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

• 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
• 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

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 肉毒神经毒素血清型A1（BONT/A1）已成为多种指示的重要治疗工具， 尽管是科学已知的最有毒的蛋白质。尽管严重的不良事件（AES）很少 所有FDA批准的BONT/A1的标签中包含的Black Box警告认识到了重要性 产品。在最近的3年期间 涉及大型肌肉群的治疗（例如中风后） 痉挛，脑瘫和宫颈肌张力障碍）。没有用于BONT/A1相关的医源性的治疗方法 AES除了支持护理以外。唯一可用的肉毒杆菌疗法是一种衍生的抗毒素（蝙蝠， 无法获得负责医源性症状的神经内神经元毒素蛋白酶的新兴生物溶液， 因此，在治疗与BONT/A1过量和脱靶的AES相关的AE方面几乎没有用。我们有 开发了一种症状的症状解毒剂，以使用神经内神经元的作用机理，以 指定的B8C1AD。 B8C1AD是通过遗传融合单域抗体（SDAB，B8）与A产生的 BONT/C1的重组毒性衍生物（用于氧化衍生物的C1AD），该衍生物充当分子媒介 BONT/A1有毒蛋白酶住宅中的神经元细胞质的B8抗体。 B8抗体是 从Camelid VHH文库中选择其潜在抑制BONT/A1蛋白酶。 B8C1AD已经过去了 在感染后有时有效地用全身性BONT/A1进行全身性BONT/A1进行抗毒性挽救动物。 常规抗体无效，因为它们无法访问神经内BONT/A1 LC蛋白酶。 B8C1AD逆转BONT/A1肠毒性症状和救援动物的安全性和有效性 我们在这里建议建立一个模型 BONT/A1通过肌内施用上剂量的剂量过量，并将B8C1AD作为一种 孤儿药治疗与临床使用BONT/A1 PHARMACETICAL 产品。成功完成拟议的研究将支持目标产品配置文件的组装 B8C1AD，将与FDA共享，要求C type C会议以获取有关监管途径的指导 B8C1AD批准为一种孤儿药，用于治疗与BONT/A1药物相关的医源性过量药物。