[PubMed] [CrossRef] [Google Scholar] 2

[PubMed] [CrossRef] [Google Scholar] 2. adverse event was reported in a placebo subject. Adverse events in the NTM-1633 groups were generally moderate and comparable in frequency and severity to the placebo group, and no security signal was recognized. NTM-1633 has a favorable PK profile with a half-life >10?days for the 0.330?mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0t). NTM-1633 also exhibited Miglustat hydrochloride low immunogenicity. NTM-1633 is usually well tolerated at the administered doses. The favorable security, PK, and immunogenicity profile supports further development as a treatment for BoNT/E intoxication and postexposure prophylaxis. KEYWORDS: species (1). To date, 7 unique serotypes of botulinum toxin have been recognized (ACH) (2, 3), of which serotypes A and B account for the majority of cases and serotype E accounts for a small percentage of cases reported in the U.S. (4). There are several mechanisms of botulinum intoxication, specifically, ingestion of food contaminated with preformed toxin, wound contamination following traumatic injury or intravenous drug use (5), toxicoinfection in infants and adults with toxin production, and iatrogenic following therapeutic or cosmetic chemodenervation (6). An additional theoretical mechanism considers dispersal DLL3 and subsequent inhalation of weaponized toxin (7, 8). While toxicoinfection in infants is Miglustat hydrochloride the most common, there is a rising incidence of wound botulism among intravenous drug users (4). Current therapies for BoNT intoxication are given postexposure to symptomatic individuals. These include an equine antitoxin (investigational heptavalent botulinum antitoxin [HBAT]) (9) and a human immune globulin reserved for infant use (Botulism Immune Globulin Intravenous [BIG-IV]) (10). Production of both the equine antitoxin and the human immune globulin is usually labor-intensive and costly, leading to restricted availability and unstainable production. The equine antitoxin, in particular, is usually highly immunogenic with a short half-life. These inherent difficulties of the current antitoxin and immune globulin supply and manufacture show an urgent unmet need for novel therapeutics in this area both Miglustat hydrochloride for treatment of diagnosed patients and for potential postexposure prophylaxis in high-risk situations. Over the past 15?years, new methodologies, such as small peptides and peptide mimetics, receptor mimics, and humanized monoclonal antibodies have emerged as attractive strategies (11). Novel mechanisms including inhibitors of neurotoxin uptake and processing as well as endopeptidases and neuronal modulation also remain attractive (12). While high-throughput screening and structure-based drug design have led to identification of potential therapeutics, the favorable profiles do not translate to efficacy (13). Small molecules, such as 3,4-diaminopyridine, are also emerging as potential symptomatic options for BoNT intoxication (14). Of the above strategies, humanized monoclonal antibodies are among the more encouraging. Comixtures of monoclonal antibodies are currently in development by Ology Biosciences with the support of the National Institute of Allergy and Infectious Diseases (NIAID) to target multiple BoNT Serotypes. The specific products targeting BoNT serotypes A (BoNT/A NTM-1631 [formely XOMA 3AB]), serotype B (BoNT/B, NTM-1632 [formerly XOMA 3B]), C and D (BoNT/C and BoNT/D, NTM-1634 [formerly XOMA 4CD]), and E (BoNT/E, NTM-1633 [formerly XOMA 3E]) are being developed for the prevention and treatment of botulism (15,C17). NTM-1633 is an equimolar mixture of 3 IgG monoclonal antibodies; each antibody is usually engineered to have unique Miglustat hydrochloride light and heavy chain variable regions that bind unique nonoverlapping epitopes on BoNT/E and common human gamma-1 and kappa constant regions. Since NTM-1633 is usually structurally much like NTM-1631, NTM-1632, and NTM-1634, the predicted mechanism is likely comparable: high affinity binding of the combination to toxin, blockade of cellular binding epitopes around the toxin, and increased hepatic clearance of the toxin-Ab immune complexes (15, 18, 19). Based on encouraging preclinical screening (20, 21) and positive results from the Phase I trials of NTM-1631 (15), NTM-1632 (17), and NTM-1634 (16), the human investigational product NTM-1633 is in clinical development for the treatment and prophylaxis of botulism caused by BoNT/E. The purpose of this study was to assess the security, tolerability, pharmacokinetics (PK), and immunogenicity of.