Immunotargeting Chemotherapy of Gastrointestinal Carcinoma using Monoclonal Antibody-Drug Conjugates

根据实验研究，单克隆抗体-药物偶联物被应用于结直肠癌患者的临床试验。从小鼠脾细胞中提取抗人结肠癌的单克隆抗体A7作为结肠癌的药物载体。抗癌药物丝裂霉素C（MMC）和新羧抑素（NCS）与A7共价结合，由A7-MMC和A7-NCS结合而成。对SW1116的体外细胞毒作用强于对游离MMC和NCS的体外细胞毒作用。偶联物A7-NCS在裸鼠体内的肿瘤浓度最高，而正常免疫球蛋白G (IgG)-NCS在各组织中分布均匀，偶联物对移植到裸鼠体内的结肠癌具有较强的抗肿瘤作用。41例结直肠癌患者接受A7-NCS治疗，其中10例有术后转移。切除标本的免疫过氧化物酶和药物浓度研究表明，NCS特异性定位于肿瘤。接受该结合物的患者没有出现严重的不良反应。在8例术后肝转移患者中，3例在计算机断层扫描（CT）上显示肿瘤缩小的证据，3例声称疼痛减轻。该结合物对多发性肺转移或腹膜转移患者无效。

Monoclonal antibody-drug coujugates were applied as a clinical trial for patients who,based on the experimental study,had colorectal cancer. Monoclonal antibody A7, from a mouse splenocyte immunized against human colon cancer,was used as a drug carrier for colon cancer. The anti-cancer drugs mitomycin C(MMC)and neocarzinostatin (NCS)were bound covalently to A7 to from the conjagates A7-MMC and A7-NCS. The in vitro cytotoxic effects of the conjugates on SW1116 were stronger than those on free MMC or NCS. The conjugate A7-NCS, when administered to nude nice, brought about the highest NCS tumor concentration, whereas normal immunoglogulin G (IgG)-NCS distributed evenly in all tissues The conjugates showed a strong antitumor effect on colon cancer transplanted into nude mice. Forty-one patients with colorectal cancer, including ten patients with postoperative metastasis, were given A7-NCS. The immunoperoxidase and drug concentration studies of the resected specimens showed that NCS was localized specifically in cancer. Patients receiving the conjugate did not experience serious adverse effects. Of the eight patients with postoperative liver metastasis, three showed evidence of tumor reduction on computed tomograghy (CT)scan and three claimed pain felief. The conjugate did not benefit patients with multiple lung metastasis or peritoneal metastasis.