Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B

• Published in: Antimicrobial agents and chemotherapy Vol. 65; no. 7; p. e0232920
• Main Authors: Guptill, J T, Raja, S M, Juel, V C, Walter, E B, Cohen-Wolkowiez, M, Hill, H, Sendra, E, Hauser, B, Jackson, P, Swamy, G K
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 17.06.2021
• Subjects: Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Botulism - drug therapy; Double-Blind Method; Experimental Therapeutics; Healthy Volunteers; Humans; Immunoglobulin G; clinical trials; Clostridium botulinum; monoclonal antibodies
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02329-20

Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments, including an equine antitoxin and human immune globulin, are given postexposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life of >20 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 (AUC ). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent antidrug antibody responses in the low and middle dosing groups and none at the highest dose. NTM-1632 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under identifier NCT02779140.).