Selective targeting of melanoma and APCs using a recombinant antibody with TCR-like specificity directed toward a melanoma differentiation antigen

被引:49
作者
Denkberg, G
Lev, A
Eisenbach, L
Benhar, I
Reiter, Y
机构
[1] Technion Israel Inst Technol, Fac Biol, IL-32000 Haifa, Israel
[2] Tel Aviv Univ, Fac Life Sci, Dept Mol Microbiol & Biotechnol, IL-69978 Tel Aviv, Israel
[3] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel
关键词
D O I
10.4049/jimmunol.171.5.2197
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Tumor-associated, MHC-restricted peptides, recognized by tumor-specific CD8(+) lymphocytes, are desirable targets for novel approaches in immunotherapy because of their highly restricted fine specificity. Abs that recognize these tumor-associated MHC-peptide complexes, with the same specificity as TCR, would therefore be valuable reagents for studying Ag presentation by tumor cells, for visualizing MHC-peptide 'complexes on cells, and eventually for developing new targeting agents for cancer immunotherapy. To generate molecules with such a unique, fine specificity, we immunized HLA-A2 transgenic mice with a single-chain HLA-A2, complexed with a common antigenic T cell HLA-A2-restricted epitope derived from the melanoma differentiation Ag gp100. Using a phage display approach, we isolated a recombinant scFv Ab that exhibits a characteristic TCR-like binding specificity, yet, unlike TCRs, it did so with a high affinity in the nanomolar range. The TCR-like Ab can recognize the native MHC-peptide complex expressed on the surface of APCs, and on peptide-pulsed or native melanoma cells. Moreover, when fused to a very potent cytotoxic effector molecule in the form of a truncated bacterial toxin, it was able to specifically kill APCs in a peptide-dependent manner. These results demonstrate the utility of high affinity TRC-like scFv recombinant Abs directed toward human cancer T cell epitopes. Such TCR-like Abs may prove to be very useful for monitoring and visualizing the expression of specific MHC-peptide complexes on the surface of tumor cells, APCs, and lymphoid tissues, as well as for developing a new family of targeting agents for immunotherapy.
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页码:2197 / 2207
页数:11
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