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Selective targeting of melanoma and APCs using a recombinant antibody with TCR-like specificity directed toward a melanoma differentiation antigen.
- 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.
- Subjects :
- Animals
Antigen Presentation genetics
Bacteriophages genetics
Binding Sites, Antibody genetics
Cytotoxicity, Immunologic genetics
HLA-A2 Antigen genetics
HLA-A2 Antigen immunology
HLA-A2 Antigen metabolism
Humans
Immunoglobulin Variable Region genetics
Intracellular Fluid immunology
Intracellular Fluid metabolism
Macromolecular Substances
Melanoma, Experimental genetics
Melanoma, Experimental metabolism
Membrane Glycoproteins metabolism
Mice
Mice, Transgenic
Neoplasm Proteins metabolism
Peptide Library
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins metabolism
Recombinant Fusion Proteins pharmacology
Recombinant Proteins biosynthesis
Recombinant Proteins metabolism
Solubility
Tumor Cells, Cultured
gp100 Melanoma Antigen
Antigen-Presenting Cells immunology
Antigen-Presenting Cells metabolism
Epitopes, T-Lymphocyte immunology
Melanoma, Experimental immunology
Melanoma, Experimental therapy
Membrane Glycoproteins immunology
Neoplasm Proteins immunology
Receptors, Antigen, T-Cell immunology
Recombinant Proteins pharmacology
Subjects
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