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

摘要 尽管免疫检查点抑制剂在治疗某些类型的癌症方面取得了成功，但总体应答率仍然 不太理想。大多数实体肿瘤不包括T细胞(称为“冷”)，因此是一个关键限制因素 癌症免疫疗法。CGAS-STING通路的激活已被证明可以诱导抗肿瘤 免疫反应在临床前研究中具有令人印象深刻的疗效。然而，临床阶段刺痛激动剂，基于 在环二核苷酸(CDN)方面，存在重大限制，包括：1)通过肿瘤内给药 注射。瘤内注射STING激动剂可迅速清除，瘤内注射可减少其 对转移性癌症的效用。2)传统的刺激剂不容易穿过细胞膜，从而失败 以最大限度地激活位于胞浆内的刺痛。3)常规STING激动剂的细胞渗透性 不偏向于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 回应。4)由于刺痛的变化，传统的刺痛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，瘤内注射的刺痛激动剂仅显示出边缘效应。 功效。因此，迫切需要一个有效的全身给药平台来改善患者的病情。 结果。Saros治疗公司正在开发一种新的纳米技术(称为SNP)，可以解决每一种 通过：1)将锰与CDN为基础的刺激剂CDA一起加入到纳米材料中。 配方。我们已经证明，锰能增强CDA对刺痛的激活，降低所需剂量。 以获得显著的生物学(I型干扰素表达)和治疗(肿瘤生长/存活)益处。2) 将锰-CDA络合物结合在纳米颗粒中可保护CDA免受降解，延长半衰期和 促进髓系细胞(DC，巨噬细胞)摄取通过免疫细胞驱动I型干扰素反应 TME。在纳米颗粒配方中加入Mn+CDA的组合也提高了安全性 这种疗法的概况，并允许静脉给药，确保全身暴露和改善反应 多发性肿瘤和转移的背景。基于我们令人信服的数据，我们将检验SNP的效力 在人类患者的活检样本中制备。我们将评估药物动力学和组织滞留 SNP在小鼠和非人类灵长类动物中的特征以及与其他刺痛激动剂的比较。我们 将开发用于大规模生产SNP的微流控方法，预计将移交给合同 开发和制造组织(CDMO)。这些研究的结果将加速 我们的新型纳米技术的发展，目的是迅速将免疫疗法的好处带给更多的人 癌症患者。

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.