Anti body-mediated EGF receptor blockade as an anticancer therapy: from the laboratory to the clinic
Anti body-mediated EGF receptor blockade as an anticancer therapy: from the laboratory to the clinic
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DOI：
10.1007/s00262-002-0354-7
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发表时间：
2003-05-01
影响因子：
5.8
通讯作者：
Mendelsohn, J
中科院分区：
文献类型：
--
作者：
Mendelsohn, J
单克隆抗体（mAb）治疗的最初研究主要集中在抗体作为免疫和炎症反应的激活剂，或抗体作为毒素和放射性核素的载体。我们的实验室是最早假设单克隆抗体可用于阻断其抗原的生理活性的实验室之一[1，2]。Gordon Sato博士和我选择EGF受体作为我们将要研究的靶抗原，这是基于最近证实的这种受体在调节细胞增殖中的重要性，以及自身抗体通过阻断某些受体的功能而引起疾病的能力的临床知识。这是值得回顾的理由选择EGF受体，这是令人信服的。到1980年，斯坦利·科恩博士的工作，导致他被授予诺贝尔生理学和医学奖，导致了EGF受体及其配体EGF的纯化，沿着激活受体在刺激细胞增殖中的功能的证明[3，4]。科恩和其他人的工作表明，该受体是一种跨膜分子，具有结合生长因子的细胞外部分，跨膜连接器和可以激活分子信号通路的细胞内部分，从而导致细胞周期穿越。到了1980年，Sato博士及其同事的工作清楚地表明，通过添加适当的生长因子和转运蛋白的混合物，可以避免细胞培养中对血清的需求[5]。在20世纪80年代早期，许多实验室的工作表明，src癌基因和活化的EGF受体具有催化细胞表面酪氨酸残基磷酸化的不寻常的酶性质。靶蛋白，表明受体与一个充分表征的癌基因共享一个重要特性[6，7，8]。
Initial investigation of therapy with monoclonal antibodies (mAb) was focused primarily on antibodies as activators of immune and inflammatory responses, or antibodies as carriers of toxins and radionuclides. Our laboratory was among those which first postulated that a mAb might be used to block the physiologic activity of its antigen [1, 2]. Dr. Gordon Sato and I selected the EGF receptor as the target antigen we would study, based on the recently demonstrated importance of this receptor in regulating cell proliferation, and clinical knowledge of the capacity of autoantibodies to cause disease by blocking the function of certain receptors. It is worthwhile reviewing the rationale for selecting the EGF receptor, which was compelling. By 1980, the work Dr. Stanley Cohen, which led to his being awarded the Nobel Prize in physiology and medicine, had resulted in the purification of both the EGF receptor and its ligand, EGF, along with demonstration of the function of the activated receptor in stimulating cell proliferation [3, 4]. The work of Cohen and others showed that the receptor was a transmembrane molecule, with an extracellular portion that binds the growth factor, a transmembrane connector, and an intracellular portion that could activate molecular signaling pathways leading to cell cycle traversal. By 1980, the work of Dr. Sato and colleagues had clearly demonstrated that the requirement for serum in cell culture could be obviated by addition of an appropriate cocktail of growth factors and transport proteins [5].In the early 1980s work from a number of laboratories demonstrated that the src oncogene and the activated EGF receptor shared the unusual enzymatic property of catalyzing phosphorylation of tyrosine residues on target proteins, showing that the receptor shared an important property with a well-characterized oncogene [6, 7, 8].