Third Generation Costimulation Blockade-Based Tolerance Strategies

项目总结（见说明）： 第二代CD 28通路共刺激阻断剂贝拉西普的批准代表了一类新的免疫抑制剂。贝拉西普的设计、翻译和临床评价是工业界和学术界合理设计一种新疗法的努力的顶峰。其结果是一种更好地保护肾功能，减少供体特异性抗体形成和减轻心血管副作用的药物。尽管取得了这些重大进展，但重要的挑战仍然存在，因为贝拉西普治疗与较高的排斥率和排斥等级相关。此外，目前的免疫抑制策略，包括基于贝拉西普的方案，缺乏特异性靶向供体反应性应答的能力，导致免疫妥协和感染易感性的普遍状态。我们早期的小鼠研究， 非人灵长类动物（NHP）将共刺激阻断抗性排斥（CoBRR）确定为研究的重要领域，并强调了开发成功的耐受策略的潜在益处。 贝拉西普最近的临床结果强调了迫切需要了解有助于CoBRR的细胞和分子途径，并制定有针对性的策略来克服它们，包括临床适用的耐受方案。在我们项目的第一个目标中，我们将与我们的行业合作伙伴合作评估新型第三代共刺激阻断疗法，包括设计用于安全和特异性阻断CD 28和CD 40途径的结构域抗体。我们预计仍将有CoBRR反应，并有来自初步小鼠和NHP的新数据。 研究表明IL-17通路的关键作用。我们还确定了利用靶向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。在目标2中，我们将进一步测试这种新型IL-12/23疗法与优化的第三代共刺激阻断剂的组合。我们将综合前两个目标的观察结果，以确定一个成功的治疗方案，然后将其与我们新的脉冲供体抗原耐受策略相结合。这些研究的结果将 有助于开发临床上可转化的耐受策略，避免慢性持续免疫抑制的发病率和死亡率。这些研究中获得的新知识将是重要的，将有助于改善结果，提高生活质量，并通过避免排斥反应，简化方案和避免长期免疫抑制导致的感染来降低发病率。

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.