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

Abstract

Objective 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 post-exposure 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. Methods 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 pre-specified time points for PK and immunogenicity analyses. Results 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 >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 (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent anti-drug antibody responses in the low and middle dosing groups and none at the highest dose. Interpretation 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 post-exposure prophylaxis.

Neutralizing Concentrations of Anti-Botulinum Toxin Antibodies Positively Correlate with Mouse Neutralization Assay Results in a Guinea Pig Model

“…An oligoclonal mixture of six IgG monoclonal antibodies (mAbs) against BoNT/A and BoNT/B, G03-52-01, comprised of a lyophilized, equimolar mixture of mAbs XA-a, XA-b, XA-c, and mAbs XB-a, XB-b, XB-c [ 24 , 25 , 26 , 27 , 28 , 44 ].…”

“…The development of a potent human monoclonal antibody (mAb) based drug product, G03-52-01, composed of multiple mAbs binding to non-overlapping epitopes on BoNT/A and BoNT/B has been described previously [ 17 , 19 , 20 , 24 , 25 , 26 ]. The BoNT/A [ 27 ], BoNT/B [ 28 ], BoNT/E (NCT03603665, unpublished results), and BoNT/C/D [ 29 ] antitoxins have completed Phase 1 testing in humans, without serious adverse side effects.…”

Radioiodination, purification, and evaluation of antihuman tumor‐derived immunoglobulin G light chain monoclonal antibody in tumor‐bearing nude mice

“…Cancer is still one of the leading causes of mortality worldwide. Over the years, antibodies have been widely used to treat cancers 1,2 . According to the traditional view, immunoglobulins (Igs) are only produced by differentiated B lymphocytes 3 .…”

“…Over the years, antibodies have been widely used to treat cancers. 1,2 According to the traditional view, immunoglobulins (Igs) are only produced by differentiated B lymphocytes. 3 However, Kimoto 4,5 reported the expression of heavy-chain constant regions of Ig and T-cell receptor gene transcripts by reverse transcription-polymerase chain reaction (RT-PCR) in human non-hematopoietic tumor cell lines such as SW1116 (colon carcinoma), HeP2 (laryngocarcinoma), MCF-7 (breast cancer), HC48 (pancreatic carcinoma), and human spermoblasts.…”

Multicolor fluorescence activated cell sorting to generate humanized monoclonal antibody binding seven subtypes of BoNT/F

“…As an alternative to equine derived antitoxin [15], highly potent human mAb-based antitoxins composed of three mAbs [13,[16][17][18] are being developed for serotypes A, B, C, D, E, F, and G with the most advanced (serotypes A, B, C, D, and E) having completed Phase 1 human testing [19][20][21][22]. The three mAbs bind non-overlapping epitopes on the BoNT molecule and elicit rapid clearance from the circulation and high potency [23,24].…”