Safe and effective anti CD154 antibodies for therapeutic intervention

描述（由申请人提供）：在概念研究和初步临床试验的动物验证中，有充分的数据证明了CD 154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，发展？CD 154作为治疗剂受到早期临床试验中观察到的抗体毒性的阻碍。仅在美国就有近5000万人患有自身免疫性疾病，治疗费用预计超过1000亿美元/年，开发安全有效的治疗方法是当务之急。全球有250万人受MS影响，其中1/5的患者在美国发现。目前尚不清楚毒性是否可以解决，疗效是否可以持续？CD 154是一种可行的和有吸引力的治疗剂，为治疗自身免疫性疾病提供了巨大的希望。我们将把MS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。这项建议的目标是产生的变体形式？本发明提供了鼠CD 154抗体，其将保留aCD 154的有益致耐受性作用，同时大大降低或消除毒性。 将使用移植、细胞和体液免疫的小鼠模型在体内评价抗体的变体形式，并评估其毒性。成功的概念验证将成为创造类似的人类抗体变体的基础，该变体将被开发为一种新型治疗药物，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。 公共卫生相关性：aCD 154作为自身免疫性疾病和移植的治疗剂的开发在人类临床试验中显示出巨大的前景，但开发受到抗体毒性问题的阻碍。在过去，当毒性降低时，抗体的功效显著降低，导致开发计划的暂停。该项目将设计aCD 154抗体的新变体，在保持耐受性的同时消除毒性，从而使aCD 154的潜力成为广泛疾病的新型治疗方法。

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.