Botulinum neurotoxins (BoNT) are potential biothreat agents due to their high lethality,\npotency, and ease of distribution, thus the development of antitoxins is a high priority to the US\ngovernment. This study examined pre-clinical pharmacokinetic studies in rats of four oligoclonal\nanti-BoNT mAb-based therapeutics (NTM-1631, NTM-1632, NTM-1633, NTM-1634) for five BoNT\nserotypes (A, B, E, C, and D). NTM-1631, NTM-1632, and NTM-1633 each consist of three IgG1\nmAbs, each with a distinct human or humanized variable region which bind to distinct epitopes\non BoNT serotype A, B, or E respectively. NTM-1634 consists of four human immunoglobulin G1\n(IgG1) mAbs binding BoNT C/D mosaic toxins. The mechanism of these antitoxins requires that three\nantibodies simultaneously bind toxin to achieve rapid clearance. Rats (total 378) displayed no adverse\nclinical signs attributed to antibody treatment from any of the antitoxins. Pharmacokinetic evaluation\ndemonstrated that the individual mAbs are slowly eliminated, exhibiting dose-dependent exposure\nand long elimination half-lives ranging from 6.5 days to 10 days. There were no consistent differences\nobserved between males and females or among the individual antibodies in each formulation in\nhalf-life. Anti-drug antibodies (ADA) were observed, as expected for human antibodies administered\nto rats. The results presented were used to support the clinical investigation of antibody-based\nbotulism antitoxins.
Loading....