Juhl H, Sievers M, Baltzer K, Helmig F, Wolf H, Brenner W, Kalthoff H
Klinik für Allgemeine Chirurgie und Thoraxchiururgie, Forschungsggruppe Molekulare Onkologie H. J., M. S., K. B., F. H., H. K, and Klinik fur Nuklearmedizin, Christian-Albrechts-Universität, Kiel, Germany.
Cancer Res. 1995 Dec 1;55(23 Suppl):5749s-5755s.
Monoclonal antibodies (mabs) have considerable potential for specific cancer treatment. However, due to the antigen heterogeneity and especially the low uptake in solid tumors, mabs have not been used successfully in most clinical trials to date. This study investigates the effects of a mab-cobra venom factor (CVF) conjugate in vitro and in vivo in an orthotopic pancreatic cancer model using nude rats. CVF, a nontoxic glycoprotein from cobra venom, permanently activates the alternative pathway of complement. Coupled to a mab with tumor-binding properties, the complement activation can be targeted to the tumor tissue. We studied the activity of a mab CA19-9-CVF conjugate with the human pancreatic cancer cells PancTu I. PancTu I cells express the complement resistance factors CD46, CD55, and CD59, as we demonstrated by immunostaining, an observation that may explain the lack of cytotoxicity of the CA19-9-CVF conjugate. However, using ELISA, Western blot, and immunostaining, we showed that CA19-9-CVF activates the complement cascade, including the release of the anaphylatoxin C3a, a mediator of an inflammatory reaction. The in vivo studies of CA19-9-CVF-treated nude rats showed an increased tumor infiltration by natural killer cells and macrophages. The tumor uptake of 99Tc-labeled anti-carcinoembryonic antigen antibody was increased approximately 2-fold in rats pretreated with 70 micrograms of CA19-9-CVF, compared to animals that received an equimolar mixture of noncoupled mab and CVF. This study indicates the value of mab-CVF conjugates in adjuvant immunotherapy. mab-CVF conjugates might be useful in pretargeting approaches by increasing the uptake of a therapeutic mab.
单克隆抗体（mabs）在特异性癌症治疗方面具有巨大潜力。然而，由于抗原异质性，尤其是实体瘤中摄取率低，单克隆抗体在迄今为止的大多数临床试验中尚未成功应用。本研究在使用裸鼠的原位胰腺癌模型中，研究了单克隆抗体-眼镜蛇毒因子（CVF）缀合物在体外和体内的作用。CVF是一种来自眼镜蛇毒的无毒糖蛋白，可永久激活补体替代途径。与具有肿瘤结合特性的单克隆抗体偶联后，补体激活可靶向肿瘤组织。我们研究了单克隆抗体CA19-9-CVF缀合物对人胰腺癌细胞PancTu I的活性。正如我们通过免疫染色所证明的，PancTu I细胞表达补体抗性因子CD46、CD55和CD59，这一观察结果可能解释了CA19-9-CVF缀合物缺乏细胞毒性的原因。然而，通过酶联免疫吸附测定（ELISA）、蛋白质印迹法和免疫染色，我们表明CA19-9-CVF激活补体级联反应，包括过敏毒素C3a的释放，C3a是炎症反应的介质。对CA19-9-CVF处理的裸鼠进行的体内研究表明，自然杀伤细胞和巨噬细胞对肿瘤的浸润增加。与接受等摩尔未偶联单克隆抗体和CVF混合物的动物相比，用70微克CA19-9-CVF预处理的大鼠中，99锝标记的抗癌胚抗原抗体的肿瘤摄取增加了约2倍。本研究表明单克隆抗体-CVF缀合物在辅助免疫治疗中的价值。单克隆抗体-CVF缀合物可能通过增加治疗性单克隆抗体的摄取而在预靶向方法中有用。
