抗真菌热休克蛋白90人重组抗体Mycograb疗效的临床前评估。

Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90.

作者信息

Matthews Ruth C, Rigg Gordon, Hodgetts Samantha, Carter Tracey, Chapman Caroline, Gregory Carl, Illidge Chris, Burnie James

机构信息

Department of Medical Microbiology, University of Manchester, Manchester M13 9WL, United Kingdom.

出版信息

Antimicrob Agents Chemother. 2003 Jul;47(7):2208-16. doi: 10.1128/AAC.47.7.2208-2216.2003.

DOI:10.1128/AAC.47.7.2208-2216.2003

PMID:12821470

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC161838/

Abstract

Mycograb (NeuTec Pharma plc) is a human genetically recombinant antibody against fungal heat shock protein 90 (HSP90). Antibody to HSP90 is closely associated with recovery in patients with invasive candidiasis who are receiving amphotericin B (AMB). Using in vitro assays developed for efficacy assessment of chemotherapeutic antifungal drugs, Mycograb showed activity against a wide range of yeast species (MICs against Candida albicans [fluconazole [FLC]-sensitive and FLC-resistant strains], Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, 128 to 256 microg/ml). Mycograb (4 or 8 microg/ml) showed synergy with AMB, the fractional inhibitory index being 0.09 to 0.31. Synergy was not evident with FLC, except for FLC-sensitive C. albicans. Murine kinetics showed that Mycograb at 2 mg/kg produced a maximum concentration of drug in serum of 4.7 microg/ml, a half-life at alpha phase of 3.75 min, a half-life at beta phase of 2.34 h, and an area under the concentration-time curve from 0 to t h of 155 microg. min/ml. Mycograb (2 mg/kg) alone produced significant improvement in murine candidiasis caused by each species: (i). a reduction (Scheffe's test, P < 0.05) in the mean organ colony count for the FLC-resistant strain of C. albicans (kidney, liver, and spleen), C. krusei (liver and spleen), C. glabrata (liver and spleen), C. tropicalis (kidney), and C. parapsilosis (kidney, liver, and spleen) and (ii). a statistically significant increase in the number of negative biopsy specimens (Fisher's exact test, P < 0.05) for C. glabrata (kidney), C. tropicalis (liver and spleen), and C. parapsilosis (liver). AMB (0.6 mg/kg) alone cleared the C. tropicalis infection but failed to clear infections caused by C. albicans, C. krusei, C. glabrata, or C. parapsilosis. Synergy with AMB, defined as an increase (Fisher's exact test, P < 0.05) in the number of negative biopsy specimens compared with those obtained using AMB alone, occurred with the FLC-resistant strain of C. albicans (kidney), C. krusei (spleen), C. glabrata (spleen), and C. parapsilosis (liver and spleen). Only by combining Mycograb with AMB was complete resolution of infection achieved for C. albicans, C. krusei, and C. glabrata.

摘要

麦考格拉布（NeuTec制药公司）是一种针对真菌热休克蛋白90（HSP90）的人源基因重组抗体。抗HSP90抗体与接受两性霉素B（AMB）治疗的侵袭性念珠菌病患者的康复密切相关。利用为评估化疗抗真菌药物疗效而开发的体外试验，麦考格拉布对多种酵母菌种显示出活性（针对白色念珠菌[氟康唑敏感和耐药菌株]、克鲁斯念珠菌、热带念珠菌、光滑念珠菌和近平滑念珠菌的最低抑菌浓度为128至256微克/毫升）。麦考格拉布（4或8微克/毫升）与AMB显示出协同作用，部分抑菌指数为0.09至0.31。除了对氟康唑敏感的白色念珠菌外，与氟康唑未显示出协同作用。小鼠动力学研究表明，2毫克/千克的麦考格拉布在血清中产生的药物最大浓度为4.7微克/毫升，α相半衰期为3.75分钟，β相半衰期为2.34小时，0至t小时的浓度-时间曲线下面积为155微克·分钟/毫升。单独使用麦考格拉布（2毫克/千克）可使由各菌种引起的小鼠念珠菌病有显著改善：（i）白色念珠菌氟康唑耐药菌株（肾脏、肝脏和脾脏）、克鲁斯念珠菌（肝脏和脾脏）、光滑念珠菌（肝脏和脾脏）、热带念珠菌（肾脏）和平滑念珠菌（肾脏、肝脏和脾脏）的平均器官菌落计数降低（谢费检验，P<0.05）；（ii）光滑念珠菌（肾脏）、热带念珠菌（肝脏和脾脏）和平滑念珠菌（肝脏）的活检阴性标本数量有统计学显著增加（费舍尔精确检验，P<0.05）。单独使用AMB（0.6毫克/千克）可清除热带念珠菌感染，但未能清除由白色念珠菌、克鲁斯念珠菌、光滑念珠菌或近平滑念珠菌引起的感染。与AMB的协同作用定义为与单独使用AMB相比活检阴性标本数量增加（费舍尔精确检验，P<0.05），在白色念珠菌氟康唑耐药菌株（肾脏）、克鲁斯念珠菌（脾脏）、光滑念珠菌（脾脏）和平滑念珠菌（肝脏和脾脏）中出现。只有将麦考格拉布与AMB联合使用，白色念珠菌、克鲁斯念珠菌和光滑念珠菌的感染才能完全消除。