Characterization of an HLA-restricted and human cytomegalovirus-specific antibody repertoire with therapeutic potential.
Antigens, Viral
/ immunology
Cell Survival
Cytomegalovirus
/ immunology
Cytomegalovirus Infections
/ immunology
Fibroblasts
/ immunology
HLA Antigens
/ immunology
Humans
Immunoglobulin Fab Fragments
/ administration & dosage
Immunotoxins
/ administration & dosage
Melanoma
/ immunology
Peptide Fragments
/ immunology
Receptors, Antigen, T-Cell
/ immunology
T-Lymphocytes, Cytotoxic
/ immunology
Viral Proteins
/ immunology
Allogeneic stem cell transplantation
HCMV infection
Immunosuppression
TCR-like antibodies
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
Aug 2020
Aug 2020
Historique:
received:
01
09
2019
accepted:
02
04
2020
pubmed:
18
4
2020
medline:
21
7
2020
entrez:
18
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32300857
doi: 10.1007/s00262-020-02564-1
pii: 10.1007/s00262-020-02564-1
pmc: PMC7347513
doi:
Substances chimiques
Antigens, Viral
0
HLA Antigens
0
Immunoglobulin Fab Fragments
0
Immunotoxins
0
Peptide Fragments
0
Receptors, Antigen, T-Cell
0
Viral Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1535-1548Références
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