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巨噬細胞集落刺激因子（GM－CSF），是人體自身具有的一種活性蛋白，具有激活人體腫瘤免疫功能，進而參與殺滅和控制腫瘤細胞，促進人體骨髓造血干細胞增生，治療和預防放化療引起的骨髓抑制、白細胞和血小板減少癥等臨床作用。 以往若采用口服途徑給藥，細胞因子會因消化酶分解而失去活性，因而蛋白口服一直難以突破。中國科學院上海生物化與細胞研究所的吳祥甫研究員以及浙江大學博士生導師張耀洲教授等人采用家蠶作為生物反應器后，家蠶中含有的多種蛋白酶抑制劑及大量脂質成份與GM－CSF形成“脂質包被”，能保護GM－CSF“躲”過消化酶，幫助穿過腸壁，進入人體血液。在大鼠試驗中，用高倍顯微鏡可以觀察到這一吸收過程。在人體健康志愿者臨床試驗中，口服細胞因子組的血清中用質譜分析發現了特異波峰，這一波峰被證明是來源于口服的GM－CSF活性肽段，這有力證明口服GM－CSF能為人體有效吸收，并保留生物活性。在截至目前的臨床試驗中，這一方式還沒有發現任何不良反應。 課題臨床專家組成員、上海市腫瘤學會主任委員、上海長征醫院腫瘤科主任王杰軍教授說，這一重要發現對臨床具有積極的現實意義。目前，腫瘤放化療導致骨髓抑制的患者，只能通過注射細胞因子的方法來予以治療，臨床副作用較大，口服GM－CSF將成為患者安全高效的新選擇。 推薦原始出處： PLoS ONE 4(5): e5353. doi:10.1371/journal.pone.0005353 Bioavailability of Orally Administered rhGM-CSF: A Single-Dose, Randomized, Open-Label, Two-Period Crossover Trial Wenping Zhang1,2#, Zhengbing Lv2#, Zuoming Nie2, Guogang Chen3, Jian Chen2, Qing Sheng2, Wei Yu2, Yongfeng Jin1, Xiangfu Wu2,4, Yaozhou Zhang2* 1 Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China, 2 The Key Laboratory of Bioreactor and Biopharmacy of Zhejiang Province, Institute of Biochemistry, Zhejiang Sci-Tech University, Hangzhou, China, 3 Zhejiang Chinagene Biopharmaceutical Co., Ltd., Haining, China, 4 Institute of Biochemistry, the Chinese Academy of Sciences, Shanghai, China Background Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is usually administered by injection, and its oral administration in a clinical setting has been not yet reported. Here we demonstrate the bioavailability of orally administered rhGM-CSF in healthy volunteers. The rhGM-CSF was expressed in Bombyx mori expression system (BmrhGM-CSF). Methods and Findings Using a single-dose, randomized, open-label, two-period crossover clinical trial design, 19 healthy volunteers were orally administered with BmrhGM-CSF (8 μg/kg) and subcutaneously injected with rhGM-CSF (3.75 μg/kg) respectively. Serum samples were drawn at 0.0h, 0.5h ,0.75h,1.0h,1.5h,2.0h ,3.0h,4.0h,5.0h,6.0h,8.0h,10.0h and 12.0h after administrations. The hGM-CSF serum concentrations were determined by ELISA. The AUC was calculated using the trapezoid method. The relative bioavailability of BmrhGM-CSF was determined according to the AUC ratio of both orally administered and subcutaneously injected rhGM-CSF. Three volunteers were randomly selected from 15 orally administrated subjects with ELISA detectable values. Their serum samples at the 0.0h, 1.0h, 2.0h, 3.0h and 4.0h after the administrations were analyzed by Q-Trap MS/MS TOF. The different peaks were revealed by the spectrogram profile comparison of the 1.0h, 2.0h, 3.0h and 4.0h samples with that of the 0.0h sample, and further analyzed using both Enhanced Product Ion (EPI) scanning and Peptide Mass Fingerprinting Analysis. The rhGM-CSF was detected in the serum samples from 15 of 19 volunteers administrated with BmrhGM-CSF. Its bioavailability was observed at an average of 1.0%, with the highest of 3.1%. The rhGM-CSF peptide sequences in the serum samples were detected by MS analysis, and their sizes ranging from 2,039 to 7,336 Da. Conclusions The results demonstrated that the oral administered BmrhGM-CSF was absorbed into the blood. This study provides an approach for an oral administration of rhGM-CSF protein in clinical settings. (責任編輯：Doctor001) |
