Antigen-specific downregulation of T cells by doxorubicin delivered through a recombinant MHC II-peptide chimera

• Published in: Nature biotechnology 2001-02, Vol.19 (2), p.142-147
• Main Authors: Casares, Sofia, Bona, Constantin A, Brumeanu, Teodor- D, Stan, Alexandru C
• Format: Article
• Language: English
• Subjects: Agriculture; Animals; Antigens; Antineoplastic agents; Apoptosis; Binding Sites; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; CD4-Positive T-Lymphocytes - immunology; DNA - chemistry; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Drug Carriers; Drug delivery systems; Drugs; Epitopes - chemistry; Epitopes - immunology; Galactose; Hemagglutinin Glycoproteins, Influenza Virus - chemistry; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - immunology; Immunoglobulins; Immunotherapy; Life Sciences; Lymphocytes; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Transgenic; Peptide Fragments - chemistry; Peptide Fragments - immunology; Peptides; Pharmacology. Drug treatments; Publishing; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Thymus gland; Toxicity; Translocation
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/84404

As the number of drugs with potential therapeutic use for T-cell-mediated diseases increases, there is a need to find methods of delivering such drugs to T cells. The major histocompatibility complex (MHC)–peptide complexes are the only antigen-specific ligands for the T-cell receptor (TCR) expressed on T cells, and they may be an appropriate drug delivery system. We engineered a soluble bivalent MHC class II–peptide chimera on the immunoglobulin scaffold (I-E d αβ/Fcγ2a/HA110-120, DEF) that binds stably and specifically to CD4 T cells recognizing the HA110-120 peptide. Doxorubicin, a powerful antimitogenic anthracycline, was enzymatically assembled on the galactose residues of a DEF chimera. The DEF-gal-Dox construct preserved both the binding capacity to hemagglutinin (HA)-specific T cells, and the drug toxicity. Brief exposure of HA-specific T cells to DEF-gal-Dox construct in vitro was followed by drug internalization in the lysosomes, translocation to the nucleus, and apoptosis. Administration of DEF-gal-Dox to mice expressing the TCR-HA transgene reduced the frequency of TCR-HA T cells in the spleen and thymus by 27% and 42%, and inhibited HA proliferative capacity by 40% and 60%, respectively. It has not been demonstrated previously that pharmacologically active drugs able to modulate T-cell functions can be delivered to T cells in an antigen-specific manner by soluble, bivalent MHC II–peptide chimeras.