Kato Chie, Kato Atsuhiko, Adachi Kenji, Fujii Etsuko, Isobe Kaori, Matsushita Tomochika, Watanabe Takeshi, Suzuki Masami
Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
J Toxicol Pathol. 2013 Mar;26(1):41-9. doi: 10.1293/tox.26.41. Epub 2013 Apr 22.
Some therapeutic antibodies as anticancer agents exert their effects through the host immune system, but the factors that predict their cytotoxicity, including complement-dependent cytotoxicity (CDC), are unclear. In the present study, we attempted to elucidate some of these factors in a preclinical model. CDC-related mesangiolysis caused by administration of the anti-Thy-1.1 antibody can be studied in the rat anti-Thy-1 glomerulonephritis model, so the model was used in this study. Three animals each were sacrificed at 0.5, 1, 8, 24 and 48 hours after i.v. administration of the anti-Thy-1.1 antibody at 1mg/kg. The distribution of the Thy-1.1 antigen and 2 membrane complement regulatory proteins (mCRPs), Crry and CD55, in three non-treated animals and the distribution of the injected antibody and C3 in the model was studied by immunohistochemistry. In the mesangial cells of the kidney, both expression of the antigen and distribution of the antibody with C3 deposition were observed with weak expression of mCRPs. There was also antigen and antibody distribution in the medullary cells of the adrenal gland and in the lymphocytes of the thymus but no C3 deposition, which was thought to be related to high expression of mCRPs. The antigen was observed in several other organs and tissues without distribution of the antibody. Cell death was only observed in the mesangial cells. These results clearly demonstrate that activation of CDC is regulated by several factors, such as distribution of the target molecule, antibody distribution and the balance among the molecules of the CDC cascade and mCRPs.
一些作为抗癌剂的治疗性抗体通过宿主免疫系统发挥作用，但预测其细胞毒性的因素，包括补体依赖性细胞毒性（CDC），尚不清楚。在本研究中，我们试图在临床前模型中阐明其中一些因素。由抗Thy-1.1抗体给药引起的与CDC相关的血管系膜溶解可在大鼠抗Thy-1肾小球肾炎模型中进行研究，因此本研究使用了该模型。以1mg/kg的剂量静脉注射抗Thy-1.1抗体后，在0.5、1、8、24和48小时分别处死三只动物。通过免疫组织化学研究了三只未处理动物中Thy-1.1抗原和两种膜补体调节蛋白（mCRP）Crry和CD55的分布，以及模型中注射抗体和C3的分布。在肾脏的系膜细胞中，观察到抗原表达以及抗体与C3沉积的分布，同时mCRP表达较弱。在肾上腺髓质细胞和胸腺淋巴细胞中也有抗原和抗体分布，但没有C3沉积，这被认为与mCRP的高表达有关。在其他几个器官和组织中观察到了抗原，但没有抗体分布。仅在系膜细胞中观察到细胞死亡。这些结果清楚地表明，CDC的激活受多种因素调节，如靶分子的分布、抗体分布以及CDC级联分子和mCRP之间的平衡。
