Safe And Effective Anti-CD154 Antibodies For Therapeutic Intervention

描述(由申请人提供)：有令人信服的证据表明CD154治疗在自身免疫和移植物排斥中具有巨大的潜力。 自身免疫力。CD154治疗狼疮和特发性血小板减少症已见临床疗效。此外，首席研究员诺埃尔博士对CD154的临床经验是基于缓解/复发多发性硬化症的I期试验。结果是惊人的：仅4周的治疗就产生了： *在所有剂量下，扩展残疾状况量表在5年基线基础上没有重大变化； *改进的扩展残疾状况量表与增加的剂量和 *长期随访显示临床复发率大幅下降 移植物排斥反应。CD154的显著特征是，一个简单的治疗可以灌输长期的移植物特异性耐受，如NHP所证明的那样。这种新的治疗方法将避免使用广谱免疫抑制药物，因为这种药物会增加移植接受者患癌症和传染病的风险。长期接受移植物而不受终身免疫抑制的治疗将显著提高患者的生活质量，并显著降低治疗成本。 不幸的是，在一些早期的临床试验中，这种令人兴奋的疗法的开发因毒性而停滞不前。 现有研究强烈表明，CD154单抗Fc区的结构域与其毒性和治疗能力有关。当在临床和NHP中观察到毒性时，对抗体进行修改。虽然这些修饰消除了NHP的毒性，但作为耐受性抗体的CD154的效力也显著降低。因此，CD154作为一种治疗药物的开发计划停滞不前。这项提议的目标是产生不同形式的小鼠CD154抗体，这种抗体将保留CD154有益的耐受作用，同时极大地降低或消除毒性。 不同形式的抗体将使用小鼠移植和体液免疫模型在体内进行评估，并评估它们的毒性。在第一阶段成功的概念证明将是在第二阶段创造一种类似的人类抗体变体的基础，这种抗体将被开发为一种新的治疗方法。到目前为止，还没有人设计出此应用程序中提出的具体更改。 在美国，近5000万人患有自身免疫性疾病。治疗费用超过1000亿美元/年。美国进行了20,000多例移植手术，每年花费在移植后免疫抑制上的资金超过5亿美元。我们的解决方案可能会帮助许多有需要的患者。

DESCRIPTION (provided by applicant): There is compelling evidence that ?CD154 treatment has great potential in autoimmunity and graft rejection. Autoimmunity. Clinical efficacy of ?CD154 treatment has been seen in Lupus and idiopathic thrombocytopenia. In addition, Principal Investigator Dr. Noelle's clinical experience with ?CD154 is based on a Phase I trial in remitting/ relapsing MS. The results were striking: treatments over just 4 weeks resulted in: * No significant changes in Expanded Disability Status Scale from baseline for 5 years at all doses; * Improved Expanded Disability Status Scale correlated with increased dose and * Long-term follow up demonstrated a profound reduction in clinical relapse rate Graft Rejection. The remarkable feature of ?CD154 is that a brief treatment can instill long-term graft- specific tolerance, as demonstrated in NHP. This novel therapeutic will avoid the use of broad spectrum immunosuppressive drugs that create increased risk of cancer and infectious disease for the graft recipient. A treatment that results in long-term graft acceptance without life-long immunosuppression will lead to substantial benefits in quality of life, and substantially reduce the cost of treatment. Unfortunately, development of this exciting therapeutic was stalled by toxicity in some early clinical trials. 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 ?CD154 while greatly reducing or eliminating toxicity. Variant forms of the antibody will be evaluated in vivo using mouse models of transplantation and humoral immunity, as well as assessing their toxicity. Successful proof of concept in Phase 1 will be the basis for creating a similar variant of the human antibody in Phase 2 that will be developed as a novel therapeutic. To date, no one has engineered the specific changes proposed in this application. In the US, nearly 50 million people suffer from autoimmune diseases. Treatment costs over $100B/year. Over 20,000 US transplants are performed and over $500M/yr is spent on immunosuppression post-transplant. Our solution may help many patients in need.