RIG-I Activating Nanoparticles for Immunopotentiation

用于免疫增强的 RIG-I 激活纳米颗粒

• 批准号: 10709018
• 负责人: Anna Marie Pyle
• 金额: $ 59.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709018
• 关键词: Address; Affinity; Agonist; Antiviral Agents; Artificial nanoparticles; Beds; Behavior; Biodistribution; Biological; Charge; Chemicals; Clinical; Cytosol; Data; Development; Disease; Double-Stranded RNA; Drug Delivery Systems; Drug Kinetics; Endosomes; Engineering; Foundations; Generations; Genes; Half-Life; Hydrophobicity; Immune Targeting; Immune checkpoint inhibitor; Immunobiology; Immunologics; Immunosuppression; Immunotherapeutic agent; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Interdisciplinary Study; Interferon Type I; Investigation; Knowledge; Lead; Length; Libraries; Modality; Modeling; Molecular; Mus; Natural Immunity; Oligonucleotides; Organism; Outcome; Pathway interactions; Pattern recognition receptor; Pharmacologic Substance; Phosphorylation; Polymer Chemistry; Polymers; Positioning Attribute; Predisposition; Property; RNA; Research; Safety; Science; Site; Structure; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transfection; Translations; Tretinoin; Tumor Immunity; Vaccine Adjuvant; Viral; Virus Diseases; adaptive immunity; antitumor effect; cancer immunotherapeutics; cancer immunotherapy; clinical application; combinatorial; cytotoxicity; design; drug development; efficacy evaluation; immune activation; immunogenic; immunogenicity; improved; in vivo; in vivo evaluation; innovation; insight; lead candidate; melanoma; mouse model; multidisciplinary; nanocarrier; nanomedicine; nanoparticle; nanopolymer; new technology; next generation; novel; nuclease; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; preclinical development; preclinical evaluation; prevent; programs; response; stem; synergism; technology platform; therapeutic RNA; tumor; tumor growth; tumor microenvironment; uptake

PROJECT SUMMARY The innate immune system can be pharmacologically programed to elicit desired immunological outcomes. Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor that has emerged as a promising innate immune target for immunopotentiation. RIG-I is activated upon recognizing 5’-triphosphorylated, double- stranded RNA (3pRNA) in the cytosol, which stimulates an antiviral-like inflammatory program that can be harnessed to treat or prevent a diversity of diseases. However, the potency and efficacy of 3pRNA has been limited by major drug delivery barriers, including nuclease degradation, inefficient cellular uptake and cytosolic delivery, and rapid clearance. To address these challenges, we have developed RIG-I activating nanoparticles (RANs). RANs are polymer nanoparticles that are engineered to promote the cytosolic delivery of synthetic, molecularly-defined, and high-affinity stem-loop RNA (SLR) RIG-I agonists recently developed by our team. The objective of this R01 application is to optimize and advance RANs as a versatile platform for pharmacological activation of RIG-I. We will accomplish this through the following Specific Aims. First, we will engineer next-generation RANs with improved properties for systemic administration through optimization of SLR and polymer charge and hydrophobicity. This approach will leverage combinatorial chemical diversity to access a new design space for 3pRNA delivery, which we expect will yield next-generation RANs with higher SLR loading efficiency, reduced cytotoxicity, protection from nuclease degradation, improved stability, and enhanced immunostimulatory activity. Second, we will establish relationships between RAN properties, innate immune activation, pharmacokinetics, polymer and SLR biodistribution, and toxicity. These studies are essential in the preclinical development of new immunotherapeutic modalities and will also yield new insight into how nanocarriers can be engineered for safe and effective activation of RIG-I. We expect these studies to yield next-generation RANs that are optimized for systemic administration of SLR therapeutics. Third, while RANs have broad potential clinical applications, we will evaluate their efficacy as a systemically administered cancer immunotherapy in poorly immunogenic mouse models of melanoma as a clinically important test case. We expect to demonstrate that systemic administration of lead-candidate RANs will activate RIG-I in the tumor microenvironment, resulting in an immunological reprograming of tumor sites that inhibits tumor growth and synergizes with immune checkpoint inhibitors. Collectively, these studies will position RANs as an enabling platform for immunopotentiation with potential to address the significant need for new cancer immunotherapies, antiviral agents, and vaccine adjuvants.

项目摘要 先天免疫系统可以被编程以引发期望的免疫结果。 视黄酸诱导基因I（RIG-I）是一种模式识别受体，已成为一种很有前途的先天免疫调节因子。 用于免疫增强免疫靶标。RIG-I在识别5 '-三磷酸化、双磷酸化和双磷酸化后被激活。 在胞质溶胶中的单链RNA（3 pRNA），它刺激抗病毒样炎症程序， 用于治疗或预防多种疾病。 然而，3 pRNA的效力和功效已经被证明是有效的。 受到主要药物递送障碍的限制，包括核酸酶降解、细胞吸收效率低下和细胞质 交付和快速清关。为了应对这些挑战，我们开发了RIG-I活化纳米颗粒， （RAN）。RAN是聚合物纳米颗粒，其被工程化以促进合成的， 分子定义的，高亲和力的茎环RNA（SLR）RIG-I激动剂最近由我们的团队开发。 此R 01应用程序的目标是优化和推进RAN作为通用平台， RIG-I的药理学活化。我们将通过以下具体目标来实现这一目标。一是 设计下一代RAN，通过优化 SLR和聚合物电荷和疏水性。这种方法将利用组合化学多样性， 进入3 pRNA递送的新设计空间，我们预计这将产生具有更高 SLR装载效率、降低的细胞毒性、防止核酸酶降解、改善的稳定性，以及 增强的免疫刺激活性。第二，我们将建立RAN属性、固有属性、 免疫活化、药代动力学、聚合物和SLR生物分布和毒性。这些研究 在新的免疫学模式的临床前开发中至关重要，也将产生新的见解 纳米载体如何被设计用于安全有效地激活RIG-I。我们希望这些研究能够 产生针对SLR治疗剂的全身给药而优化的下一代RAN。第三是要 RAN具有广泛的潜在临床应用，我们将评估其作为全身给药的有效性。 在免疫原性差的黑色素瘤小鼠模型中进行癌症免疫治疗，作为临床上重要的测试案例。 我们希望证明全身给予先导候选RAN将激活肿瘤中的RIG-I 微环境，导致肿瘤部位的免疫重编程，抑制肿瘤生长， 与免疫检查点抑制剂协同作用。总的来说，这些研究将把RAN定位为一种 免疫增强的平台，有可能解决对新癌症免疫疗法的重大需求， 抗病毒剂和疫苗佐剂。