Sjögren H O, Isaksson M, Willner D, Hellström I, Hellström K E, Trail P A
Department of Cell and Molecular Biology, University of Lund, Sweden.
Cancer Res. 1997 Oct 15;57(20):4530-6.
The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen that is abundantly expressed on the surface of human carcinoma cells. BR96-DOX binds to RCA, a human colon carcinoma cell line, and BN7005, a transplantable colon carcinoma induced in a Brown Norway (BN) rat by 1,2-dimethyl-hydrazine. BR96-DOX produces cures of established s.c. RCA human colon carcinomas in athymic mice and rats. BR96-DOX also cured both s.c. and intrahepatic BN7005 tumors in immunocompetent BN rats. Unconjugated DOX, given at its maximum tolerated dose, and matching doses of nonbinding IgG-DOX conjugate were not active against RCA or BN7005 carcinomas. An anticonjugate antibody response was produced in BN rats treated with BR96-DOX. However, this could be largely prevented by administering the immunosuppressive drug deoxyspergualin. These results confirm the concept of antibody-directed therapy in models in which the targeted antigen is expressed both in normal tissues and tumors. The findings in BN7005 further demonstrate efficacy of BR96-DOX therapy in a model in which the tumor is syngeneic and the host is immunocompetent.
内化单克隆抗体BR96通过与阿霉素(DOX)形成酸不稳定腙键以及与单克隆抗体形成硫醚键,与抗癌药物阿霉素(DOX)偶联。所得偶联物称为BR96-DOX,它能与肿瘤相关的Lewis(y)抗原结合,该抗原在人癌细胞表面大量表达。BR96-DOX能与RCA(一种人结肠癌细胞系)以及BN7005(由1,2-二甲基肼在棕色挪威(BN)大鼠中诱导产生的可移植结肠癌)结合。BR96-DOX可治愈无胸腺小鼠和大鼠中已建立的皮下RCA人结肠癌。BR96-DOX还能治愈免疫功能正常的BN大鼠的皮下和肝内BN7005肿瘤。以最大耐受剂量给予的未偶联DOX以及匹配剂量的非结合IgG-DOX偶联物对RCA或BN7005癌均无活性。用BR96-DOX治疗的BN大鼠产生了抗偶联物抗体反应。然而,通过给予免疫抑制药物脱氧精胍菌素可在很大程度上预防这种情况。这些结果证实了在正常组织和肿瘤中均表达靶向抗原的模型中抗体导向治疗的概念。在BN7005中的发现进一步证明了BR96-DOX治疗在肿瘤是同基因且宿主具有免疫活性的模型中的疗效。