Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2
Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2
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DOI：
10.1073/pnas.1313857110
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发表时间：
2013-09-17
影响因子：
11.1
通讯作者：
Sela, Michael
中科院分区：
文献类型：
--
作者：
Maron, Ruth;Schechter, Bilha;Sela, Michael
由于其固有的侵袭性和缺乏有效的治疗方法，胰腺癌的预后仍然令人沮丧。由于唯一被批准用于胰腺导管腺癌的分子靶向药物是表皮生长因子受体（EGFR）特异性的激酶抑制剂，并且该受体与另一种称为HER2（人类egf受体2）的激酶协同作用，我们假设靶向EGFR和/或HER2的药物将有效延缓胰腺导管腺癌。因此，在动物模型中测试了两种免疫策略：(i)两种能够结合EGFR或HER2不同表位的抗体分别组合，以及（ii）一种针对EGFR和另一种针对HER2的抗体对。不同于各自单克隆抗体的弱效应，两种类型的抗体组合在动物实验中具有协同抑制肿瘤的作用。免疫合作可能不依赖于受体密度、抗原位点或突变RAS蛋白的存在。然而，两种类型的抗体组合都增强了受体的降解。未来的努力将检查每种策略的可行性和结合它们实现持续肿瘤抑制的潜力。
Due to intrinsic aggressiveness and lack of effective therapies, prognosis of pancreatic cancer remains dismal. Because the only molecular targeted drug approved for pancreatic ductal adenocarcinoma is a kinase inhibitor specific to the epidermal growth factor receptor (EGFR), and this receptor collaborates with another kinase, called HER2 (human EGF-receptor 2), we assumed that agents targeting EGFR and/or HER2 would effectively retard pancreatic ductal adenocarcinoma. Accordingly, two immunological strategies were tested in animal models: (i) two antibodies able to engage distinct epitopes of either EGFR or HER2 were separately combined, and (ii) pairs of one antibody to EGFR and another to HER2. Unlike the respective single monoclonal antibodies, which induced weak effects, both types of antibody combinations synergized in animals in terms of tumor inhibition. Immunological cooperation may not depend on receptor density, antigenic sites, or the presence of a mutant RAS protein. Nevertheless, both types of antibody combinations enhanced receptor degradation. Future efforts will examine the feasibility of each strategy and the potential of combining them to achieve sustained tumor inhibition.