Treg-depleting immunotherapy

摘要 Sonoval正在扩大其成功的生物药物平台技术，以开发第二代 癌症治疗Ontak，有可能推进调节性T细胞（Tcells）耗竭领域， 通过以前单独Ontak特有的机制进行免疫治疗。Sonova的治疗方法将针对Tibetan 用于治疗每年折磨> 50，000名美国人的主要实体瘤， 消耗这些CD 25+细胞，同时对其他细胞类型无毒。甲状腺激素通过以下方式促进癌症进展： 抑制抗肿瘤免疫反应到目前为止，第二代候选人中的一位已经 与未治疗相比，作为单一疗法显示出3-5倍的抗肿瘤效果，并且在新的应用中， 在小鼠实体瘤模型中，将检查点抑制剂（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，使其成为第一种抗体。 FDA批准使用的非单克隆来源的融合蛋白。Ontak也被发现在以下方面有效 通过肿瘤微环境中的瞬时Treg耗竭治疗几种实体瘤。尽管 Ontak的临床成功有两个关键缺点：25%的血管渗漏综合征（VLS）发生率， 显著的生产不一致性，包括蛋白质聚集体水平可变（高达40%）， 洗涤剂污染。这些问题导致该药物于2011年退出市场。 Sonoval的Ontak第二代版本SON-211和SON-301都显示出减小的VLS， 开发的潜在先导药物。此外，Sonoval拥有一种新的生产方法的知识产权， 制造问题，并且使得能够以0%聚集和无洗涤剂制备产品。初步 实验，与Ontak相比，SON-211显示出改善的安全性特征;较低的剂量反应;以及 在3种鼠肿瘤模型（黑色素瘤、结肠癌、肾细胞癌）中的等效抗肿瘤功效。在这些 在相同的模型中，添加CPI后SON-211单药治疗显着增强，为新型药物铺平了道路 序贯联合治疗方案。此外，SON-211已显示消耗⑶ 39+活化的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，同时不消耗 脾脏中的静息T细胞。本快速通道项目的目的是最终确定先导化合物识别（阶段 I），并满足进展至IND批准所需的安全性、有效性和生产里程碑（II期）。 第一阶段的唯一目的是根据SON-211和SON-301在以下方面优于Ontak的水平来评估它们： 安全性（VLS测试），有和没有CPI的抗肿瘤功效，以及5升发酵的生产效率 规模II期目的包括：1）确定抗癌单药治疗和双重治疗的最佳给药方案 CPI序贯免疫治疗; 2）优化生产/纯化; 3）进行IND前药代动力学 4）肿瘤重复给药研究，以评估肿瘤根除和/或至肿瘤复发的时间; 在小鼠肿瘤模型中复发。

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.