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.

摘要