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

基本信息

批准号：
8253027
负责人：
Susan Dana Jones
金额：
$ 30万
依托单位：
IMMURX LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8253027
关键词：
Affect Alloantigen Allograft Tolerance Animals Antibodies Autoimmune Diseases Autoimmunity Binding Cell Transplantation Cells Clinic Clinical Clinical Trials Complement Data Development Disease Disease model Disease remission Engineering Evaluation Event Experimental Autoimmune Encephalomyelitis Failure Goals Government Graft Rejection Human Humoral Immunities Immune Immune response Immunity Intervention Investigation Knowledge Laboratories Lung Mediating Modeling Modification Monkeys Multiple Sclerosis Mus Mutate Organ Transplantation Outcome Patients Persons Pharmaceutical Preparations Pharmacologic Substance Phase Phase II Clinical Trials Production Program Development Severe Adverse Event Study models Suspension substance Suspensions T-Lymphocyte TNFSF5 gene Testing Therapeutic Therapeutic Agents Therapeutic Intervention Thrombus Toxic effect Transplantation Treatment Cost Treatment Efficacy Variant antibody engineering base effective therapy in vivo mouse model nonhuman primate novel novel therapeutics programs receptor skin allograft therapeutic target

项目摘要

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 autoimmune diseases and organ transplantation. However, development of ?CD154 as a therapeutic has been impeded by antibody toxicity observed in early clinical trials. With nearly 50 million people suffering from autoimmune diseases, in the US alone, and with treatment costs projected to be over $100B/yr, development of safe, effective therapies is an utmost priority. Worldwide 2.5 million people are affected by MS, with 1/5 of patients found in the US. It is clear if toxicity can be resolved, and efficacy sustained, ?CD154 i a viable and attractive therapeutic that offers great promise for the treatment of autoimmune diseases. We will target MS 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. The goal of this proposal is to generate variant forms of the ?murine CD154 antibody that will retain the beneficial tolerogenic effects of aCD154 while greatly reducing or eliminating toxicity. Variant forms of the antibody will be evaluated in vivo using mouse models of transplantation, cell and humoral immunity, as well as assessing their toxicity. Successful proof of concept will be the basis for creating a similar variant of the human antibody that will be developed as a novel therapeutic, which could have far-reaching impacts on the treatment of autoimmune diseases and organ transplantation. PUBLIC HEALTH RELEVANCE: Development of aCD154 as a therapeutic for autoimmune diseases and transplantation has shown great promise in human clinical trials but development has been hindered by problems with antibody toxicity. In the past, when toxicity was reduced, the efficacy of the antibody was dramatically decreased leading to the suspension of developmental programs. This project will engineer new variants of the aCD154 antibody that will eliminate toxicity while maintaining tolerogenicity, thus allowing the potential of aCD154 to be harnessed as a novel treatment for a wide range of diseases.

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，有充足的数据证明了 CD154 阻断治疗自身免疫性疾病和器官移植的潜在治疗益处。然而，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。仅在美国就有近 5000 万人患有自身免疫性疾病，治疗费用预计每年将超过 100B 美元，开发安全、有效的疗法是当务之急。全球有 250 万人受到多发性硬化症的影响，其中 1/5 的患者出现在美国。很明显，如果毒性能够得到解决并且疗效能够持续，那么CD154就是一种可行且有吸引力的治疗方法，为自身免疫性疾病的治疗提供了巨大的前景。我们将把多发性硬化症作为我们商业开发的第一个临床适应症现有研究强烈表明，CD154 mAb Fc 区内的结构域有助于其毒性和治疗能力。当在临床和回顾性观察 NHP 的毒性时，对抗体进行了修改；虽然这些修饰消除了 NHP 中的毒性，但 ?CD154 作为耐受性抗体的功效也显着降低。结果，作为治疗剂的 γCD154 的开发计划陷入停滞。该提案的目标是产生小鼠 CD154 抗体的变体形式，该抗体将保留 aCD154 的有益耐受性作用，同时大大减少或消除毒性。抗体的变体形式将使用小鼠移植模型、细胞和体液免疫进行体内评估，并评估其毒性。成功的概念验证将成为创建人类抗体的类似变体的基础，该变体将被开发为一种新型疗法，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。公共健康相关性：aCD154 作为自身免疫性疾病和移植治疗药物的开发在人体临床试验中显示出巨大的前景，但开发一直受到抗体毒性问题的阻碍。过去，当毒性降低时，抗体的功效会急剧下降，导致开发计划暂停。该项目将设计 aCD154 抗体的新变体，消除毒性，同时保持耐受性，从而使 aCD154 的潜力能够被用作治疗多种疾病的新疗法。