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
{"title":"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。","authors":"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","doi":"10.1093/jacamr/dlae100","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The widespread emergence of antibiotic resistance including MDR in Gram-negative bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium.</p><p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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). <i>In vitro</i> activities of the DFCs were assessed by MIC testing. Neutropenic mouse models of thigh infection, septicaemia and pneumonia were used to evaluate <i>in vivo</i> efficacy. Pharmacokinetics were evaluated in mice and cynomolgus monkeys.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>These data support the continued development of Cloudbreak™ DFCs as broad-spectrum prophylactic agents against Gram-negative infections.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11276960/pdf/","citationCount":"0","resultStr":"{\"title\":\"CTC-177, a novel drug-Fc conjugate, shows promise as an immunoprophylactic agent against multidrug-resistant Gram-negative bacterial infections.\",\"authors\":\"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\",\"doi\":\"10.1093/jacamr/dlae100\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The widespread emergence of antibiotic resistance including MDR in Gram-negative bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium.</p><p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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). <i>In vitro</i> activities of the DFCs were assessed by MIC testing. Neutropenic mouse models of thigh infection, septicaemia and pneumonia were used to evaluate <i>in vivo</i> efficacy. Pharmacokinetics were evaluated in mice and cynomolgus monkeys.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>These data support the continued development of Cloudbreak™ DFCs as broad-spectrum prophylactic agents against Gram-negative infections.</p>\",\"PeriodicalId\":14594,\"journal\":{\"name\":\"JAC-Antimicrobial Resistance\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-07-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11276960/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JAC-Antimicrobial Resistance\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/jacamr/dlae100\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"INFECTIOUS DISEASES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAC-Antimicrobial Resistance","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/jacamr/dlae100","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
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.