Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody
Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody
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DOI：
10.1016/j.ijrobp.2003.09.098
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发表时间：
2004-03-01
影响因子：
7
通讯作者：
Schwab, GM
中科院分区：
文献类型：
--
作者：
Foon, KA;Yang, XD;Schwab, GM
表皮生长因子受体（EGFR）是一种跨膜糖蛋白，具有细胞外配体结合结构域和细胞内酪氨酸激酶结构域。配体结合诱导EGFR二聚化和细胞内结构域中几个酪氨酸残基的自磷酸化，导致促有丝分裂信号转导。EGFR过表达与预后不良相关，并且通常与多种上皮癌的恶性转化相关。ABX-EGF是一种高亲和力（解离常数KD = 5 × 10（-11）M）的抗人EGFR的全人源IgG 2单克隆抗体。ABX-EGF结合EGFR并阻断EGF和转化生长因子-α的受体结合，抑制EGFR酪氨酸磷酸化和肿瘤细胞活化。ABX-EGF可预防肿瘤形成，并根除异种移植模型中已建立的大A431肿瘤。肿瘤生长抑制发生在相对低的剂量，没有伴随化疗或放疗。当与化疗药物组合时，ABX-EGF产生了额外的抗肿瘤活性。一项I期临床试验已经证明了它在几种肿瘤类型中的活性，而一项针对肾细胞癌的II期试验的结果也显示出适度的活性。治疗通常耐受良好，无统计学显著不良事件。EGFR的单克隆抗体阻断代表了癌症治疗的一个新的和令人兴奋的方向。(C)2004年爱思唯尔公司
The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, with an extracellular ligand-binding domain and intracellular tyrosine kinase domain. Ligand binding induces EGFR dimerization and autophosphorylation on several tyrosine residues in the intracellular domain, leading to mitogenic signal transduction. EGFR overexpression correlates with a poor prognosis and is often associated with malignant transformation in a variety of epithelial cancers. ABX-EGF is a high-affinity (dissociation constant K-D = 5 X 10(-11) M) fully human IgG2 monoclonal antibody against human EGFR. ABX-EGF binds EGFR and blocks receptor binding of EGF and transforming growth factor-alpha, inhibiting EGFR tyrosine phosphorylation and tumor cell activation. ABX-EGF prevents tumor formation and eradicates large, established A431 tumors in xenograft models. Tumor growth inhibition occurs at relatively low doses, without concomitant chemotherapy or radiotherapy. When combined with chemotherapeutic agents, ABX-EGF has resulted in additive antitumor activity. A Phase I clinical trial has demonstrated activity in several tumor types, and the results from a Phase II trial for renal cell cancer also showed modest activity. Therapy was generally well tolerated without statistically significant adverse events. Monoclonal antibody blockade of EGFR represents a new and exciting direction in cancer therapy. (C) 2004 Elsevier Inc.