Treg-depleting immunotherapy

摘要 Sonoval正在扩展其成功的生物药物平台技术，以开发第二代版本的 癌症治疗药物Ontak，有可能推进调节性T细胞(Tregs)耗尽领域 通过一种以前只有Ontak独有的机制进行免疫治疗。索诺瓦：S疗法将瞄准特雷格 用于治疗主要实体肿瘤，每年折磨着50,000美国人，通过短暂和有效的 消耗这些CD25+细胞，同时对其他类型的细胞无毒。Tregs通过以下途径促进癌症进展 到目前为止，抑制抗肿瘤免疫反应的第二代主要候选人之一已经 与不治疗相比，单一治疗显示出3-5倍的抗肿瘤效果，并且在新的应用中， 在实体瘤小鼠模型中，将检查点抑制物(CPI)活性提高高达5倍。 十多年来，Ontak被批准用于治疗皮肤T细胞淋巴瘤，使其成为第一个抗体 经FDA批准使用的非克隆来源的融合蛋白。Ontak也被发现对治疗 肿瘤微环境下一过性Treg去除治疗几种实体瘤尽管它的 临床成功Ontak有两个关键缺陷：血管渗漏综合征(VLS)的发生率为25%； 重大制造不一致，包括不同水平的蛋白质聚集体(高达40%)和 洗涤剂污染。这些问题导致该药于2011年下架。 Sonoval的第二代Ontak版本SON-211和SON-301都显示出更低的VLS，并且 潜在的用于开发的先导药物。此外，Sonoval拥有一种解决先前问题的新生产方法的知识产权 制造问题，并使产品能够生产出0%的团聚和不含洗涤剂的产品。在预赛中 实验表明，与Ontak相比，SON-211具有更好的安全性；剂量反应更低；以及 在3种小鼠肿瘤模型(黑色素瘤、结肠癌、肾癌)中具有相同的抗肿瘤效果。穿着这些 同样的型号，SON-211单一疗法通过添加CPI显著增强，为创新铺平了道路 序贯联合治疗方案。此外，SON-211已被证明耗尽CD39+激活Treg 在肿瘤微环境中增加72%，并增加肿瘤中效应T细胞的水平，同时不耗尽 在脾里休息的树。此快速通道项目的目的是最终确定铅化合物识别(阶段 I)，并达到IND批准所需的安全性、有效性和制造里程碑(第二阶段)。 第一阶段的单一目标将是评估SON-211和SON-301在#年相对于Ontak的优势水平 安全性(VLS测试)、使用和不使用CPI的抗肿瘤效果，以及发酵的生产效率，在5升 比例。第二阶段的目标包括：1)确定抗癌单药和双药的最佳给药方案 使用CPI进行序贯免疫治疗；2)优化生产/纯化；3)进行前IND，药代动力学 铅药物在大鼠身上的研究；4)肿瘤重复给药研究，以评估肿瘤根除和/或时间 小鼠肿瘤模型的复发。

Abstract Sonoval is expanding its successful biologic drug platform technology to develop second generation versions of the cancer therapeutic Ontak, with the potential to advance the field of regulatory T cells (Tregs)-depleting immunotherapy through a mechanism previously unique to Ontak alone. Sonova;’s therapeutics will target Tregs for treatment of major solid tumors, which afflict >50,000 Americans per year, by transiently and potently depleting these CD25+ cells while being non-toxic to other cell types. Tregs contribute to cancer progression by suppressing anti-tumor immune responses Thus far, one of the lead second generation candidates has demonstrated 3-5-fold anti-tumor effect as monotherapy compared to no treatment, and in novel application, enhances check-point inhibitor (CPI) activity by up to 5-fold in murine models of solid tumors. For over a decade, Ontak was approved for treatment of cutaneous T-cell lymphoma, making it the first antibody fusion protein of non-monoclonal origin approved for use by the FDA. Ontak was also found to be effective in the treatment of several solid tumors by transient Treg depletion in the tumor microenvironment. Despite its clinical success Ontak suffered from two critical drawbacks: a 25% rate of vascular leak syndrome (VLS), and significant manufacturing inconsistencies that included variable levels of protein aggregates (up to 40%) and detergent contamination. These issues led to the drug being taken off the market in 2011. Sonoval’s second generation versions of Ontak, SON-211 and SON-301, both show reduced VLS and are potential lead drugs for development. Further, Sonoval holds IP on a novel production method that solves prior manufacturing problems and enables product to be made with 0% aggregation and no detergent. In preliminary experiments, compared to Ontak, SON-211 shows an improved safety profile; a lower dose response; and equipotent anti-tumor efficacy in 3 murine tumor models (melanoma, colon carcinoma, renal cell cancer). in these same models, SON-211 monotherapy is significantly potentiated by the addition of CPI, paving the path to novel sequential combination treatment regimens. Further, SON-211 has been show to deplete CD39+ activated Treg in the tumor microenvironment by 72%, and to increase levels of effector T cells in tumors, while not depleting resting Tregs in spleen. The purpose of this Fast Track project is to finalize lead compound identification (Phase I), and to meet safety, efficacy and manufacturing milestones (Phase II) needed to progress to IND approval. Phase I’s single Aim will be to evaluate SON-211 and SON-301 based on their levels of superiority to Ontak in safety (VLS testing), anti-tumor efficacy with and without CPI, and production efficiency of fermentation, at 5-liter scale. Phase II Aims include: 1) Determine optimal dosing regimen as anti-cancer monotherapy and as dual sequential immunotherapy with CPI; 2) Optimize production/purification; 3) Conduct pre-IND, pharmacokinetics studies of lead drug in rats; 4) Tumor repetitive dosing studies to evaluate tumor eradication and/or time to relapse in Murine tumor models.