Derbyshire E J, Wawrzynczak E J
Drug Targeting Laboratory, Institute of Cancer Research, Sutton, Surrey, UK.
Int J Cancer. 1992 Oct 21;52(4):624-30. doi: 10.1002/ijc.2910520422.
Monoclonal antibodies (MAbs) known to recognize epithelial mucin or defined carbohydrate structures present on mucin molecules were screened for their ability to form cytotoxic agents with ricin A-chain active against human small-cell lung cancer (SCLC) in an indirect assay of immunotoxin cytotoxicity. Anti-X hapten and anti-Y hapten antibodies binding to a high proportion of SCLC cells mediated only weak to moderate effects on 3H-leucine incorporation in combination with the screening agent, sheep anti-mouse IgG F'ab-ricin A-chain. In contrast, the mouse MAb BrE-3, recognizing the polypeptide core of the MUCI mucin gene product, exerted potent and selective cytotoxic effects in the assay. An immunotoxin made by the direct attachment of ricin A-chain to BrE-3 was selectively toxic to SCLC cell lines in tissue culture. The cytotoxic activity of BrE-3-ricin A-chain was enhanced 100-fold in the presence of monensin but not by lysosomotropic amines or calcium antagonists. Our findings suggest that anti-mucin immunotoxins may have a therapeutic role to play in the treatment of SCLC.
在免疫毒素细胞毒性的间接检测中，筛选了已知可识别上皮粘蛋白或粘蛋白分子上特定碳水化合物结构的单克隆抗体（MAb），以检测其与蓖麻毒素A链形成对人小细胞肺癌（SCLC）具有活性的细胞毒性剂的能力。与高比例SCLC细胞结合的抗X半抗原和抗Y半抗原抗体，与筛选剂羊抗小鼠IgG F'ab-蓖麻毒素A链联合使用时，对3H-亮氨酸掺入仅产生微弱至中等程度的影响。相比之下，识别MUCI粘蛋白基因产物多肽核心的小鼠MAb BrE-3在检测中表现出强大且选择性的细胞毒性作用。通过将蓖麻毒素A链直接连接到BrE-3上制备的免疫毒素在组织培养中对SCLC细胞系具有选择性毒性。在莫能菌素存在下，BrE-3-蓖麻毒素A链的细胞毒性活性增强了100倍，但溶酶体促渗胺或钙拮抗剂对其无增强作用。我们的研究结果表明，抗粘蛋白免疫毒素可能在SCLC的治疗中发挥治疗作用。
