Krinner Eva-Maria, Raum Tobias, Petsch Silke, Bruckmaier Sandra, Schuster Ioana, Petersen Laetitia, Cierpka Ronny, Abebe Derege, Mølhøj Michael, Wolf Andreas, Sørensen Poul, Locher Mathias, Baeuerle Patrick A, Hepp Julia
Micromet AG, Staffelseestr. 2, D 81477 Munich, Germany.
Mol Immunol. 2007 Feb;44(5):916-25. doi: 10.1016/j.molimm.2006.03.020. Epub 2006 May 11.
The pro-inflammatory cytokine GM-CSF is aberrantly produced in many autoimmune and chronic inflammatory human diseases. GM-CSF neutralization by antibodies has been shown to have a profound therapeutic effect in animal models of rheumatoid arthritis, inflammatory lung diseases, psoriasis and multiple sclerosis. Moreover, the absence of GM-CSF in null mutant mice ameliorates or prevents certain of these diseases. Here we describe the biophysical and biological properties of a human anti-GM-CSF IgG1 antibody designated MT203, which was derived by phage display guided selection. MT203 bound with picomolar affinity to an epitope on human and macaque GM-CSF involved in high-affinity receptor interaction. As a consequence, the antibody potently prevented both GM-CSF-induced proliferation of TF-1 cells with a sub-nanomolar IC50 value and the production of the chemokine IL-8 by U937 cells. MT203 neutralized equally well recombinant (r) human (h) GM-CSF from Escherichia coli and yeast, and also normally glycosylated GM-CSF secreted by human lung epithelial cells in response to IL-1beta stimulation. Furthermore, MT203 significantly reduced both survival and activation of peripheral human eosinophils as may be required for effective treatment of inflammatory lung diseases. The antibody did not show a detectable loss of neutralizing activity after 5 days in human serum at 37 degrees C. Based on its favorable properties, MT203 has been selected for development as a novel anti-inflammatory human monoclonal antibody with therapeutic potential in a multitude of human autoimmune and inflammatory diseases.
促炎细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）在许多人类自身免疫性疾病和慢性炎症性疾病中异常产生。在类风湿性关节炎、炎性肺病、银屑病和多发性硬化症的动物模型中，抗体对GM-CSF的中和作用已显示出具有深远的治疗效果。此外，GM-CSF基因敲除小鼠缺乏GM-CSF可改善或预防其中某些疾病。在此，我们描述了一种名为MT203的人抗GM-CSF IgG1抗体的生物物理和生物学特性，该抗体是通过噬菌体展示引导筛选获得的。MT203以皮摩尔亲和力与人及猕猴GM-CSF上参与高亲和力受体相互作用的表位结合。因此，该抗体能有效阻止GM-CSF诱导的TF-1细胞增殖，其IC50值低于纳摩尔，同时也能阻止U937细胞产生趋化因子IL-8。MT203对来自大肠杆菌和酵母的重组人GM-CSF以及人肺上皮细胞在IL-1β刺激下分泌的正常糖基化GM-CSF具有同等良好的中和作用。此外，MT203可显著降低外周血人嗜酸性粒细胞的存活和活化，这可能是炎性肺病有效治疗所必需的。该抗体在37℃的人血清中放置5天后未显示出可检测到的中和活性丧失。基于其良好的特性，MT203已被选定开发为一种新型抗炎人单克隆抗体，在多种人类自身免疫性疾病和炎性疾病中具有治疗潜力。
