Abstract
MHC class I molecules are important components of immune surveillance. There are no available methods to directly visualize and determine the quantity and distribution of MHC/peptide complexes on individual cells or to detect such complexes on antigen-presenting cells in tissues. MHC-restricted recombinant antibodies with the same specificity of T cell receptors (TCR) may become a valuable tool to address these questions. They may also serve as valuable targeting molecules that mimic the specificity of cytotoxic T cells. We isolated by phage display a panel of human recombinant Fab antibodies with peptide-specific, MHC-restricted TCR-like reactivity directed toward HLA-A2-restricted T cell epitopes derived from a novel antigen termed TCRgamma alternative reading frame protein (TARP) which is expressed on prostate and breast cancer cells. We have characterized one of these recombinant antibodies and demonstrated its capacity to directly detect specific HLA-A2/TARP T cell epitopes on antigen-presenting cells that have complexes formed by naturally occurring active intracellular processing of the antigen, as well as on the surface of tumor cells. Moreover, by genetic fusion we armed the TCR-like antibody with a potent toxin and demonstrated that it can serve as a targeting moiety killing tumor cells in a peptide-specific, MHC-restricted manner similar to cytotoxic T lymphocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP Ribose Transferases / administration & dosage
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ADP Ribose Transferases / genetics
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ADP Ribose Transferases / pharmacology
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ADP Ribose Transferases / therapeutic use
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Amino Acid Substitution
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Animals
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Antibodies, Monoclonal / biosynthesis
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Antibodies, Monoclonal / immunology*
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Antigens, Neoplasm / immunology
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use
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Bacterial Toxins / administration & dosage
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Bacterial Toxins / genetics
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Bacterial Toxins / pharmacology
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Bacterial Toxins / therapeutic use
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Breast Neoplasms / immunology
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Epitopes, T-Lymphocyte / biosynthesis
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology
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Exotoxins / administration & dosage
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Exotoxins / genetics
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Exotoxins / pharmacology
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Exotoxins / therapeutic use
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Female
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HLA-A2 Antigen / genetics
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HLA-A2 Antigen / immunology
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Humans
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Immunoglobulin Fab Fragments / biosynthesis
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Immunoglobulin Fab Fragments / genetics
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Immunoglobulin Fab Fragments / immunology
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Immunotoxins / immunology
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Immunotoxins / pharmacology
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Immunotoxins / therapeutic use
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Male
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Mammary Neoplasms, Experimental / immunology
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Mammary Neoplasms, Experimental / pathology
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Mammary Neoplasms, Experimental / prevention & control
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Mice
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Mice, Nude
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Molecular Sequence Data
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology*
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Peptide Fragments / biosynthesis
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Peptide Fragments / genetics
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Peptide Fragments / immunology
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Prostatic Neoplasms / immunology
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Prostatic Neoplasms / pathology
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Pseudomonas aeruginosa Exotoxin A
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology*
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / immunology*
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Virulence Factors / administration & dosage
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Virulence Factors / genetics
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Virulence Factors / pharmacology
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Virulence Factors / therapeutic use
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Antigens, Neoplasm
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Antineoplastic Agents
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Bacterial Toxins
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Epitopes, T-Lymphocyte
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Exotoxins
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HLA-A2 Antigen
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Immunoglobulin Fab Fragments
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Immunotoxins
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Nuclear Proteins
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Peptide Fragments
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Receptors, Antigen, T-Cell
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Recombinant Proteins
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TARP
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Virulence Factors
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ADP Ribose Transferases
Associated data
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GENBANK/AY894556
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GENBANK/AY900167