Improving tumor targeting and therapeutic potential of Salmonella VNP20009 by displaying cell surface CEA-specific antibodies
Improving tumor targeting and therapeutic potential of Salmonella VNP20009 by displaying cell surface CEA-specific antibodies
复制标题
DOI：
10.1016/j.vaccine.2007.03.008
复制
发表时间：
2007-05-22
期刊：
影响因子：
5.5
通讯作者：
Kaufman, Howard L.
中科院分区：
文献类型：
--
作者：
Bereta, Michal;Hayhurst, Andrew;Kaufman, Howard L.
转基因鼠伤寒沙门氏菌VNP20009（VNP）是一种用于癌症治疗和疫苗开发的有用载体，但在体内表现出有限的肿瘤靶向。我们设计了一种新的VNP衍生物，在细胞表面表达癌胚抗原（CEA）特异性单链抗体片段（scFv），以增加肿瘤特异性靶向。当用荧光标记的CEA探测细胞时，通过流式细胞术和共聚焦显微镜观察到显著的scFv细胞表面展示。对整个细菌的原子力显微镜（AFM）测量证实了未标记的CEA与所展示的scFv的结合。修饰的VNP菌株在CEA转基因小鼠的上消化道中表现出增加的定位，并在CEA表达肿瘤中积累。此外，单剂量VNP衍生物治疗可抑制MC38CEA肿瘤的生长，并与CD3（+）T细胞和CD11b（+）巨噬细胞的局部积聚有关。抗体片段在VNP表面上的展示代表了靶向CEA表达肿瘤和增加基于沙门氏菌的癌症疫苗的免疫原性的新策略。(c)2007爱思唯尔有限公司保留所有权利。
Genetically modified Salmonella typhimurium VNP20009 (VNP) is a useful vehicle for cancer therapy and vaccine development but exhibits limited tumor targeting in vivo. We engineered a novel VNP derivative that expressed carcinoembryonic antigen (CEA)-specific single chain antibody fragments (scFv) on the cell surface to increase tumor-specific targeting. There was significant scFv cell surface display visualized by flow cytometry and confocal microscopy when cells were probed with fluorescently labeled CEA. Atomic force microscopy (AFM) measurements on whole bacteria confirmed binding of unlabeled CEA to the displayed scFv. The modified VNP strain exhibited increased localization in the upper gastrointestinal tract of CEA transgenic mice and accumulated in CEA-expressing tumors. Furthermore, treatment with a single dose of the VNP derivative inhibited growth of MC38CEA tumors and was associated with local accumulation of CD3(+) T cells and CD11b(+) macrophages. The display of antibody fragments on the surface of VNP represents a novel strategy for both targeting CEA-expressing tumors and increasing the immunogenicity of Salmonella-based vaccines for cancer. (c) 2007 Elsevier Ltd. All rights reserved.