Third Generation Costimulation Blockade-Based Tolerance Strategies

第三代基于共刺激封锁的耐受策略

• 批准号: 8705983
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 67.6万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705983
• 关键词: Academia; Achievement; Address; Adverse effects; Antibodies; Antibody Formation; Antigens; Area; Biology; CD28 gene; Cardiovascular system; Chronic; Clinical; Collaborations; Data; Development; Engineering; Generations; Grant; Health; Immune; Immunity; Immunosuppression; Immunosuppressive Agents; In Vitro; Industry; Infection; Instruction; Interleukin-12; Interleukin-17; Investigation; Knowledge; Life; Malignant Neoplasms; Molecular; Morbidity - disease rate; Mus; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physiologic pulse; Predisposition; Quality of life; Regimen; Regulation; Renal function; Resistance; Role; System; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic; Translations; Transplantation; Transplantation Tolerance; Work; base; design; end-stage organ failure; improved; in vivo; inhibitor/antagonist; insight; interleukin-23; kidney allograft; mortality; nonhuman primate; novel; novel therapeutics; research clinical testing; response; translational study

PROJECT SUMMARY (See instructions): The approval of belatacept, a 2rd generation CD28 pathway costimulation blocker, represents a new class of immunosuppressive agents. The design, translation and clinical evaluation of belatacept was the culmination of efforts by industry and academia to rationally engineer a new therapeutic. The result is an agent that better preserves renal function, reduces donor-specific antibody formation and mitigates cardiovascular side effects. Despite these significant advances, important challenges remain as belatacept treatment is associated with higher rates and grades of rejection. In addition, current immunosuppressive strategies, including belatacept-based regimens, lack the ability to specifically target donor-reactive responses resulting in a generalized state of immune compromise and infectious susceptibility. Our early studies in mice and non-human primates (NHP) identified costimulation blockade resistant rejection (CoBRR) as an important area for investigation and emphasized the potential benefits of developing a successful tolerance strategy. The recent clinical results with belatacept highlight the pressing need to understand the cellular and molecular pathways that contribute to CoBRR and to develop targeted strategies to overcome them, including clinically applicable tolerance regimens. In the first aim of our project we will evaluate novel 3rd generation costimulation blockade therapeutics in collaboration with our partners in industry including domain antibodies designed to safely and specifically block both the CD28 and CD40 pathways. We anticipate that there will still be a CoBRR response and have new data from preliminary murine and NHP studies suggesting a critical role for the IL-17 pathway. We have also identified a successful strategy utilizing an antibody targeting both IL-12 and IL-23 to control this break-through rejection response. In aim 2 we will further test this novel IL-12/23 therapy in combination with optimized 3rd generation costimulation blockade. We will synthesize observations from the first two aims to define a successful therapeutic regimen that we will then couple to our novel pulsed donor antigen tolerance strategy. Results from these studies will help develop a clinically translatable tolerance strategy, which avoids the morbidity and mortality of chronic continuous immunosuppression. The new knowledge obtained in these studies will be significant and wilt contribute to improved outcomes, enhanced quality of life, and reduced morbidity by avoiding rejection, simplifying regimens, and avoiding infection as a result of long-term immunosuppression.

项目摘要（请参阅说明）： 第二代CD28途径cotimulation阻滞剂Belatacept的批准代表了一类新的免疫抑制剂。 Belatacept的设计，翻译和临床评估是行业和学术界为合理设计一种新的治疗方法的努力的高潮。结果是一种更好地保留肾功能，减少供体特异性抗体形成并减轻心血管副作用的药物。尽管有这些重大进展，但由于Belatacept治疗与较高的比率和排斥等级有关，因此仍然存在重要的挑战。此外，包括基于BELATACEPT的方案在内的当前免疫抑制策略缺乏针对供体反应反应的能力，从而导致免疫妥协和感染性敏感性的普遍状态。我们在小鼠和 非人类灵长类动物（NHP）确定了抗抑制作用的抗拒排斥（COBRR）是研究的重要领域，并强调了制定成功的公差策略的潜在益处。 Belatacept的最新临床结果突出了迫切需要了解有助于CoproR的细胞和分子途径，并开发有针对性的策略来克服它们，包括临床适用的公差方案。在我们项目的第一个目的中，我们将与我们的行业合作伙伴合作评估新型第三代COTIMATION BLOCKADE BLOCKADE THERAPEITACS，包括旨在安全和专门阻止CD28和CD40途径的域抗体。我们预计仍然会有一个Cobrr响应，并具有初步鼠和NHP的新数据 研究表明IL-17途径的关键作用。我们还使用针对IL-12和IL-23的抗体来控制这种突破性排斥反应的成功策略。在AIM 2中，我们将进一步测试这种新型的IL-12/23治疗，并结合优化的第三代共刺激封锁。我们将综合前两个目的的观察结果，以定义成功的治疗方案，然后我们将与新型的脉冲供体抗原耐受策略相结合。这些研究的结果将 有助于制定临床上可翻译的耐受性策略，从而避免了慢性连续免疫抑制的发病率和死亡率。在这些研究中获得的新知识将是重要的，并且枯萎有助于改善结果，增强的生活质量，并通过避免排斥，简化治疗方案并避免由于长期免疫抑制而避免感染，从而降低发病率。