑制剂的使用，这两者都与许多副作用有关。?因此，CD 154具有竞争优势，因为大多数其他正在开发的药物将需要某种形式的类固醇或钙调磷酸酶抑制剂的联合治疗。由于有效诱导耐受，在实体器官移植受者中存在改善临床结果的类似机会。此外，几乎所有的自身免疫性疾病模型可以有效地改善？CD 154治疗，观察到长期缓解。我们将靶向GVHD和与移植相关的慢性排斥反应，作为我们商业开发的第一个临床适应症。 现有的研究强烈表明，域内的Fc区的？CD 154单克隆抗体有助于其毒性和治疗能力。当在临床和回顾性NHP中观察到毒性时，对抗体进行了修改;虽然这些修改消除了NHP的毒性，但NHP的疗效？作为致耐受性抗体的CD 154也显著降低。因此，发展计划？CD 154作为一种治疗药物停滞不前。在1期研究中，我们确定了在小鼠模型中测试的导致安全有效的CD 154版本的修饰。这项建议的目标是建立在这些意见，并产生不同形式的？人CD 154抗体，保留了有益的致耐受性作用？CD 154，同时大大降低或消除毒性。将在NHP模型中评价抗体变体形式的安全性和有效性。在NHP移植模型中成功的概念验证将是创造一种新疗法的基础，这可能对自身免疫性疾病和器官移植的治疗产生深远的影响。