Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma
Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma
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DOI：
10.1073/pnas.1219817110
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发表时间：
2013-01-02
影响因子：
11.1
通讯作者：
Sampson, John H.
中科院分区：
文献类型：
--
作者：
Choi, Bryan D.;Kuan, Chien-Tsun;Sampson, John H.
双特异性抗体（bscAb），特别是双特异性T细胞粘附分子（BiTE）亚类的那些，已经显示出有效地重定向T细胞对抗癌症。然而，先前针对肿瘤和正常组织中表达的抗原的努力产生了显著的毒性。此外，像其他大分子一样，bscAb可能被限制进入“免疫特权”CNS。表皮生长因子受体EGFRvIII的肿瘤特异性突变是一种组成型激活的酪氨酸激酶，在正常组织中未发现，但经常在胶质母细胞瘤和许多其他肿瘤中表达。由于EGFRvIII仅定位于肿瘤组织，因此它是免疫治疗的理想靶点。在这里，我们报告了EGFRvIII靶向BiTE，bscEGFRvIIIxCD 3的临床前评价。我们的研究结果表明，bscEGFRvIIIxCD 3在极低浓度（10 ng/mL）和效靶比（2.5：1）下激活T细胞，以介导体外表达EGFRvIII的胶质瘤的有效和抗原特异性裂解（P < 0.001）。静脉注射bscEGFRvIIIxCD 3治疗可延长脑内肿瘤小鼠的生存期（P < 0.05），并可达到75%的持久完全治愈率。抗肿瘤功效在阻断EGFRvIII结合时显著消除，证明体外和体内均需要靶抗原特异性。这些结果表明，BiTE可用于引发CNS中的功能性抗肿瘤免疫，并且BiTE介导的活性的肽阻断可大大增强抗体重定向T细胞疗法的安全性。最后，bscEGFRvIIIxCD 3代表了BiTE技术的独特进步，因为它具有精致的肿瘤特异性，可以精确消除癌症，而没有自身免疫毒性的风险。
Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the "immunologically privileged" CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity.