重组人促黄体激素释放激素-绿脓杆菌外毒素A融合蛋白Ⅰ期人体耐受性临床研究  

Phase I clinical trial of lyophilized recombinant human luteinizing hormone releasing hormone-exotoxin of pseudomonas aeruginosa fusion protein

作　　者：周爱萍[1] 杜春霞[1] 刘鹏[1] 孙永琨[1] 吴广谋 朱平 王金万[1] 

机构地区：[1]中国医学科学院肿瘤医院内科,北京100021 [2]长春基因药物工程研究所,长春130062

出　　处：《中国新药杂志》2011年第17期1683-1687,共5页Chinese Journal of New Drugs

摘　　要：目的:考察人体对冻干重组人促黄体激素释放激素-绿脓杆菌外毒素A融合蛋白(lyophilizedrecombinant human luteinizing hormone releasing hormone-exotoxin of pseudomonas aeruginosa fusion protein,简称LHRH-PE40)的耐受性、最大耐受剂量(MTD)和药代动力学特点,以及人体对LHRH-PE40产生抗体的规律,并初步观察LHRH-PE40的抗肿瘤活性。方法:LHRH-PE40经静脉输注给药。单次给药试验共10例患者接受单剂LHRH-PE40治疗,剂量范围为220～1 110μg.m-2。每日给药试验14例患者接受LHRH-PE40输注每日1次,连用14 d,剂量范围120～600μg.m-2;隔日给药试验共7例患者接受LHRH-PE40输注隔日1次,共14次,剂量为600和700μg.m-2。结果:每日给药方法的MTD为400μg.m-2,剂量限制性毒性为乏力、食欲下降和肾功能损害。肾功能损害为一过性和可逆的。隔日给药方法的MTD为600μg.m-2。在MTD剂量时,LHRH-PE40的一般不良反应包括乏力、食欲下降、疼痛、发热、头疼头晕、过敏反应、恶心/呕吐、胃黏膜炎、手足麻木和心悸,大多为1/2度。对肝功能影响较小,对血液学无抑制作用。机体存在对LHRH-PE40的基础抗体,滴度23～25,治疗后抗体滴度可上升至210～212。1例卵巢癌患者CA125下降了620 U.mL-1。结论:在MTD剂量时,LHRH-PE40的不良反应温和可控。对卵巢癌可能有一定的抗肿瘤活性,值得进一步研究。Ib和Ⅱ期研究中应考察抗体对疗效和药代动力学的影响。Objective： To determine the safety, pharmacokinetics combinant human luteinizing hormone releasing hormone-exotoxin of and recommended dose of lyophilized repseudomonas aeruginosa fusion protein （LHRH-PE40） , a novel chimeric toxin, in patients with malignancies. The secondary endpoint is to evaluate how human produce antibody to LHRH-PE40. Methods： LHRH-PE40 was administered by intravenous infusion. Ten patients received 220 -1110μg·m^-2 of LHRH-PE40 as a single dose. Fourteen patients received doses ranging from 120 to 600 μg·m^-2 given once a day for consecutive 14 days. Seven patients received 600 or 700 μg·m^-2 once every 2 days for 14 doses. Results： The MTD of LHRH-PE40 when given once a day for 14 days was 400 -2 Ixg＂ m with the dose-limiting toxicity being grade III asthenia, grade III anorexia and acute renal dysfunction. The renal dysfunction was transient and reversible. The MTD of LHRH-PE40 when given once every 2 days for 14 doses was 600 μg·m^-2 The common adverse events at the MTD included fatigue, anorxia, pain, fever, headache, aller-gic reaction, nausea/vomiting, and gastric mucosities. LHRH-PE40 showed no heamotologic toxicity and a mild impact on liver function. Antibodies against LHRH-PE40 were detected in patients at baseline and found to be elevated during treatment. One advanced ovarian cancer patient had a decline of CA125 by 620 U·mL-1. Conclusion： LHRH-PE40 displays mild and manageable toxicity at MTD. LHRH-PE40 might have antitumor activities in ovarian cancer which warrants further investigation. The clinical relevance of antibody needs further illustration.

关 键 词：重组人促黄体激素释放激素-绿脓杆菌外毒素A融合蛋白 Ⅰ期临床试验 剂量限制性毒性 最大耐受剂量 

分 类 号：R979.1[医药卫生—药品] R969.4[医药卫生—药学]