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Fiveprime Therapeutics Inc., 111 Oyster Point Blvd, South San Francisco, CA 94080, USA.
Toxins (Basel). 2019 Jun 17;11(6):345. doi: 10.3390/toxins11060345.
Botulinum neurotoxins (BoNT) are potential biothreat agents due to their high lethality, potency, and ease of distribution, thus the development of antitoxins is a high priority to the US government. This study examined pre-clinical pharmacokinetic studies in rats of four oligoclonal anti-BoNT mAb-based therapeutics (NTM-1631, NTM-1632, NTM-1633, NTM-1634) for five BoNT serotypes (A, B, E, C, and D). NTM-1631, NTM-1632, and NTM-1633 each consist of three IgG1 mAbs, each with a distinct human or humanized variable region which bind to distinct epitopes on BoNT serotype A, B, or E respectively. NTM-1634 consists of four human immunoglobulin G1 (IgG1) mAbs binding BoNT C/D mosaic toxins. The mechanism of these antitoxins requires that three antibodies simultaneously bind toxin to achieve rapid clearance. Rats (total 378) displayed no adverse clinical signs attributed to antibody treatment from any of the antitoxins. Pharmacokinetic evaluation demonstrated that the individual mAbs are slowly eliminated, exhibiting dose-dependent exposure and long elimination half-lives ranging from 6.5 days to 10 days. There were no consistent differences observed between males and females or among the individual antibodies in each formulation in half-life. Anti-drug antibodies (ADA) were observed, as expected for human antibodies administered to rats. The results presented were used to support the clinical investigation of antibody-based botulism antitoxins.
肉毒神经毒素（BoNT）由于其高致死率、效力和易于传播，因此是潜在的生物威胁剂，美国政府将开发抗毒素作为当务之急。本研究检查了针对五种 BoNT 血清型（A、B、E、C 和 D）的四种基于寡克隆抗 BoNT mAb 的治疗药物（NTM-1631、NTM-1632、NTM-1633 和 NTM-1634）的大鼠临床前药代动力学研究。NTM-1631、NTM-1632 和 NTM-1633 各由三种 IgG1 mAb 组成，每种 mAb 都具有独特的人源化或人源可变区，分别与 BoNT 血清型 A、B 或 E 的不同表位结合。NTM-1634 由四种与人免疫球蛋白 G1（IgG1）结合 BoNT C/D 嵌合毒素的 mAb 组成。这些抗体的作用机制需要三种抗体同时结合毒素以实现快速清除。来自任何一种抗毒素的大鼠（共 378 只）均未显示出与抗体治疗相关的不良临床症状。药代动力学评估表明，单个 mAb 缓慢消除，表现出剂量依赖性暴露和长达 6.5 至 10 天的长消除半衰期。在半衰期方面，未观察到雄性和雌性之间或每种制剂中各抗体之间存在一致差异。正如预期的那样，给予大鼠的人抗体观察到了抗药物抗体（ADA）。所呈现的结果用于支持基于抗体的肉毒中毒抗毒素的临床研究。
