CTC-177是一种新型药物-Fc共轭物,有望作为一种免疫预防药剂用于抗耐多药革兰氏阴性菌感染。

IF 3.7 Q2 INFECTIOUS DISEASES
JAC-Antimicrobial Resistance Pub Date : 2024-07-26 eCollection Date: 2024-08-01 DOI:10.1093/jacamr/dlae100
Arianne Lovey, Annie Lee, Allison Yu, Mila Krel, Mingming Wang, Padmaja Paderu, Thomas Brady, Grayson Hough, Qiping Zhao, James M Balkovec, David S Perlin, Yanan Zhao
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引用次数: 0

摘要

背景:抗生素耐药性(包括革兰氏阴性细菌病原体中的 MDR)的广泛出现对目前的抗菌药物组合构成了严峻挑战:目的:创造一种新型药物-Fc共轭物(DFC),这种药物-Fc共轭物可以持续、长时间地给药,同时激活宿主免疫反应,以对抗MDR革兰氏阴性菌感染:方法:利用 Cloudbreak™ 平台开发了由靶向分子(TM)(一种多粘菌素衍生二聚体)和效应分子(EM)(人类 IgG1 的 Fc 结构域)组成的 DFCs。通过 MIC 测试评估了 DFCs 的体外活性。中性粒细胞小鼠大腿感染、败血症和肺炎模型用于评估体内疗效。对小鼠和猕猴的药代动力学进行了评估:结果:在败血症和肺炎小鼠模型中,单剂量预防性服用我们的先导 DFC CTC-177 能显著减少细菌负担,减轻炎症反应,与每日服用可乐定治疗效果相当。此外,CTC-177 还能在耐秋水仙碱的败血症中恢复秋水仙碱的疗效,使细菌负担减少到检测不到的程度。最后,CTC-177 在小鼠和猴体内的终末半衰期分别超过 24 小时和 65 小时:这些数据支持继续开发 Cloudbreak™ DFCs,将其作为抗革兰氏阴性菌感染的广谱预防药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CTC-177, a novel drug-Fc conjugate, shows promise as an immunoprophylactic agent against multidrug-resistant Gram-negative bacterial infections.

Background: The widespread emergence of antibiotic resistance including MDR in Gram-negative bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium.

Objectives: To create a novel drug-Fc conjugate (DFC) that can be delivered at sustained and prolonged levels while simultaneously activating the host immune response to combat MDR Gram-negative infections.

Methods: The Cloudbreak™ platform was used to develop DFCs consisting of a targeting moiety (TM) (a polymyxin-derived dimer) attached via a non-cleavable linker to an effector moiety (EM) (the Fc domain of human IgG1). In vitro activities of the DFCs were assessed by MIC testing. Neutropenic mouse models of thigh infection, septicaemia and pneumonia were used to evaluate in vivo efficacy. Pharmacokinetics were evaluated in mice and cynomolgus monkeys.

Results: A single prophylactic dose of our lead DFC, CTC-177, resulted in significantly decreased bacterial burdens and reduced inflammation comparable to daily treatment with colistin in septicaemia and pneumonia mouse models. Furthermore, CTC-177 prophylaxis was able to restore colistin efficacy in colistin-resistant septicaemia, reducing bacterial burdens beyond the limit of detection. Finally, CTC-177 displayed a long terminal half-life of over 24 and 65 h in mice and cynomolgus monkeys, respectively.

Conclusions: These data support the continued development of Cloudbreak™ DFCs as broad-spectrum prophylactic agents against Gram-negative infections.

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来源期刊
CiteScore
5.30
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