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

基本信息

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
项目类别：
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

项目摘要

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.

概括尽管免疫切除点抑制剂成功地抑制了某些类型的癌症，但总体反应率仍然存在次优。大多数实体肿瘤不包括T细胞（称为“冷”），因此提出了关键的限制因素癌症免疫疗法。已经证明CGAS丁字道途径的激活可以诱导抗肿瘤临床前研究中具有令人印象深刻的效率的免疫反应。但是，基于临床阶段的刺痛激动剂在循环二核苷酸（CDN）上，受到重大局限性，包括：1）通过肿瘤内给药注射。肿瘤内给药的刺痛激动剂迅速清除，肿瘤内注射减少针对转移性癌症的实用性。 2）常规的刺痛激动剂不容易越过细胞膜，失败以最大程度地激活位于细胞质内的刺激性。 3）常规刺痛激动剂的细胞渗透不偏向树突状细胞和巨噬细胞，这是驱动抗肿瘤免疫所需的细胞类型回复。 4）由于刺痛的差异，传统的刺痛激动剂不起作用单倍型。实际上，在最近的I期临床试验中，刺痛的激动剂仅在肿瘤内暴露于边缘功效。因此，迫切需要一个潜在的刺痛激动剂的潜在平台来改善患者结果。 Saros Therapeutics正在开发一种新颖的纳米技术（称为SNP），该学在以下局限性的局限公式。我们已经表明，MN增加了CDA的激活，从而降低了必要的剂量为了获得重要的生物学（I型IFN表达）和治疗（肿瘤生长/生存）益处。 2）将Mn-CDA复合物纳入纳米颗粒可保护CDA免受降解，延长半衰期和促进髓样细胞（DC，巨噬细胞）的摄取，从 TME。纳米颗粒配方中的Mn+CDA的组合也提高了安全性该疗法的特征并允许通过IV进行给药，确保系统性暴露并改善了反应多个肿瘤和转移的设置。根据我们的引人注目的数据，我们将研究SNP的效力人类患者活检样本中的制剂。我们将评估药代动力学和组织保留率 SNP在小鼠和非人类灵长类动物中的特征以及针对其他刺痛激动剂的基准。我们将开发用于大规模生产SNP的微流体方法，以期转移到合同开发与制造组织（CDMO）。这些研究的结果将加速开发我们的新型纳米技术，目的是快速带来免疫疗法的好处癌症患者。