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

Authors :
Denkberg G
Lev A
Eisenbach L
Benhar I
Reiter Y
Source :
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2003 Sep 01; Vol. 171 (5), pp. 2197-207.
Publication Year :
2003

Abstract

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.

Details

Language :
English
ISSN :
0022-1767
Volume :
171
Issue :
5
Database :
MEDLINE
Journal :
Journal of immunology (Baltimore, Md. : 1950)
Publication Type :
Academic Journal
Accession number :
12928363
Full Text :
https://doi.org/10.4049/jimmunol.171.5.2197