Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen.
Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen.
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DOI：
10.1054/bjoc.2001.1891
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发表时间：
2001-07-06
影响因子：
8.8
通讯作者：
Dohlsten, M
中科院分区：
文献类型：
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作者：
Forsberg, G;Ohlsson, L;Brodin, T;Bjork, P;Lando, P A;Shaw, D;Stern, P L;Dohlsten, M
超抗原通过将T细胞受体连接至抗原呈递细胞上的MHC II类来激活T细胞，并且可以通过将超抗原融合至靶向分子来引入新的反应性。因此，一种抗体靶向的超抗原，可以激活T细胞摧毁肿瘤细胞，可能被用作癌症治疗。合适的靶点是5 T4癌胚抗原，其在许多癌上表达。我们从识别5 T4抗原的单克隆抗体的Fab和工程化超抗原构建了融合蛋白。重组产物5 T4 FabV 13-SEAD 227 A以1.2 nM的Kd结合在人非小细胞肺癌细胞系Calu-1上表达的5 T4抗原，而超抗原部分中的Asp 227替换为Ala降低了对MHC II类的结合活性。通过免疫组织化学在7/7个NSCLC样品中证实了5 T4 FabV 13-SEAD 227 A肿瘤反应性，而正常组织反应性为低至中度。5 T4 FabV 13-SEAD 227 A诱导了对敏感的5 T4携带Calu-1细胞的显著的T细胞依赖性体外杀伤，在10− 10 M时具有最大裂解，而裂解表达MHC II类细胞的能力的有效性约低1000倍。在用人外周血单核细胞重建的SCID小鼠中研究5 T4 FabV 13-SEAD 227 A针对人NSCLC的免疫疗法。携带腹膜内生长的Calu-1细胞的小鼠在用5 T4 FabV 13-SEAD 227 A静脉内治疗后显示出肿瘤质量和数量的显著减少。因此，5 T4 FabV 13-SEAD 227 A对于人NSCLC的治疗具有高度吸引人的性质。© 2001年癌症研究运动http://www.bjcancer.com
Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEAD227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a Kd of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEAD227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEAD227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10−10M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEAD227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEAD227A. Thus, 5T4FabV13-SEAD227A has highly attractive properties for therapy of human NSCLC. © 2001 Cancer Research Campaign http://www.bjcancer.com