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：
8394297
负责人：
RANDOLPH J. NOELLE
金额：
$ 29.09万
依托单位：
IMMUNEXT, INC.
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：
2012-12-15 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8394297
关键词：
Alloantigen Allograft Tolerance Antibodies Autoimmune Diseases Autoimmunity Binding Clinic Clinical Clinical Trials Communicable Diseases Complement Data Development Disease Disease model Disease remission Dose Employee Strikes Engineering Evaluation Event Failure Goals Government Graft Rejection Graft Tolerance Human Humoral Immunities Immune Immune response Immunosuppression Immunosuppressive Agents Intervention Investigation Laboratories Lead Life Lung Lupus Modeling Modification Monkeys Multiple Sclerosis Mus Mutate Outcome Patients Persons Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Phase II Clinical Trials Principal Investigator Production Program Development Quality of life Relapse Severe Adverse Event Solutions Study models Suspension substance Suspensions T-Lymphocyte TNFSF5 gene Testing Therapeutic Therapeutic Agents Therapeutic Intervention Thrombocytopenia Thrombus Toxic effect Transplantation Treatment Cost Treatment Efficacy Variant antibody engineering base brief intervention cancer risk clinical efficacy disability experience follow-up improved in vivo insight mouse model nonhuman primate novel novel therapeutics programs public health relevance receptor response skin allograft therapeutic target

项目摘要

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.

描述（由申请人提供）：有令人信服的证据表明，CD154治疗在自身免疫性和移植排斥中具有巨大的潜力。自身免疫性。在狼疮和特发性血小板减少症中，CD154治疗的临床功效已被发现。此外，首席研究员Noelle博士对CD154的临床经验是基于I期试验来汇总/复发MS的。结果令人惊讶：在短短4周内治疗导致： *从基准量表从基线增加了5年，所有剂量都没有显着变化； *改善的扩大残疾状态量表与剂量增加和 *长期随访显示临床复发率大幅降低移植拒绝。 CD154的显着特征是短暂的处理可以灌输长期的移植特异性耐受性，如NHP所示。这种新型的治疗方法将避免使用广谱免疫抑制药物，从而增加了移植者患癌症和感染性疾病的风险。这种治疗导致长期接收疗法而没有终身免疫抑制的治疗将导致生活质量的大量收益，并大大降低治疗成本。不幸的是，在一些早期临床试验中，这种令人兴奋的治疗性的发展被毒性停滞了。现有研究强烈表明，CD154 MAB的FC区域内的域有助于其毒性和治疗能力。当在临床中观察到毒性并在NHP中回顾性时，对抗体进行了修饰。尽管这些修饰消除了NHP的毒性，但CD154作为耐受性抗体的功效也显着降低。结果，CD154作为治疗性停滞的开发计划。该提案的目的是生成鼠CD154抗体的变异形式，该抗体将保留？CD154的有益耐受作用，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估抗体的变异形式，并评估其毒性。第1阶段的成功概念证明将是创建第2阶段人类抗体类似变体的基础，该变体将作为一种新颖的治疗性开发。迄今为止，没有人设计了本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$ 100B/年。进行了超过20,000次美国移植，每年超过5亿美元用于移植后移植。我们的解决方案可能会帮助许多有需要的患者。