胃癌单克隆抗体与丝裂霉素C交联物导向治疗研究──附3例临床初步试用报告

TARGETING CHEMOTHERAPY STUDY OF MITOMYCIN-C CONJUGATED WITH MONOCLONAL ANTIBODY AGAINST GASTRICCANCER-WITH A PRELIMINARY PHASE I TRIAL REPORT OF 3 CASES

本文报告采用活性酯方法制备了胃癌单克隆抗体３Ｈ１１与ＭＭＣ直接交联物３Ｈ１１－ＭＭＣ，又以ＳＰＤＰ为交联剂，人血清白蛋白（ＨＳＡ）为中间载体制备了间接交联物３Ｈ１１－ＨＳＡ－ＭＭＣ。３Ｈ１１与ＭＭＣ克分子比，前者为１∶７，后者为１∶４０，两者抗体活性均近完全保留，ＢＧＣ８２３体外细胞毒实验ＩＣ５０分别为０．７μｇ／ｍｌ及０．９μｇ／ｍｌ，游离ＭＭＣＩＣ５０为４．３μｇ／ｍｌ。裸鼠胃癌移植瘤抑制率两种交联物均为７１．４％，明显优于游离ＭＭＣ（４６．９％）及非特导性抗体交联物（４％）（Ｐ＜０．０１）。３例晚期及手术后复发胃癌病人接受８、１６ｍｇＭＭＣ量的３Ｈ１１－ＨＳＡ－ＭＭＣ治疗，副反应包括寒战、轻至中度发热及恶心、呕吐；２例肿瘤稳定，１例进展。２例血中检出抗鼠抗体（ＨＡＭＡ）。

Mitomycin C(MMC)was conjugated with a MAb against gastric cancer-3H11, with HSA as intermediate. The conjugate 3H11-HSA-MMC had a MMCto 3H11 molar ratio of 40∶1, which was 6 times higher than that of direct conjugate 3H11-MMC.Both conjugates retained the antibnody activity perfectly.In cytotoxicity assay on BGC 823 cell line,IC50 for 3H11-HSA-MMC and 3H11-MMC were 0.9μg/ml and 0.7μg/ml respectivily,whereas for MMC,4.3μg/ml. the results of tumor bearing nude mice treatment showed that the two type of conjugate could significantly inhibit tumor growth.Three pitients with advanced or refractory gastric cancer received 3H11-HSA-MMC.The total dosage of MMC equivalent range from 8mg to 16mg.Mild to moderate side effects include chills, fever, nausea and vomiting.Two patients had stable diseases,the other one had no clinical response.Of three patients, two had detectable human anti-mouse antibody response.