A Novel Complement Inhibitor for Rheumatoid Arthritis

类风湿关节炎的新型补体抑制剂

• 批准号: 6886366
• 负责人: Woodruff Emlen
• 金额: $ 9.73万
• 依托单位: TALIGEN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2005-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6886366
• 关键词: affinity labeling; antigen antibody reaction; arthritis therapy; biotechnology; cellular immunity; complement inhibitors; disease /disorder model; drug screening /evaluation; genetically modified animals; immunotherapy; inflammation; laboratory mouse; monoclonal antibody; nonhuman therapy evaluation; pathologic process; pharmacokinetics; rheumatoid arthritis

DESCRIPTION (provided by applicant): Rheumatoid Arthritis (RA) affects 1-2% of the world's population, including an estimated 2.5 million people in the US. Although therapies targeted at tumor necrosis factor alpha (TNF) have been highly successful, they are ineffective in up to 50% of individuals. RA remains a debilitating and life-long affliction for which there is a substantial unmet need for novel therapeutic approaches targeted at inhibiting mechanisms of inflammation other than TNF. Preliminary work in knock-out mice has shown that expression of factor B of the alternative complement pathway is essential for the development of severe arthritis induced by transfer of anti-type II collagen antibodies, and that inhibition of early complement pathways downregulates pro-inflammatory cytokine production. Taligen has licensed novel antibody inhibitors of factor B and is working towards developing these antibodies as a novel therapeutic for RA. This Phase I SBIR will accomplish the following: 1. Demonstrate that inhibition of factor B results in a 70% or greater reduction in clinical inflammation and joint injury when given either prior to or following the development of arthritis in the CIA model. 2. Identify the optimal monoclonal antibody candidate for further development in Phase II by determining the binding affinity and pharmacokinetics of inhibitory activity of each inhibitory antibody. After identifying the optimal mAb (longest half-life of inhibition in vivo), the effect of this mAb on the induction and the effector phases of arthritis will be examined in an active and a passive model of CIA. Criteria for success will be a 70% reduction in clinical and histologic scores and decreased C3 depostion and cytokine production in the synovium. Demonstration of a therapeutic effect of this magnitude will provide proof of principle for further development and the basis for a Phase II SBIR application focusing on affinity maturation (as necessary) of the optimal mAb candidate, antibody humanization and toxicology.

描述（由申请人提供）：类风湿性关节炎 (RA) 影响着世界人口的 1-2%，其中估计有 250 万美国人。尽管针对肿瘤坏死因子 α (TNF) 的疗法非常成功，但对高达 50% 的个体无效。 RA仍然是一种使人衰弱的终生疾病，对于针对TNF以外的炎症机制的新治疗方法的需求尚未得到满足。在基因敲除小鼠中的初步研究表明，替代补体途径的因子 B 的表达对于抗 II 型胶原蛋白抗体转移诱导的严重关节炎的发展至关重要，并且早期补体途径的抑制会下调促炎细胞因子生产。 Taligen 已获得 B 因子新型抗体抑制剂的许可，并正在致力于开发这些抗体作为 RA 的新型治疗剂。第一阶段 SBIR 将实现以下目标： 1. 证明在 CIA 模型中出现关节炎之前或之后，抑制 B 因子可导致临床炎症和关节损伤减少 70% 或更多。 2. 通过确定每种抑制性抗体的结合亲和力和抑制活性的药代动力学，确定用于 II 期进一步开发的最佳候选单克隆抗体。 确定最佳 mAb（体内抑制半衰期最长）后，将在 CIA 主动和被动模型中检查该 mAb 对关节炎诱导期和效应期的影响。成功的标准是临床和组织学评分减少 70%，以及滑膜中 C3 沉积和细胞因子产生减少。如此巨大的治疗效果的证明将为进一步开发提供原理证明，并为 II 期 SBIR 应用奠定基础，重点关注最佳 mAb 候选物的亲和力成熟（必要时）、抗体人源化和毒理学。