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（参见说明）： Belatacept 是第二代 CD28 通路共刺激阻断剂，它的批准代表了一类新型免疫抑制剂。 Belatacept 的设计、转化和临床评估是工业界和学术界合理设计新疗法的努力的结晶。其结果是一种能够更好地保护肾功能、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更高的排斥率和等级相关。此外，当前的免疫抑制策略，包括基于贝拉西普的治疗方案，缺乏专门针对供体反应性反应的能力，导致普遍的免疫损害和感染易感性状态。我们对小鼠的早期研究 非人类灵长类动物 (NHP) 将共刺激封锁抗性排斥 (CoBRR) 确定为重要的研究领域，并强调制定成功的耐受策略的潜在好处。 Belatacept 最近的临床结果凸显了迫切需要了解导致 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，包括旨在安全、特异性阻断 CD28 和 CD40 途径的域抗体。我们预计仍然会有 CoBRR 反应，并且有来自初步小鼠和 NHP 的新数据 研究表明 IL-17 通路发挥着关键作用。我们还确定了一种成功的策略，利用针对 IL-12 和 IL-23 的抗体来控制这种突破性的排斥反应。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的结合。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，然后将其与我们的新型脉冲供体抗原耐受策略相结合。这些研究的结果将 帮助制定临床可转化的耐受策略，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具有重要意义，并且将有助于通过避免排斥、简化治疗方案和避免长期免疫抑制导致的感染来改善结果、提高生活质量和降低发病率。