Development of B8C1ad as an Orphan Drug for Iatrogenic Botulism

B8C1ad 作为治疗医源性肉毒杆菌中毒的孤儿药的开发

基本信息

批准号：
10603832
负责人：
PHILIP Arthur BAND
金额：
$ 29.54万
依托单位：
CYTODEL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10603832
关键词：
Adverse event Affinity Affinity Chromatography Amino Acid Substitution Animals Antibodies Antidotes Biological Biological Assay Black race Botulinum Antitoxin Botulinum Toxins Botulism C-terminal Cells Cerebral Palsy Cervical Dystonia Chemistry Chimeric Proteins Clinical Communication Cytoplasm Data Development Disulfides Dose Effectiveness Engineering Equus caballus Excision FDA approved Formulation Gastrocnemius Muscle Iatrogenesis Intoxication Intramuscular Label Laboratories Lead Libraries Light Link Maximum Tolerated Dose Measures Mechanical ventilation Methodology Modeling Molecular Mus Muscle N-terminal Neurons Orphan Drugs Overdose Paralysed Patients Peptide Hydrolases Pharmacodynamics Pharmacologic Substance Phase Plant Resins Process Production Proteins Publishing Recombinants Regulatory Pathway Reporting Safety Science Serious Adverse Event Serotyping Severities Site Small Business Innovation Research Grant Specific qualifier value Specificity Sterility Supportive care Symptoms TEV protease Testing Therapeutic Thrombin Toxin Validation Viral antitoxin digital drug testing effectiveness measure good laboratory practice manufacture meetings nanobodies nonhuman primate polyhistidine post stroke post-market preclinical study response spasticity stability testing success tobacco etch virus tool trafficking weapons

项目摘要

Abstract Botulinum neurotoxin serotype A1 (BoNT/A1) has become an important therapeutic tool for multiple indications, despite being the most toxic protein known to science. Although serious Adverse Events (AEs) are rare, their importance is recognized by the Black Box warning included in the labeling for all FDA-approved BoNT/A1 products. During a recent 3-year period FDA received 13,087 AE reports specifically described as “overdose”, primarily associated with therapeutic indications. involving the treatment of large muscle groups (eg post-stroke spasticity, cerebral palsy and cervical dystonia). No treatment is available for BoNT/A1-associated iatrogenic AEs other than supportive care. The only available botulism therapeutic is an equine-derived antitoxin (BAT, Emergent Biosolutions) that cannot access the intraneuronal toxin protease responsible for iatrogenic symptoms, and is therefore of little use in treating AEs associated with BoNT/A1 overdose and off-target actions. We have developed a post-symptomatic antidote to BoNT/A1 intoxication with an intraneuronal mechanism of action, designated B8C1ad. B8C1ad is produced by genetically fusing a single domain antibody (sdAb, B8) to a recombinant atoxic derivative of BoNT/C1 (C1ad for atoxic derivative) that acts as a molecular vehicle to deliver the B8 antibody to the neuronal cytoplasm where the BoNT/A1 toxic protease resides. The B8 antibody was selected from a camelid VHH library for its potent inhibition of the BoNT/A1 protease. B8C1ad has been demonstrated to effectively rescue animals with systemic BoNT/A1 intoxication at times post-intoxication when conventional antibodies are ineffective, because they cannot access the intra-neuronal BoNT/A1 LC protease. The safety and effectiveness of B8C1ad to reverse BoNT/A1 intoxication symptoms and rescue animals has been published in three species, including non-human primates. We here propose establishing a model for BoNT/A1 overdose via intramuscular administration of supratherapeutic doses, and developing B8C1ad as an Orphan Drug to treat off-target iatrogenic AEs associated with the clinical use of BoNT/A1 pharmaceutical products. Successful completion of the proposed studies will support assembly of a target product profile for B8C1ad, which will be shared with FDA to request a Type C meeting for guidance on the regulatory pathway for B8C1ad approval as an Orphan Drug to treat iatrogenic overdose associated with BoNT/A1 pharmaceuticals.

抽象的肉毒杆菌神经毒素血清型 A1 (BoNT/A1) 已成为多种适应症的重要治疗工具，尽管是科学上已知毒性最强的蛋白质，但严重的不良事件 (AE) 很少见。所有 FDA 批准的 BoNT/A1 的标签中都包含黑框警告，从而认识到其重要性在最近 3 年期间，FDA 收到了 13,087 份 AE 报告，具体描述为“用药过量”，主要与涉及大肌肉群治疗的治疗适应症有关（例如中风后）。痉挛、脑瘫和颈肌张力障碍）目前尚无针对 BoNT/A1 相关医源性治疗的治疗方法。除支持治疗外，唯一可用的肉毒杆菌疗法是马源抗毒素（BAT， Emergent Biosolutions）无法接触导致医源性症状的神经元内毒素蛋白酶，因此，在治疗与 BoNT/A1 过量和脱靶行为相关的 AE 方面作用不大。开发了一种具有神经元内作用机制的 BoNT/A1 中毒症状后解毒剂，指定为 B8C1ad 的 B8C1ad 是通过将单域抗体 (sdAb、B8) 基因融合而产生的。 BoNT/C1 的重组无毒衍生物（C1ad 代表无毒衍生物），作为分子载体传递 B8 抗体针对 BoNT/A1 有毒蛋白酶所在的神经元细胞质。因其对 BoNT/A1 蛋白酶的有效抑制作用而从骆驼 VHH 文库中筛选出来。被证明可以有效地拯救全身 BoNT/A1 中毒的动物，有时在中毒后常规抗体无效，因为它们无法接触神经元内的 BoNT/A1 LC 蛋白酶。 B8C1ad 逆转 BoNT/A1 中毒症状和拯救动物的安全性和有效性已在包括非人类灵长类动物在内的三个物种中发表。我们在此建议建立一个模型。通过肌肉注射超治疗剂量来解决 BoNT/A1 过量问题，并开发 B8C1ad 作为治疗药物治疗与 BoNT/A1 药物临床使用相关的脱靶医源性 AE 的孤儿药成功完成拟议的研究将支持目标产品概况的组装。 B8C1ad，将与 FDA 共享，以请求召开 C 类会议，以获取有关监管途径的指导 B8C1ad 被批准为孤儿药，用于治疗与 BoNT/A1 药物相关的医源性过量用药。