CCR4-IL2 Bispecific Immunotoxin for Targeted Therapy of Cutaneous T-Cell Lymphoma

CCR4-IL2 双特异性免疫毒素用于皮肤 T 细胞淋巴瘤的靶向治疗

• 批准号: 10800128
• 负责人: Zhirui Wang
• 金额: $ 87.58万
• 依托单位: ROCK IMMUNE LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10800128
• 关键词: Blood Cells; CC chemokine receptor 4; Cancerous; Chronic Disease; Clinical Trials; Colorado; Cutaneous T-cell lymphoma; Data; Denileukin Diftitox; Diphtheria Toxin; Drug Kinetics; Escherichia coli; Extranodal; Fusion Toxin; Genetic Engineering; Goals; Good Manufacturing Process; Human; IL2 gene; IL2RA gene; Immune response; Immunologic Deficiency Syndromes; Immunotherapy; Immunotoxins; Indolent; Infiltration; Interleukin-2; Invaded; Lymphoma; Lymphoma cell; Malignant - descriptor; Malignant Neoplasms; Medical; Miniature Swine; Modeling; Mus; Mycosis Fungoides; Non-Hodgkin' s Lymphoma; Organ; Patients; Pharmaceutical Preparations; Phase; Pichia; Procedures; Production; Progressive Disease; Rattus; Recurrence; Refractory; Regulatory T-Lymphocyte; Research Contracts; Resistance; Sezary Syndrome; Skin; Surface; System; T-Lymphocyte; Texas; Therapeutic; Toxicology; Treatment Efficacy; Universities; Yeasts; animal facility; anti-tumor immune response; cancer type; clinical diagnosis; drug candidate; effective therapy; experience; good laboratory practice; immunogenicity; improved; innovation; manufacturing facility; neoplasm immunotherapy; new therapeutic target; novel; novel therapeutics; objective response rate; palliative; pre-clinical; preclinical efficacy; receptor; response; skin lesion; targeted treatment; therapeutic candidate; treatment strategy; tumor

Abstract Cutaneous T-cell lymphoma (CTCL) is a type of extra-nodal non-Hodgkin’s lymphoma characterized by skin lesions resulting from infiltration of malignant T lymphocytes. Mycosis fungoides and Sezary syndrome are the two most common types of CTCL. Although treatments exist, they are mainly palliative with low response and durability of response without any cure. The objective response rate remains approximately 30% with the current treatment strategies for refractory or recurrent CTCL. Despite CTCL being an indolent, chronic disease in most cases, some patients experience severe debilitating itchiness, while others have progressive disease with extensive skin and organ involvement. There is an unmet medical need for more effective treatments with improved response for refractory or recurrent CTCL patients. The majority of clinically diagnosed CTCL highly express the surface markers CC chemokine receptor 4 (CCR4) and/or CD25. We have generated a promising diphtheria toxin based CCR4-IL2 bispecific immunotoxin therapeutic candidate for targeted immunotherapy of CTCL. Our candidate drug is genetically engineered to contain both anti-human CCR4 scFv and human IL2 fused to a truncated diphtheria toxin. Our candidate drug has demonstrated promising preclinical efficacy in a mouse tumor model showing 106% improvement in survival (69 vs. 33.5 days) compared to an Ontak® -like human IL-2 fusion toxin. Our candidate drug is expressed using a novel, advanced diphtheria toxin-resistant yeast (Pichia pastoris) expression system. Our yeast expression system overcomes expression and purification problems encountered with E. coli-based expressions systems to deliver high production levels and excellent purification quality of our immunotoxin. Importantly, the surface receptors CCR4 and CD25 are also expressed on tumor-infiltrating effector T regulatory cells (Tregs) known to play a role in suppressing anti-tumor immune responses. Therefore, a potential follow-on indication for our candidate drug is depletion of tumor infiltrating CCR4+ or/and CD25+ Tregs to boost tumor immunotherapy for a broad spectrum of cancers. In phase I of this application, we will perform pilot non-GLP toxicology, pharmacokinetics, and immunogenicity studies in both rats and minipigs. In phase II, we will 1) develop a scalable standard operating procedure (SOP) for large-scale good manufacturing practice (GMP) production and produce enough GMP grade CCR4-IL2 bispecific immunotoxin for phase I and II clinical trials, and 2) perform GLP toxicology, pharmacokinetics, and immunogenicity studies in both rats and minipigs. Our goal is to prepare an IND-ready preclinical data package and then move this product into clinical trials.

摘要 皮肤T细胞淋巴瘤（CTCL）是一种结外非霍奇金淋巴瘤，其特征在于皮肤 由于恶性T淋巴细胞浸润而引起的病变。蕈样肉芽肿和塞扎里综合征是 两种最常见的CTCL类型。虽然存在治疗方法，但它们主要是缓解性的，反应低， 反应的持久性，无需任何固化。客观反应率保持在30%左右， 难治性或复发性CTCL的治疗策略。尽管CTCL是一种无痛性慢性疾病， 在一些病例中，一些患者经历了严重的衰弱性瘙痒，而另一些患者则患有进行性疾病， 广泛的皮肤和器官受累存在对更有效的治疗的未满足的医疗需求， 改善难治性或复发性CTCL患者的缓解。大多数临床诊断的CTCL高度 表达表面标志物CC趋化因子受体4（CCR 4）和/或CD 25。我们创造了一个有希望的 用于靶向免疫治疗的基于白喉毒素的CCR 4-IL 2双特异性免疫毒素治疗候选物 关于CTCL我们的候选药物是基因工程改造的，含有抗人CCR 4 scFv和人IL 2 与截短的白喉毒素融合我们的候选药物已经在一个临床试验中证明了有希望的临床前疗效。 与Ontak®相比，小鼠肿瘤模型显示出106%的存活改善（69天对33.5天） - 就像 人IL-2融合毒素。我们的候选药物是使用一种新型的，先进的白喉毒素耐药表达 酵母（毕赤酵母）表达系统。我们的酵母表达系统克服了表达和纯化 遇到的问题E.基于大肠杆菌的表达系统，以提供高生产水平和卓越的 免疫毒素的纯化质量。重要的是，表面受体CCR 4和CD 25也表达 对肿瘤浸润效应T调节细胞（TCFs）的作用，已知TCFs在抑制抗肿瘤免疫中发挥作用， 应答因此，我们的候选药物的潜在后续适应症是消除肿瘤浸润， CCR 4+或/和CD 25 + T淋巴细胞，以加强对广谱癌症的肿瘤免疫治疗。在第一阶段， 申请中，我们将在两只大鼠中进行初步非GLP毒理学、药代动力学和免疫原性研究 和迷你猪在第二阶段，我们将1）为大规模货物开发可扩展的标准操作程序（SOP） 生产规范（GMP）生产并生产足够的GMP级CCR 4-IL 2双特异性免疫毒素 用于I期和II期临床试验，2）进行GLP毒理学、药代动力学和免疫原性研究 在老鼠和小型猪身上都有。我们的目标是准备一个IND准备好的临床前数据包，然后将其 产品进入临床试验。