Yano S, Kaku S, Suzuki K, Terazaki C, Sakayori T, Kawasaki T, Kawamura K, Sugita Y, Hoshino K, Masuho Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba City, Japan.
Eur J Immunol. 1995 Nov;25(11):3128-33. doi: 10.1002/eji.1830251121.
A humanized monoclonal IgG1 antibody, designated hC4G1, recognizes the fibrinogen receptor glycoprotein (GP)IIb/IIIa on platelets and inhibits platelet aggregation. When the F(ab')2 fragment of hC4G1 (F(ab')2 hC4G1) was administered to cynomolgus monkeys, all the monkeys showed inhibition of platelet aggregation ex vivo. Unexpectedly, a significant decrease in platelet count was observed in 5 of 18 monkeys. Antibodies against F(ab')2 hC4G1 were detected in the plasma of these monkeys by ELISA. Antibody activity in the plasma of these monkeys was significantly correlated with the intensity of platelet decrease (r = 0.84). The natural monkey antibodies to F(ab')2 hC4G1 were directed against the C-terminal region of F(ab')2 fragment common to all human and humanized IgG antibodies. Natural homo-reactive antibodies were also detected in human plasma from 15 of 40 healthy volunteers. Specificity was closely similar to that of the monkey antibodies. Affinity-purified human homoreactive antibodies enhanced phagocytosis of platelets treated with the F(ab')2 hC4G1. Monkey plasma with high homo-reactive antibody activity was confirmed to decrease platelet count when administered together with F(ab')2 hC4G1 to a monkey with low antibody activity. These results suggest that F(ab')2 of humanized and human antibodies causes elimination of the corresponding antigens from the circulation by homo-reactive antibodies.
一种名为hC4G1的人源化单克隆IgG1抗体可识别血小板上的纤维蛋白原受体糖蛋白（GP）IIb/IIIa，并抑制血小板聚集。当将hC4G1的F(ab')2片段（F(ab')2 hC4G1）给予食蟹猴时，所有猴子的体外血小板聚集均受到抑制。出乎意料的是，18只猴子中有5只出现血小板计数显著下降。通过ELISA在这些猴子的血浆中检测到了针对F(ab')2 hC4G1的抗体。这些猴子血浆中的抗体活性与血小板减少的强度显著相关（r = 0.84）。食蟹猴针对F(ab')2 hC4G1的天然抗体针对的是所有人类和人源化IgG抗体共有的F(ab')2片段的C末端区域。在40名健康志愿者中的15人的人血浆中也检测到了天然的同种反应性抗体。其特异性与猴子抗体的特异性非常相似。亲和纯化的人同种反应性抗体增强了用F(ab')2 hC4G1处理的血小板的吞噬作用。当将具有高同种反应性抗体活性的猴子血浆与F(ab')2 hC4G1一起给予抗体活性低的猴子时，证实会降低血小板计数。这些结果表明，人源化抗体和人抗体的F(ab')2会通过同种反应性抗体导致相应抗原从循环中清除。
