Process Development and Preclinical Advancement of a Novel Nanoparticle Formulation for Immune Activation

用于免疫激活的新型纳米颗粒制剂的工艺开发和临床前进展

• 批准号: 10758714
• 负责人: Richard Johnson
• 金额: $ 119.67万
• 依托单位: SAROS THERAPEUTICS INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758714
• 关键词: Acceleration; Address; Agonist; Antitumor Response; Benchmarking; Biodistribution; Biological; Biopsy Specimen; Blood Chemical Analysis; Breast Cancer Patient; Cancer Patient; Cell membrane; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Complex; Contracts; Cytosol; Data; Dendritic Cells; Development; Dinucleoside Phosphates; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Encapsulated; Ensure; Enzymes; Exclusion; Excretory function; Exhibits; Filtration; Formulation; Funding; Future; Gene Activation; Generations; Half-Life; Haplotypes; Head and Neck Squamous Cell Carcinoma; Human; Immune checkpoint inhibitor; Immune response; Immunotherapy; Incubated; Inflammation; Injections; Interferon-beta; Interferons; Knowledge; Lead; Legal patent; Liver; Macrophage; Malignant Neoplasms; Manganese; Mediating; Metabolism; Methods; Michigan; Microfluidics; Modeling; Mus; Myeloid Cells; Nanotechnology; Natural Killer Cells; Nature; Neoplasm Metastasis; Oryctolagus cuniculus; Pathway interactions; Patient-Focused Outcomes; Patients; Penetration; Periodicity; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Pilot Projects; Plasma; Population; Preparation; Process; Production; Public Health; Reproducibility; Research; Rights; Safety; Sampling; Small Business Innovation Research Grant; Solid Neoplasm; Stimulator of Interferon Genes; System; T-Lymphocyte; Technology; Technology Transfer; Therapeutic; Time; Tissues; Toxicology; Universities; Variant; Work; anti-tumor immune response; cancer immunotherapy; cancer type; cell type; clinic ready; clinical development; comparative efficacy; design; drug development; experience; healthy volunteer; immune activation; immune checkpoint blockade; improved; improved outcome; large scale production; lead candidate; manufacture; manufacturing organization; manufacturing scale-up; monocyte; nano; nanoformulation; nanoparticle; nonhuman primate; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; response; safety study; scale up; success; technology platform; therapeutic candidate; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; uptake

Summary Despite the success of immune checkpoint inhibitors for some types of cancer, the overall response rate remains suboptimal. The majority of solid tumors exclude T-cells (termed “cold”), thus presenting a key limiting factor for cancer immunotherapy. Activation of the cGAS-STING pathway has been demonstrated to induce anti-tumor immune responses with impressive efficacy in preclinical studies. However, clinical stage STING agonists, based on cyclic dinucleotides (CDNs), suffer from major limitations, including: 1) Administration via intratumoral injection. STING agonists administered intratumorally are cleared rapidly, and intratumoral injection reduces their utility against metastatic cancer. 2) Conventional STING agonists do not readily cross the cell membrane, failing to maximize activation of STING located within the cytosol. 3) Cell penetration of conventional STING agonists is not biased to the dendritic cells and macrophages which is the cell type needed to drive an anti-tumor immune response. 4) Conventional STING agonists do not work across the human population due to variations in STING haplotypes. Indeed, in recent phase I clinical trials, STING agonists given intratumorally exhibited only marginal efficacy. Hence, a potent platform for systemic delivery of STING agonists is urgently needed to improve patient outcomes. Saros Therapeutics is developing a novel nanotechnology (referred to as SNP) that addresses each of these limitations by: 1) Incorporating manganese along with CDA, a CDN-based STING agonist, in the nano- formulation. We have shown that Mn augments the activation of STING by CDA, lowering the dose necessary to achieve a significant biologic (Type I IFN expression) and therapeutic (tumor growth/survival) benefit. 2) Incorporating the Mn-CDA complex in a nanoparticle protects the CDA from degradation, extending half-life and facilitating uptake by myeloid cells (DC, macrophages) that drives a Type I IFN response by the immune cells in the TME. The combination of Mn+CDA incorporated into a nanoparticle formulation also improves the safety profile of this therapy and allows administration by IV, ensuring systemic exposure and improved responses in settings of multiple tumors and metastasis. Based on our compelling data, we will examine the potency of SNP preparations in human patient biopsy samples. We will assess pharmacokinetic and tissue retention characteristics of SNP in both mice and non-human primates and benchmark against other STING agonists. We will develop microfluidic methods for large scale production of SNP in anticipation of transfer to a contract development and manufacturing organization (CDMO). Results from these studies will accelerate the development of our novel nanotechnology with the aim of quickly bringing immunotherapy’s benefits to more patients with cancer.

总结 尽管免疫检查点抑制剂对某些类型的癌症取得了成功，但总体缓解率仍然很低。 次优大多数实体瘤不包括T细胞（称为“冷”），因此呈现出肿瘤生长的关键限制因素。 癌症免疫疗法已经证明cGAS-STING途径的激活诱导抗肿瘤活性。 在临床前研究中具有令人印象深刻的疗效。然而，临床阶段STING激动剂，基于 在环状二核苷酸（CDN）上，存在主要的局限性，包括：1）通过肿瘤内给药， 注射肿瘤内施用的STING激动剂被快速清除，并且肿瘤内注射减少了它们的毒性。 对转移性癌症的效用。2)常规的STING激动剂不容易穿过细胞膜， 以最大化位于胞质溶胶内的STING的活化。3)常规STING激动剂的细胞渗透 不偏向于树突细胞和巨噬细胞，这是驱动抗肿瘤免疫所需的细胞类型 反应4)由于STING的变化，常规STING激动剂在人群中不起作用。 单倍型。事实上，在最近的I期临床试验中，肿瘤内给予的STING激动剂仅表现出轻微的 功效因此，迫切需要一种用于全身递送STING激动剂的有效平台，以改善患者的耐受性。 结果。Saros Therapeutics正在开发一种新的纳米技术（称为SNP）， 1）将锰沿着与CDA（一种基于CDN的STING激动剂）一起在纳米- 公式化。我们已经表明，Mn增强了CDA对STING的激活，降低了必需的剂量。 以实现显著的生物学（I型IFN表达）和治疗（肿瘤生长/存活）益处。（二） 将Mn-CDA络合物包埋在纳米颗粒中保护CDA免于降解，延长半衰期， 促进骨髓细胞（DC，巨噬细胞）的摄取，其驱动免疫细胞的I型IFN应答， 的TME。掺入纳米颗粒制剂中的Mn+CDA的组合也提高了安全性。 这种疗法的特点，并允许通过静脉给药，确保全身暴露和改善反应， 多发肿瘤和转移的情况。基于我们令人信服的数据，我们将研究SNP的效力， 在人类患者活检样品中的制备。我们将评估药代动力学和组织保留 在小鼠和非人灵长类动物中的SNP的特征和针对其他STING激动剂的基准。我们 将开发用于大规模生产SNP的微流体方法，预计将转移到合同中 开发和制造组织（CDMO）。这些研究的结果将加速 我们的新纳米技术的发展，目的是迅速使免疫治疗的好处， 癌症患者。