20年磨一剑 首个口服抗肿瘤药成功研制

　　

生物通报道，来自中国科学院上海生物化与细胞研究所的吴祥甫研究员以及浙江大学博士生导师张耀洲教授等人在权威期刊《PLoS One》上发表20年研究所结的丰硕成果，Bioavailability of Orally Administered rhGM-CSF: A Single-Dose, Randomized, Open-Label, Two-Period Crossover Trial。

 

张耀洲，吴祥甫研究小组以家蚕为生物反应器，合成了能躲避消化酶的细胞因子口服剂，从而实现细胞因子的口服吸收。这一成果标志着细胞因子的肿瘤治疗应用前景将出现重大突破。  

 

巨噬细胞集落刺激因子（ＧＭ－ＣＳＦ），是人体自身具有的一种活性蛋白，具有激活人体肿瘤免疫功能，进而参与杀灭和控制肿瘤细胞，促进人体骨髓造血干细胞增生，治疗和预防放化疗引起的骨髓抑制、白细胞和血小板减少症等临床作用。  

 

据新华网的报道，以往若采用口服途径给药，细胞因子会因消化酶分解而失去活性，因而蛋白口服一直难以突破。采用家蚕作为生物反应器后，家蚕中含有的多种蛋白酶抑制剂及大量脂质成份与ＧＭ－ＣＳＦ形成“脂质包被”，能保护ＧＭ－ＣＳＦ“躲”过消化酶，帮助穿过肠壁，进入人体血液。在大鼠试验中，用高倍显微镜可以观察到这一吸收过程。在人体健康志愿者临床试验中，口服细胞因子组的血清中用质谱分析发现了特异波峰，这一波峰被证明是来源于口服的ＧＭ－ＣＳＦ活性肽段，这有力证明口服ＧＭ－ＣＳＦ能为人体有效吸收，并保留生物活性。在截至目前的临床试验中，这一方式还没有发现任何不良反应。  

 

 课题临床专家组成员、上海市肿瘤学会主任委员、上海长征医院肿瘤科主任王杰军教授说，这一重要发现对临床具有积极的现实意义。目前，肿瘤放化疗导致骨髓抑制的患者，只能通过注射细胞因子的方法来予以治疗，临床副作用较大，口服ＧＭ－ＣＳＦ将成为患者安全高效的新选择。

 

生物通推荐原文摘要：Bioavailability of Orally Administered rhGM-CSF: A Single-Dose, Randomized, Open-Label, Two-Period Crossover Trial

【Abstract】

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.