Burnie James, Matthews Ruth
University Department of Medical Microbiology, and NeuTec Pharma plc, 2nd floor, Clinical Sciences Building 1, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK.
Expert Opin Biol Ther. 2004 Feb;4(2):233-41. doi: 10.1517/14712598.4.2.233.
Historically, the therapy of serious fungal infection has been dominated by monotherapy with the polyene antibiotic amphotericin B. Clinical failures, side effects, the lack of alternatives and the toxicity of this drug have heightened the need to produce alternative therapies, which have included fluconazole, voriconazole and caspofungin. The observation that recovery from disseminated candidiasis was associated with an antibody response to the 47 kDa Candida heat-shock protein (HSP)90 homologue, coupled with the ability to sequence all the antibodies from patients who have recovered from the infection and to re-express the dominant ones as fragments in Escherichia coli, has opened the possibility of immunotherapy. The first recombinant antibody fragment, Mycograb (Neu Tec Pharma plc), against Candida HSP90 is now in clinical trials in patients with disseminated candidiasis in Europe and the US. Laboratory and early clinical data support the concept of synergy between Mycograb and amphotericin B. This should improve outcome and diminish the risk of resistance occurring to either drug, without an increase in toxicity, as this should be minimal in a human antibody fragment representing the natural antibody that a patient produces on recovery.
从历史上看，严重真菌感染的治疗一直以多烯抗生素两性霉素B的单一疗法为主。临床治疗失败、副作用、缺乏替代药物以及该药物的毒性，都加剧了研发替代疗法的必要性，这些替代疗法包括氟康唑、伏立康唑和卡泊芬净。有观察发现，播散性念珠菌病的康复与针对47 kDa念珠菌热休克蛋白（HSP）90同源物的抗体反应有关，再加上能够对从感染中康复的患者的所有抗体进行测序，并在大肠杆菌中作为片段重新表达占主导地位的抗体，这开启了免疫治疗的可能性。首个针对念珠菌HSP90的重组抗体片段Mycograb（Neu Tec Pharma plc）目前正在欧洲和美国对播散性念珠菌病患者进行临床试验。实验室和早期临床数据支持Mycograb与两性霉素B协同作用的概念。这应该会改善治疗结果，并降低对任何一种药物产生耐药性的风险，同时不会增加毒性，因为对于代表患者康复后产生的天然抗体的人源抗体片段来说，毒性应该是最小的。
