Treg-depleting immunotherapy

Treg消耗免疫疗法

• 批准号: 10376845
• 负责人: WILLIAM Ramses BISHAI
• 金额: $ 81.14万
• 依托单位: SONOVAL LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376845
• 关键词: 4T1; Affinity; American; Animals; Antibodies; Antineoplastic Agents; Biological; Biological Assay; Bioluminescence; Blood Vessels; CT26; Cells; Chimeric Proteins; Cicatrix; Clinical; Colon Carcinoma; Companions; Contracts; Corynebacterium diphtheriae; Cutaneous T-cell lymphoma; Data; Denileukin Diftitox; Detergents; Disease Progression; Dose; Drug Kinetics; Evans blue stain; Fermentation; Generations; Growth; Homeostasis; IL2 gene; IL2RA gene; Immune; Immune checkpoint inhibitor; Immunity; Immunotherapy; In Vitro; Interleukin 2 Receptor; Lead; Malignant Neoplasms; Manufacturer Name; Methods; Modeling; Mus; PD-1 inhibitors; Persons; Pharmaceutical Preparations; Phase; Play; Production; Rattus; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Renal Cell Carcinoma; Rest; Retreatment; Role; Safety; Self Tolerance; Solid Neoplasm; Spleen; Sprague-Dawley Rats; Syndrome; System; T-Cell Lymphoma; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Toxin; Tracer; Treatment Protocols; anti-PD-1; anti-cancer; anti-tumor immune response; antitumor effect; base; cell type; checkpoint therapy; drug development; effector T cell; experimental study; improved; in vivo; inhibitor; melanoma; mouse model; novel; prevent; promoter; protein aggregation; response; side effect; success; targeted agent; triple-negative invasive breast carcinoma; tumor; tumor eradication; tumor growth; tumor microenvironment; tumor progression

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.

抽象的 Sonoval正在扩大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Ontak，有可能发展调节性T细胞（Tregs）的领域 免疫疗法通过以前仅由ONTAK独有的机制进行的机制。 Sonova;的疗法将针对Tregs 用于治疗主要的实体瘤，每年遭受少> 50,000名美国人的治疗 对这些CD25+细胞耗尽，同时对其他细胞类型无毒。 Tregs通过 抑制远距离的抗肿瘤免疫反应，第二代候选人之一 与没有治疗相比，与无治疗相比，有3-5倍的抗肿瘤作用是单一疗法，在新的应用中， 在实体瘤的鼠模型中，可增强检查点抑制剂（CPI）活性。 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 非单克隆起源的融合蛋白已批准为FDA使用。也发现Ontak有效 肿瘤微环境中的瞬时Treg耗竭治疗几个实体瘤。尽管有它 临床成功安达克遭受了两个关键缺点：血管泄漏综合征（VLS）和 重要的制造不一致，包括蛋白质聚集体的可变水平（高达40％）和 洗涤剂污染。这些问题导致该药物在2011年被取消。 Sonoval的第二代版本的Ontak，Son-211和Son-301显示了VLS的减少，并且是 潜在的铅药物进行开发。此外，Sonoval持有IP的新型生产方法，该方法解决了先验 制造问题并使产品可以使用0％的聚合和无探测器制造。在初步 与Ontak相比，SON-211的实验显示了改进的安全性。较低的剂量反应；和 3种鼠肿瘤模型（黑色素瘤，结肠癌，肾细胞癌）中的抗肿瘤效率。在这些 相同的模型，通过添加CPI，SON-211单一疗法具有显着潜在的潜在潜力，从而粘贴了新的路径 顺序组合治疗方案。此外，SON-211已被证明以取代CD39+激活的Treg 在肿瘤的微环境中，肿瘤中的效应T细胞水平增加了，而没有耗尽 在索伦中休息。这个快速轨道项目的目的是最终确定铅复合识别（阶段） i），并且要满足安全，有效性和制造业里程碑（第二阶段）需要进行IND批准。 第一阶段的单一目的是根据其优越程度来评估SON-211和SON-301。 安全性（VLS测试），有或没有CPI的抗肿瘤效率以及发酵的生产效率，在5升 规模。第二阶段的目的包括：1）确定最佳给药方案作为抗癌单一疗法和双重 CPI的顺序免疫疗法； 2）优化生产/纯化； 3）进行预先指示药代动力学 大鼠铅药的研究； 4）肿瘤重复给药研究，以评估肿瘤洗脱和/或时间 鼠肿瘤模型中的复发。