Characterization of an HLA-restricted and human cytomegalovirus-specific antibody repertoire with therapeutic potential
| Autor: | Frank Neumann, Niels Murawski, Joerg Thomas Bittenbring, Gerhard Held, Lorenz Thurner, Stephan Stilgenbauer, Dominic Kaddu-Mulindwa, Gabi Carbon, Sigrun Smola, Arne Felbel, Klaus-Dieter Preuss, Konstantinos Christofyllakis, Moritz Bewarder, Birgit Bette, Alexander Hasse |
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| Rok vydání: | 2019 |
| Předmět: |
Human cytomegalovirus
Cancer Research Phage display Cell Survival viruses Immunology Receptors Antigen T-Cell Cytomegalovirus Human leukocyte antigen Biology 03 medical and health sciences Immunoglobulin Fab Fragments Viral Proteins 0302 clinical medicine Antigen HLA Antigens medicine Immunology and Allergy Pseudomonas exotoxin Humans Antigens Viral Melanoma 030304 developmental biology HCMV infection 0303 health sciences Immunotoxins T-cell receptor Fibroblasts medicine.disease TCR-like antibodies Virology Peptide Fragments Allogeneic stem cell transplantation Oncology Cell culture 030220 oncology & carcinogenesis Cytomegalovirus Infections biology.protein Original Article Antibody Immunosuppression T-Lymphocytes Cytotoxic |
| Zdroj: | Cancer Immunology, Immunotherapy |
| ISSN: | 1432-0851 |
| Popis: | With an infection rate of 60–90%, the human cytomegalovirus (HCMV) is very common among adults but normally causes no symptoms. When T cell-mediated immunity is compromised, HCMV reactivation can lead to increased morbidity and mortality. HCMV antigens are processed and presented as peptides on the cell surface via HLA I complexes to the T cell receptor (TCR) of T cells. The generation of antibodies against HCMV peptides presented on HLA complexes (TCR-like antibodies) has been described, but is without therapeutic applications to date due to the polygenic and polymorphic nature of HLA genes. We set out to obtain antibodies specific for HLA/HCMV-peptides, covering the majority of HLA alleles present in European populations. Using phage display technology, we selected 10 Fabs, able to bind to HCMV-peptides presented in the 6 different HLA class I alleles A*0101, A*0201, A*2402, B*0702, B*0801 and B*3501. We demonstrate specific binding of all selected Fabs to HLA-typed lymphoblastoid cell lines (EBV-transformed B cells) and lymphocytes loaded with HCMV-peptides. After infection with HCMV, 4/10 tetramerized Fabs restricted to the alleles HLA-A*0101, HLA-A*0201 and HLA-B*0702 showed binding to infected primary fibroblasts. When linked to the pseudomonas exotoxin A, these Fab antibodies induce highly specific cytotoxicity in HLA matched cell lines loaded with HCMV peptides. TCR-like antibody repertoires therefore represent a promising new treatment modality for viral infections and may also have applications in the treatment of cancers. Electronic supplementary material The online version of this article (10.1007/s00262-020-02564-1) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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