Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens.
Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens.
复制标题
单克隆抗体抗 APO-1 类转换变体诱导细胞凋亡依赖于 APO-1 细胞表面抗原的交联。
DOI：
10.4049/jimmunol.149.10.3166
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发表时间：
1992
影响因子：
4.4
通讯作者：
Peter H. Krammer
中科院分区：
文献类型：
--
作者：
J. Dhein;Peter T. Daniel;B. Trauth;A. Oehm;P. Möller;Peter H. Krammer
细胞凋亡，程序性细胞死亡，以前被证明是由单克隆抗体抗APO-1（IgG 3，κ）通过结合到APO-1细胞表面Ag，神经生长因子/TNF受体超家族的新成员诱导。为了研究IG H链Fc区的作用，我们比较了原始mAb IgG 3抗APO-1与抗APO-1 F（ab '）2片段和不同抗APO-1同种型（IgG 1、IgG 2b、IgG 2a和伊加）通过连续传代分离的细胞凋亡诱导。我们发现IgG 3是最活跃的同种型; IgG 1、IgG 2a和伊加显示中等活性，IgG 2b和F（ab '）2无活性。分别用蛋白A、抗小鼠IG或抗小鼠IG F（ab '）2完全重建无活性或活性较低的抗体制剂的细胞毒性活性。因此，APO-1介导的细胞凋亡诱导依赖于APO-1细胞表面Ag的有效交联，并通过抗APO-1 Fc-Fc自聚集间接增强。由于其不同的体外活性，我们选择IgG 3-、IgG 2 B-和伊加抗APO-1来测试它们对SCID小鼠中实体人B淋巴母细胞样肿瘤的抗肿瘤活性。同种型显示出不同的血清半衰期（IgG 3：9.2-10.4天，IgG 2b：1.9-2.6天，伊加：14.1-29.2小时）和腹膜内注射后4小时不同的初始肿瘤定位（IgG 3在血管周围，IgG 2b均匀分布，伊加在肿瘤中不均匀分布）。所有抗体制剂均通过诱导细胞凋亡诱导肿瘤消退，甚至IgG 2b抗APO-1在体外无交联无活性。伊加抗APO-1的活性不介导补体依赖性细胞毒性或抗体依赖性细胞毒性，表明细胞凋亡可用作体内诱导肿瘤消退的主要机制（如果不是唯一机制的话）。与体外一样，IgG 3抗APO-1在体内也是最有效的同种型。该结果表明，肿瘤细胞表面上的APO-1的交联也可能是体内通过细胞凋亡的肿瘤消退所需的。总之，我们的数据表明，选择性靶向肿瘤细胞凋亡可能是一种有效的抗肿瘤机制。
Apoptosis, programmed cell death, was previously shown to be induced by the mAb anti-APO-1 (IgG3, kappa) by binding to the APO-1 cell surface Ag, a new member of the nerve growth factor/TNF receptor superfamily. To investigate the role of the Ig H chain Fc regions we compared induction of apoptosis by the original mAb IgG3 anti-APO-1 with anti-APO-1 F(ab')2 fragments and different anti-APO-1 isotypes (IgG1, IgG2b, IgG2a, and IgA) isolated by sequential sublining. We found that IgG3 was the most active isotype; IgG1, IgG2a, and IgA showed intermediate activity, and IgG2b and F(ab')2 were inactive. Cytotoxic activity of the inactive or less active antibody preparations was fully reconstituted by protein A, anti-mouse Ig, or anti-mouse Ig F(ab')2, respectively. Thus, APO-1-mediated induction of apoptosis was dependent on efficient cross-linking of APO-1 cell surface Ag, indirectly augmented by anti-APO-1 Fc-Fc self-aggregation. Because of their different in vitro activity we selected IgG3-, IgG2b-, and IgA anti-APO-1 to test their antitumor activity against solid human B lymphoblastoid tumors in SCID mice. The isotypes showed a different serum half-life (IgG3: 9.2-10.4 days, IgG2b: 1.9-2.6 days, and IgA: 14.1-29.2 h) and a different initial tumor localization 4 h after i.p. injection (IgG3 around the blood vessels, IgG2b homogeneously, and IgA heterogeneously distributed in the tumor). All antibody preparations induced tumor regression by induction of apoptosis, even IgG2b anti-APO-1 inactive in vitro without cross-linking. The activity of IgA anti-APO-1, which did not mediate complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity indicates that apoptosis may be used as the main if not the only mechanism of induction of tumor regression in vivo. As with in vitro, IgG3 anti-APO-1 was the most effective isotype also in vivo. This result suggests that cross-linking of APO-1 on the tumor cell surface may also be required for tumor regression by apoptosis in vivo. Taken together, our data show that selective targeting of apoptosis to tumors may be an efficient antitumor mechanism.