Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors
Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors
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DOI：
10.1073/pnas.130166597
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发表时间：
2000-06-20
影响因子：
11.1
通讯作者：
Bigner, DD
中科院分区：
文献类型：
--
作者：
Sampson, JH;Crotty, LE;Bigner, DD
表皮生长因子受体（EGFR）经常在脑、乳腺、肺和卵巢肿瘤中扩增和结构重排。最常见的突变EGFRvIII的特征在于801个碱基对的框内缺失，导致在融合连接处产生新的肿瘤特异性表位。产生人EGFRvIII突变的鼠同源物，并产生识别该肿瘤特异性抗原的人和鼠等效物的IgG 2a鼠mAb Y10。在体外，发现Y10抑制DNA合成和细胞增殖，并诱导自主的，补体介导的，抗体依赖性细胞介导的细胞毒性。i. p. Y10皮下注射全身给药转染稳定表达鼠EGFRvIII的B16黑色素瘤导致所有治疗小鼠的长期存活（n = 20; P < 0.001）。i. p. Y10的类似治疗未能增加脑中表达EGFRvIII的B16黑色素瘤小鼠的中位生存期;然而，单次瘤内注射Y10的治疗使中位生存期平均增加286%，其中26%为长期存活者（n = 117; P < 0.001）。通过体内补体和细胞亚群耗竭，证明Y10的体内作用机制不依赖于补体、粒细胞、自然杀伤细胞和T淋巴细胞。在Fc受体敲除小鼠中用Y10处理证明了Y10的机制是Fe受体依赖性的。这些数据表明，非武装，肿瘤特异性单克隆抗体可能是一种有效的免疫疗法，对人类肿瘤和潜在的其他病理过程中的“免疫特权”中枢神经系统。
The epidermal growth factor receptor (EGFR) is often amplified and rearranged structurally in tumors of the brain, breast, lung, and ovary. The most common mutation, EGFRvIII, is characterized by an in-frame deletion of 801 base pairs, resulting in the generation of a novel tumor-specific epitope at the fusion junction. A murine homologue of the human EGFRvIII mutation was created, and an IgG2a murine mAb, Y10, was generated that recognizes the human and murine equivalents of this tumor-specific antigen. In vitro, Y10 was found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibody-dependent cell-mediated cytotoxicity. Systemic treatment with i.p. Y10 of s.c. B16 melanomas transfected to express stably the murine EGFRvIII led to long-term survival in all mice treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to increase median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 increased median survival by an average 286%, with 26% long-term survivors (n = 117; P < 0.001). The mechanism of action of Y10 in vivo was shown to be independent of complement, granulocytes, natural killer cells, and T lymphocytes through in vivo complement and cell subset depletions. Treatment with Y10 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fe receptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially other pathologic processes in the "immunologically privileged" central nervous system.