Safety and pharmacokinetics of a four monoclonal antibody combination against botulinum C and D neurotoxins

Abstract

Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A to G), which differ by 35% to 68% in amino acid sequences, necessitates the development of serotype-specific countermeasures. We present results of a phase 1 clinical study of an anti-toxin to BoNT serotypes C and D, NTM-1634, which consists of an equimolar mixture of four fully human IgG1 monoclonal antibodies (MAbs), each binding to nonoverlapping epitopes on BoNT serotypes C and D, resulting in potent toxin neutralization in rodents. This first in-human study evaluated the safety and pharmacokinetics of escalating doses of NTM-1634 administered intravenously to healthy adults. Three cohorts of eight healthy subjects received single intravenous doses of NTM-1634 at 0.33 mg/kg, 0.66 mg/kg, or 1 mg/kg or placebo. Follow-up examinations and pharmacokinetics evaluations were continued up to 121 days postinfusion. Subjects were monitored by using physical examinations, hematology and chemistry blood tests, and electrocardiograms. Pharmacokinetics parameters were estimated using noncompartmental methods. The results demonstrated that the materials were safe and well tolerated with the expected half-lives for human MAbs and with minimal antidrug antibodies detected over the dose ranges and duration of the study.