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？CD 154治疗在自身免疫和移植排斥反应中具有巨大的潜力。 自体免疫临床疗效如何？CD 154治疗已见于狼疮和特发性血小板减少症。此外，主要研究者Noelle博士的临床经验？CD 154是基于缓解/复发MS的I期试验。结果是惊人的：治疗仅4周就导致： * 在所有剂量下，5年内扩展残疾状态量表较基线无显著变化; * 改良扩展残疾状态量表与剂量增加相关， * 长期随访显示临床复发率显著降低 移植排斥反应。的显著特征？CD 154的另一个优点是，如NHP中所证明的，短暂的治疗可以灌输长期的移植物特异性耐受。这种新的治疗方法将避免使用广谱免疫抑制药物，这些药物会增加移植受体患癌症和感染性疾病的风险。导致长期移植物接受而没有终身免疫抑制的治疗将导致生活质量的实质性益处，并显著降低治疗成本。 不幸的是，这种令人兴奋的治疗方法的发展在一些早期临床试验中因毒性而停滞不前。 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NHP中回顾性观察到毒性时，对抗体进行了修改。虽然这些修改消除了NHP的毒性，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？鼠CD 154抗体，将保留有益的致耐受作用？CD 154，同时大大降低或消除毒性。 将使用移植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。第一阶段的成功概念验证将是在第二阶段创建类似的人抗体变体的基础，该变体将被开发为新型治疗药物。到目前为止，还没有人设计出本申请中提出的具体更改。 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。美国进行了超过20，000例移植手术，每年花费超过5亿美元用于移植后的免疫抑制。我们的解决方案可以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.