Sullivan-Bólyai John Z, Allen Larry B, Cannon Rebecca, Cohane Kenya P, Dunzo Elise, Goldwater Ronald, StCyr Kathleen, Wang Yang, Klempner Mark S
MassBiologics of the University of Massachusetts Chan Medical School, Boston, Massachusetts.
Parexel, Durham, North Carolina.
J Infect Dis. 2025 Sep 15;232(3):534-539. doi: 10.1093/infdis/jiae499.
Diphtheria is a recurrent threat with endemic still occurs in many parts of the world. The standard of care is horse serum-derived diphtheria antitoxin (eDAT), which is in critical short supply globally. S315 is a fully human, monoclonal immunoglobulin G1 neutralizing antibody, specific to the receptor-binding domain of diphtheria toxin. S315 is intended to be a safer, more readily available alternative to replace eDAT.
This first-in-human, randomized, double-blind, dose escalation study evaluated the safety, tolerability, and pharmacokinetics of S315 in healthy adults. Cohorts of study subjects received single intravenous infusions of S315 (480 mg, 960 mg, 1920 mg, 3840 mg, and 7680 mg) or matched placebo. Safety was assessed by standard clinical and laboratory evaluations. Serum S315 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and an in vitro diphtheria toxin neutralization assay, followed by pharmacokinetic analyses.
Forty-one subjects were enrolled. S315 was safe and well tolerated. Most adverse events were mild or moderate. Peak mean serum concentrations ranged from 199 µg/mL to 2872 µg/mL (ELISA) and from 234 AU/mL to 1147 AU/mL (neutralization assay), with low variability. Mean serum half-life ranged from 12 to 27 days (ELISA) and from 17 to 22 days (neutralization assay).
S315 was generally safe and well tolerated by healthy subjects. Pharmacokinetic data suggest that S315 serum neutralizing activity is an order of magnitude greater than that attained by eDAT. The results of this study support continued development of S315 as a replacement for eDAT to address critical global supply issues. Clinical Trials Registration. NCT04075175.
白喉仍是一种反复出现的威胁，在世界许多地区仍有地方性流行。治疗的标准是马血清来源的白喉抗毒素（eDAT），而这种药物在全球范围内严重短缺。S315是一种完全人源化的单克隆免疫球蛋白G1中和抗体，对白喉毒素的受体结合域具有特异性。S315旨在成为一种更安全、更容易获得的替代品，以取代eDAT。
这项首次在人体进行的随机、双盲、剂量递增研究评估了S315在健康成年人中的安全性、耐受性和药代动力学。研究对象队列接受了单次静脉输注S315（480毫克、960毫克、1920毫克、3840毫克和7680毫克）或匹配的安慰剂。通过标准的临床和实验室评估来评估安全性。通过酶联免疫吸附测定（ELISA）和体外白喉毒素中和测定法测量血清S315浓度，随后进行药代动力学分析。
招募了41名受试者。S315安全且耐受性良好。大多数不良事件为轻度或中度。平均血清峰值浓度范围为199微克/毫升至2872微克/毫升（ELISA）和234 AU/毫升至1147 AU/毫升（中和测定），变异性较低。平均血清半衰期范围为12至27天（ELISA）和17至22天（中和测定）。
S315总体上对健康受试者安全且耐受性良好。药代动力学数据表明，S315血清中和活性比eDAT高一个数量级。这项研究的结果支持继续开发S315以替代eDAT，以解决全球关键供应问题。临床试验注册编号：NCT04075175。
