A novel immunotolerizing therapy for autoimmune vitiligo

一种治疗自身免疫性白癜风的新型免疫耐受疗法

• 批准号: 9408764
• 负责人: Kanneganti Murthy
• 金额: $ 103.91万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408764
• 关键词: Acute; Address; Affect; Aftercare; Age; Amino Acids; Animals; Appearance; Autoimmune Diseases; Autoimmune Process; Basic Science; Biological Assay; Chicago; Clinical; Collaborations; Control Groups; Cutaneous; DNA; Data; Dendritic Cells; Development; Disease; Documentation; Dose; Ensure; Escherichia coli; Family suidae; FarGo; GTP-Binding Protein alpha Subunits, Gs; Goals; Growth; Hair; Heat-Shock Proteins 70; High Pressure Liquid Chromatography; Human; Human Volunteers; ITGAM gene; ITGAX gene; Incentives; Inflammatory; Institution; Investigation; Laboratories; Lesion; Measures; Medical; Methods; Modeling; Modification; Mus; No-Observed-Adverse-Effect Level; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Pigmentation physiologic function; Pigments; Plasmids; Prevention; Preventive; Production; Proteins; Published Comment; Records; Recruitment Activity; Reference Standards; Regressing Melanoma; Reporting; Route; Safety; Scanning; Skin; Small Business Innovation Research Grant; Social Interaction; Stem cells; Suggestion; System; T-Cell Receptor; T-Lymphocyte; Technology Transfer; Therapeutic; Toxic effect; Toxicology; Transgenic Mice; Translating; Treatment Efficacy; Universities; Variant; Vitiligo; analytical method; cell bank; clinically relevant; drug market; illness length; innovation; man; manufacturing facility; meetings; melanocyte; mouse model; novel; preclinical safety; professor; quality assurance; safety study; safety testing; scale up; skin color; subcutaneous

Radikal Therapeutics (RTX) is developing a pioneering therapy to restore immunotolerance and arrest progressive depigmentation in vitiligo. At our partnering institution, Loyola University Chicago, a variant to inducible Heat Shock Protein 70 was developed with remarkable potential for the prevention and treatment of autoimmune vitiligo. Carrying only a single amino acid modification to the protein, this variant HSP70iQ435A (“CM”) was found to have a curative effect involving long-lasting tolerization of dendritic cells (DCs) and inhibition of T cell influx to the skin. In the Phase 1 SBIR we examined the CM in a model of spontaneous depigmentation in Sinclair swine, characterized by regressing melanoma and newly developing vitiligo. Paralleling the clinical presentation, in this system the inflammatory CD11b+CD11c+ subset of DCs held responsible for precipitating and perpetuating vitiligo is found in increased abundance among circulating and skin infiltrating DC. We observed that untreated lesions in the control group gradually increased in size by 32%, whereas repigmentation of 37% was observed in CM treated lesions (p=0.0045). This change in cutaneous pigmentation was associated in treated pigs with a 50% reduction in infiltrating T cells (p<0.04). We thus hypothesize that the CM-encoding DNA will likewise interfere with progressive depigmentation in human vitiligo patients, providing incentive for the development of the CM into a marketable drug. Aim #1: Scale-up and produce GMP-grade CM The PI will synthesize de novo a high-producing E. coli clone expressing the CM plasmid. RTX will finalize optimization of the growth conditions, develop product-specific HPLC release assays, and generate a reference standard. Aldevron will generate a Master Cell Bank and Working Cell Bank expressing the CM, and generate a g GMP batch of the CM in order to support clinical Phase 1a safety and efficacy investigations in clinical vitiligo, and to perform stability analysis. Analytical methods will be developed to characterize the CM for GMP release and stability studies. Aim #2: Relate CM treatment efficacy to disease duration in a murine model of vitiligo. RTX will measure efficacy of the CM in relation to disease duration in h3TA2 mice with progressive vitiligo. We will treat mice 6-36 weeks at age at onset to measure disease arrest and repigmentiation by scanning. Aim #3: Establish the acute safety, toxicity, and tolerance of CM in GLP toxicology studies required for FDA IND application. RTX will carry out a 13-week GLP study wherein the CM is dosed via a subcutaneous route of administration in order to elucidate the NOAEL in mice and provide the basis for the dose range to test for safety and tolerance in man. Aim #4: Compile and prepare a pre-IND application to the FDA RTX will prepare and submit regulatory documentation to support a clinical GCP Phase 1a study to evaluate the safety of the CM in human volunteers with active vitiligo. RTX will meet with the FDA to present our efficacy data to gain concurrence on a clinical registration pathway leading to drug registration in 2022.

Radikal Therapeutics (RTX) 正在开发一种开创性疗法，以恢复免疫耐受和阻止 在我们的合作机构芝加哥洛约拉大学，进行性白癜风的一种变体。 诱导型热休克蛋白 70 的开发具有显着的预防和治疗潜力 自身免疫性白癜风的这种变体仅对蛋白质进行单一氨基酸修饰。 HSP70iQ435A（“CM”）被发现具有涉及树突状细胞持久耐受的疗效 (DC) 和抑制 T 细胞流入皮肤 在第一阶段 SBIR 中，我们检查了模型中的 CM。 辛克莱猪自发色素脱失，其特征是黑色素瘤消退和新出现 与临床表现相似，该系统中存在炎症性 CD11b+CD11c+。 负责诱发和延续白癜风的树突状细胞亚群被发现丰度增加 我们观察到对照组中未经治疗的病变。 尺寸逐渐增大 32%，而在 CM 治疗的病变中观察到 37% 的色素沉着 (p=0.0045) 治疗猪的皮肤色素沉着变化与色素减少 50% 相关。 因此，我们发现 CM 编码 DNA 也会类似地干扰。 人类白癜风患者进行性色素脱失，为 CM 的发展提供动力 目标#1：扩大规模并生产 GMP 级 CM PI 将重新合成 表达 CM RTX 的高产大肠杆菌克隆将最终优化生长。 Aldevron 将在条件下开发特定产品的 HPLC 释放测定并生成参考标准品。 生成表达 CM 的主细胞库和工作细胞库，并生成 g GMP 批次 CM 以支持临床白癜风的临床 1a 期安全性和有效性研究，并进行 将开发分析方法来表征 CM 的 GMP 释放和稳定性。 研究目标#2：将 CM 治疗效果与 RTX 小鼠模型的疾病持续时间联系起来。 我们将测量 CM 与进行性白癜风 h3TA2 小鼠疾病持续时间的关系。 对发病时 6-36 周龄的小鼠进行治疗，通过扫描测量疾病停止和色素沉着。 在 FDA IND 所需的 GLP 毒理学研究中确定 CM 的急性安全性、毒性和耐受性 RTX将进行为期13周的GLP研究，而CM则通过皮下途径给药。 给药以阐明小鼠的 NOAEL 并为测试剂量范围提供基础 目标#4：向 FDA RTX 编制并准备预 IND 申请。 准备并提交监管文件以支持临床 GCP 1a 期研究，以评估 CM 在患有活动性白癜风的人类志愿者中的安全性将与 FDA 会面，介绍我们的研究成果。 功效数据，以就 2022 年药品注册的临床注册途径达成一致。