重组人肿瘤坏死因子a衍生物3a研究的综合报告

Overall research on derivative3a of recombinant human tumor necrosis factor alpha

目的 :将采用点突变技术获取的重组人肿瘤坏死因子α衍生物 3a(rh- TNFα- D3a)研究开发为临床新药。方法 :与野生型 TNFα比较 ,采用动物体内抑瘤试验测定其 ED50 ;急性毒性试验测定 L D50 ;长期毒性试验测定安全剂量并观察毒性反应发生的程度 ; 期临床试验观察人体可耐受的安全剂量 ; - 期临床试验观察其对肿瘤患者的临床疗效。 结果 :rh- TNFα-D3a体内抑瘤的 ED50 为其野生型的 2 / 3;L D50 为野生型的 11倍 ;恒河猴长期毒性的安全剂量为日本同类产品 PT0 5 0的 6 4倍 ; 期临床试验表明 ,≤ 2× 10 6 IU/ (m2· d)× 7d为人体可耐受的安全剂量 ,本品与野生型药物比较 ,其毒性反应的发生率及反应程度远远降低 ; - 期临床试验表明 ,胸腔内注射对恶性胸水 ,静脉途径对多种实体瘤包括恶性淋巴瘤、乳腺癌、恶性黑素瘤和肾癌等均有较好的疗效。 结论 :研制新一代高效。

Objective:To obtain a recombinant hum an tumor necrosis factorα(rh- TNF- α) derivative with higher efficiency in anti- tum or activity and less toxicity via the substitution of its I→ S at position80 ,K→ H at90 and N→ V at92 . Methods:A TNFα m utant nom inated as rh- TNFα- D3a was tested for its tum or- growth inhibition(ED50 ) in a mice model, acute toxicity(L D50 ) in a mice m odel,safe dosage and toxic manifestations in a rhesus long- term toxicity model in comparison with its wild- type one.Determ ination of its tolerable dose was done in Phase clinical trial and its anti- tumor efficacy via Phase - trials in tumor patients.Results:Pre- clinical trials showed that its inhibition on tumor growth in vivo estimated by ED50 was2 / 3that of the wild- type,L D50 for m ice was about10 - fold higher that of the wild one,and the safe dosage evaluated from long- term toxicity to rhesus was6 4 - fold higher com pared with that of PT0 5 0 .Phase clinical trial indicated that≤ 2× 10 6 IU/ (m2· d)× 7d was its tolerable safe dose,and the concomitant toxicities exhibited were m uch less than its wild one either considering in frequency and severity as reported.Phase - trials suggested it was effective to malignant hydrothorax by intrathoracic injection,and to various solid tumors including m alignant lymphoma,breast cancer,malignant melanoma and renal carcinoma by intravenous injection.Conclusion:A novel tumor necrosis factor derivative with higher efficiency in anti- tum or activity and less toxicity is developed. [