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）正在开发一种先驱疗法，以恢复免疫力和停滞 白癜风的渐进发展。在我们的合作机构洛约拉大学芝加哥，一种 诱导热休克蛋白70是开发的，在预防和治疗方面具有巨大的潜力 自身免疫性白癜风。该变体仅携带单个氨基酸修饰， 发现HSP70IQ435A（“ CM”）具有涉及树突状细胞长期耐受性的治愈作用 （DC）和抑制T细胞对皮肤的影响。在第1阶段SBIR中，我们在一个模型中检查了CM 辛克莱猪的赞助部署，其特征是黑色素瘤和新的。 开发白癜风。与临床表现平行，在该系统中 DC的子集负责沉淀和永久性的白化病。 在循环和皮肤浸润的DC中。我们观察到对照组未经治疗的病变 逐渐增加的大小增加了32％，而在CM处理水平中观察到37％ （p = 0.0045）。皮肤色素沉着的这种变化与处理过的猪有关，降低了50％ 浸润T细胞（P <0.04）。因此，我们假设CM编码的DNA同样会干扰 人类白癜风患者的逐步发展，为商业的发展提供了动力 变成可销售的药物。目标＃1：扩展和产生GMP级CM PI将合成NOVO A 表达CM质粒的高生产大肠杆菌克隆。 RTX将最终确定增长的优化 条件，开发特定于产品的HPLC释放分析并生成参考标准。 Aldevron Will 生成一个主机库和表达CM的工作单元格，并生成GMP批次 CM以支持临床1A的安全性和在临床白癜风中的有效研究，并执行 稳定性分析。将开发分析方法来表征GMP释放和稳定性的CM 研究。 AIM＃2：将CM治疗效率与白癜风模型中的疾病持续时间联系起来。 RTX会 测量CM与疾病持续时间有关的H3TA2小鼠的效率。我们将 一开始时年龄为6-36周的小鼠通过扫描来衡量疾病阻止和抑制。 AIM＃3： 在FDA IND所需的GLP毒理学研究中，建立CM的急性安全性，毒性和耐受性 应用。 RTX将进行13周的GLP研究，其中CM通过皮下途径进行。 为了阐明小鼠中的Noael，并为测试剂量范围提供了基础 人的安全性和宽容。 AIM＃4：编译并准备向FDA RTX的预先申请 准备并提交监管文件，以支持临床GCP 1A阶段研究以评估 CM在具有主动白癜风的人类志愿者中的安全性。 RTX将与FDA会面，以展示我们的 疗效数据可获得在2022年导致药物注册的临床注册途径的同时发生。