A Human Antibody-Drug Conjugate Targeting EphA2 Inhibits Tumor Growth In vivo
A Human Antibody-Drug Conjugate Targeting EphA2 Inhibits Tumor Growth In vivo
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DOI：
10.1158/0008-5472.can-08-1933
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Tice, David A.
中科院分区：
文献类型：
--
作者：
Jackson, Dowdy;Gooya, John;Tice, David A.
EphA 2受体酪氨酸激酶在许多不同的人类肿瘤表面上选择性表达。我们先前已经表明，肿瘤细胞可以通过EphA 2单克隆抗体靶向，并且这些抗体部分地通过诱导EphA 2内化和降解来发挥作用。在这份报告中，我们描述了选择性结合人类和啮齿动物EphA 2受体的全人单克隆抗体（1C 1）的分离和表征。在细胞结合后，抗体诱导EphA 2受体的快速酪氨酸磷酸化、内化和降解。由于选择性结合肿瘤细胞并内化的单克隆抗体提供了细胞毒素靶向递送的载体，因此使用稳定的马来酰亚胺基己酰基接头将1C 1与微管抑制剂monomethyauristatin苯丙氨酸缀合。抗EphA 2抗体-药物缀合物[1C 1-马来酰亚胺基己酰基-MMAF（mcMMAF）]刺激半胱天冬酶-3/半胱天冬酶-7的活化和表达EphA 2的细胞的死亡，IC 50值低至3 ng/mL。类似地，缀合物诱导EphA 2受体的降解并抑制体内肿瘤生长。以低至1 mg/kg的剂量每周一次给予1C 1-mcMMAF导致表达EphA 2的肿瘤的显著生长抑制，而在小鼠异种移植物和大鼠同基因肿瘤模型中没有任何可观察到的副作用。我们的数据支持使用抗体-药物缀合物方法来选择性地靶向和抑制表达EphA 2的肿瘤的生长。[Cancer Res 2008;68（22）：9367-74]
The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by EphA2 monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. In this report, we describe the isolation and characterization of a fully human monoclonal antibody (1C1) that selectively binds both the human and rodent EphA2 receptor. After cell binding, the antibody induces rapid tyrosine phosphorylation, internalization, and degradation of the EphA2 receptor. Because monoclonal antibodies that selectively bind tumor cells and internalize provide a vehicle for targeted delivery of cytotoxics, 1C1 was conjugated to the microtubule inhibitor monomethylauristatin phenylalanine using a stable maleimidocaproyl linker. The anti-EphA2 antibody-drug conjugate [1C1-maleimidocaproyl-MMAF (mcMMAF)] stimulated the activation of caspase-3/caspase-7 and the death of EphA2-expressing cells with IC50 values as low as 3 ng/mL. Similarly, the conjugate induced degradation of the EphA2 receptor and inhibited tumor growth in vivo. Administration of 1C1-mcMMAF at doses as low as 1 mg/kg once weekly resulted in significant growth inhibition of EphA2-expressing tumors without any observable adverse effects in mouse xenograft and rat syngeneic tumor models. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of EphA2-expressing tumors. [Cancer Res 2008;68(22):9367-74]