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: 8523637
• 负责人: RANDOLPH J. NOELLE
• 金额: $ 99.8万
• 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/8523637
• 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，有充足的数据表明CD154阻断剂在治疗GVHD、器官移植和自身免疫性疾病方面具有潜在的治疗益处。然而，在早期临床试验中观察到的抗体毒性阻碍了CD154作为治疗药物的发展。