Mechanism of antitumor activity in mice for anti-epidermal growth factor receptor monoclonal antibodies with different isotypes.
Mechanism of antitumor activity in mice for anti-epidermal growth factor receptor monoclonal antibodies with different isotypes.
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发表时间：
1986-11
期刊：
影响因子：
11.2
通讯作者：
H. Masui;T. Moroyama;J. Mendelsohn
中科院分区：
文献类型：
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作者：
H. Masui;T. Moroyama;J. Mendelsohn
在以前的研究中，针对表皮生长因子（EGF）受体的单克隆抗体（mAb）的528 IgG2a和225 IgG1都显示出抑制A431细胞异种移植物在无胸腺小鼠中的生长。这两种单克隆抗体的抗肿瘤活性相似，虽然它们的同种型不同，但它们具有许多共同的特性。这两种单克隆抗体以相同的亲和力结合EGF受体，与EGF竞争结合EGF受体，下调受体相同，阻断EGF诱导的酪氨酸蛋白激酶活性活化至相当的程度，并阻断EGF诱导的培养细胞增殖变化。这些生理效应的相似性允许直接比较IgG 1和IgG 2a同种型mAb的作用机制。我们使用528个IgG2a和225个IgG1 mAb检测了对A431细胞的体外细胞毒性。通过51 Cr释放试验和培养的A431细胞的生长抑制，528 IgG2a（而非225 IgG1）表现出部分补体介导的细胞毒性。528 IgG2a，而不是225 IgG1，在活化的腹腔巨噬细胞存在下，对A431细胞具有细胞毒性，如通过释放掺入的[3H]胸苷所证明的。在含有K细胞的非粘附脾细胞存在下，两种mAb均未显示对A431细胞的任何显著细胞毒性。体外细胞毒实验结果表明，528 IgG2a的抗肿瘤活性可由巨噬细胞介导，而225 IgG1则不能。这通过体内实验证实，其中s.c.含有活化的巨噬细胞的肿瘤细胞接种物在用次优剂量的528 IgG 2a每周两次腹膜内处理3周的动物中显示出增强的抗肿瘤作用。当225 IgG 1用于相同的程序时，未观察到这种增强。这些实验的结果表明，涉及活化的巨噬细胞或补体的免疫机制可能有助于抗EGF受体mAb的抗肿瘤活性与IgG2a同种型，但不是与IgG1同种型。该观察结果证实了其他人在其他模型系统中检查IgG2a mAb抗肿瘤活性的结果。IgG1 mAb 225和可能的IgG2a mAb 528可能通过改变EGF受体的生理功能而不是通过免疫机制来预防人肿瘤异种移植物的生长。
In previous studies of monoclonal antibodies (mAbs) against the receptor for epidermal growth factor (EGF) both 528 IgG2a and 225 IgG1 were shown to inhibit growth of A431 cell xenografts in athymic mice. The antitumor activities of the two mAbs were similar and, although they differ in their isotypes, they share many properties. The two mAbs bind to EGF receptors with identical affinities, compete with EGF for binding to EGF receptors, down regulate the receptors identically, block EGF-induced activation of tyrosine protein kinase activity to a comparable degree, and block EGF-induced changes in the proliferation of cultured cells. These similarities in physiological effects permit a direct comparison of the mechanisms of action mAbs of the IgG1 and IgG2a isotypes. We examined in vitro cytotoxicity against A431 cells, using 528 IgG2a and 225 IgG1 mAbs. 528 IgG2a, but not 225 IgG1, demonstrated partial complement-mediated cytotoxicity by the 51Cr release assay and by growth inhibition of cultured A431 cells. 528 IgG2a, but not 225 IgG1, was cytotoxic to A431 cells in the presence of activated peritoneal macrophages, as demonstrated by release of incorporated [3H]thymidine. Neither mAb showed any significant cytotoxicity to A431 cells in the presence of nonadherent spleen cells which contain K-cells. The results of in vitro cytotoxicity experiments suggested that the antitumor activity of 528 IgG2a, but not 225 IgG1, could be mediated by macrophages. This was verified by in vivo experiments in which s.c. tumor cell inocula containing activated macrophages showed enhancement of antitumor effects in animals treated i.p. twice weekly for 3 weeks with suboptimal doses of 528 IgG2a. This enhancement was not observed when 225 IgG1 was used with the same procedure. The results of these experiments suggest that immune mechanisms involving activated macrophages or complement could contribute to the antitumor activity of anti-EGF receptor mAb with the IgG2a isotype, but not with the IgG1 isotype. This observation confirms the findings of others who examined the antitumor activity of IgG2a mAbs in other model systems. IgG1 mAb 225, and possibly IgG2a mAb 528, may prevent growth of human tumor xenografts by altering the physiological functions of the EGF receptor rather than by immune mechanisms.