A novel immunotolerizing therapy for autoimmune vitiligo

Radikal Therapeutics（RTX）正在开发一种恢复免疫耐受性和免疫停滞的开创性疗法 白癜风的进行性色素脱失在我们的合作机构，洛约拉大学芝加哥，一个变种， 诱导型热休克蛋白70在预防和治疗中具有显著的潜力 自身免疫性白癜风这种变体只对蛋白质进行了一个氨基酸修饰， 发现HSP 70 iQ 435 A（“CM”）具有涉及树突状细胞的持久耐受化的疗效。 (DCs)和抑制T细胞流入皮肤。在第1阶段SBIR中，我们在以下模型中检查了CM： Sinclair猪的自发性色素脱失，特征为黑色素瘤消退和新发 发展中的白癜风与临床表现相似，在该系统中，炎性CD 11b + CD 11 c + 一个负责促进和维持白癜风的DC亚群被发现越来越多 在循环和皮肤浸润DC中。我们观察到对照组中未治疗的病变 逐渐增加的大小为32%，而37%的再色素沉着，观察到在CM治疗病变 （p=0.0045）。治疗猪的皮肤色素沉着变化与皮肤色素沉着减少50%有关。 浸润性T细胞（p<0.04）。因此，我们假设CM编码DNA同样会干扰 在人类白癜风患者中进行性色素脱失，为CM的发展提供了动力 变成了可销售的药物目标#1：扩大规模并生产GMP级CM PI将重新合成 高产E.表达CM质粒的大肠杆菌克隆。RTX将完成增长的优化 条件，开发产品特定的HPLC放行测定，并生成参比标准品。阿尔德弗隆将 产生表达CM的主细胞库和工作细胞库，并产生表达CM的gGMP批次。 CM，以支持临床白癜风的临床1a期安全性和疗效研究，并进行 稳定性分析将开发分析方法，以表征CM的GMP放行和稳定性 问题研究目的#2：在白癜风的鼠模型中将CM治疗功效与疾病持续时间相关联。RTX将 测量CM在患有进行性白癜风的h3 TA 2小鼠中与疾病持续时间相关的功效。我们将 在发病时处理6-36周龄的小鼠，以通过扫描测量疾病停止和色素再沉着。目标3： 在FDA IND要求的GLP毒理学研究中确定CM的急性安全性、毒性和耐受性 应用程序. RTX将进行一项为期13周的GLP研究，其中CM通过皮下途径给药， 为了阐明小鼠中的NOAEL，并为测试的剂量范围提供基础， 目标#4：编写并准备向FDA提交的IND前申请 准备并提交监管文件，以支持临床GCP 1a期研究， CM在患有活动性白癜风的人类志愿者中的安全性RTX将与FDA会面， 有效性数据，以获得临床注册途径的同意，从而在2022年实现药物注册。

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.