MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors
MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors
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DOI：
10.1016/j.molimm.2005.07.034
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发表时间：
2006-03-01
影响因子：
3.6
通讯作者：
Baeuerle, PA
中科院分区：
文献类型：
--
作者：
Brischwein, K;Schlereth, B;Baeuerle, PA
我们已经开发了一种新的单链Ep-CAM-/CD 3-双特异性单链抗体构建体，命名为MT 110。MT 110重定向未刺激的人外周T细胞以诱导测试的每个表达Ep-CAM的肿瘤细胞系的特异性裂解。MT 110诱导了CD 4和CD 8阳性T细胞的共刺激非依赖性多克隆活化，如CD 69和CD 25的从头表达，以及干扰素γ、肿瘤坏死因子α和白细胞介素2、4和10的分泌所示。CD 8阳性T细胞对MT 110重定向的肿瘤细胞裂解做出了主要贡献。随着延迟，CD 4阳性细胞也可能有助于推测作为一个戏剧性的上调颗粒酶B表达的结果。MT 110在具有皮下生长的SW 480人结肠癌细胞的NOD/SCID小鼠模型中是高度有效的。在第0-4天，每天5次1 μ g MT 110剂量完全阻止了所有治疗小鼠的肿瘤生长。双特异性抗体构建体还导致在肿瘤接种后第8-12天用1 μ g剂量的MT 110处理的所有小鼠中建立的肿瘤的持久根除。最后，MT 110可以根除NOD/SCID小鼠皮肤下生长的患者来源的转移性卵巢癌组织。MT 110似乎是治疗人Ep-CAM过表达癌的有吸引力的双特异性抗体候选物。(c)2005爱思唯尔有限公司保留所有权利。
We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1 mu g MT110 on days 0-4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1 mu g doses of MT110 on days 8-12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas. (c) 2005 Elsevier Ltd. All rights reserved.