Lovey Arianne, Lee Annie, Yu Allison, Krel Mila, Wang Mingming, Paderu Padmaja, Brady Thomas, Hough Grayson, Zhao Qiping, Balkovec James M, Perlin David S, Zhao Yanan
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA.
Departments of Medicinal Chemistry and Protein Chemistry, Cidara Therapeutics, Inc., San Diego, CA 92121, USA.
JAC Antimicrob Resist. 2024 Jul 26;6(4):dlae100. doi: 10.1093/jacamr/dlae100. eCollection 2024 Aug.
The widespread emergence of antibiotic resistance including MDR in Gram-negative bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium.
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.
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). activities of the DFCs were assessed by MIC testing. Neutropenic mouse models of thigh infection, septicaemia and pneumonia were used to evaluate efficacy. Pharmacokinetics were evaluated in mice and cynomolgus monkeys.
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.
These data support the continued development of Cloudbreak™ DFCs as broad-spectrum prophylactic agents against Gram-negative infections.
革兰氏阴性菌病原体中包括多重耐药性在内的抗生素耐药性广泛出现，对当前的抗菌药物库构成了严峻挑战。
创建一种新型药物-Fc偶联物（DFC），其能够以持续和延长的水平递送，同时激活宿主免疫反应以对抗多重耐药革兰氏阴性菌感染。
使用Cloudbreak™平台开发DFC，其由通过不可裂解的接头连接到效应部分（EM）（人IgG1的Fc结构域）的靶向部分（TM）（一种多粘菌素衍生的二聚体）组成。通过MIC测试评估DFC的活性。使用大腿感染、败血症和肺炎的中性粒细胞减少小鼠模型来评估疗效。在小鼠和食蟹猴中评估药代动力学。
在败血症和肺炎小鼠模型中，单剂量预防性给予我们的先导DFC CTC-177，与每日用粘菌素治疗相比，可显著降低细菌载量并减轻炎症。此外，CTC-177预防能够恢复粘菌素在耐粘菌素败血症中的疗效，将细菌载量降低到检测限以下。最后，CTC-177在小鼠和食蟹猴中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™ DFC作为针对革兰氏阴性菌感染的广谱预防剂。
