Characterization of an HLA-restricted and human cytomegalovirus-specific antibody repertoire with therapeutic potential.

Characterization of an HLA-restricted and human cytomegalovirus-specific antibody repertoire with therapeutic potential.

Publication date: Aug 01, 2020

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.

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Concepts Keywords
Alleles Pseudomonas
Antibodies Therapeutic potential infection
Antibody Medical specialties
Antigens Branches of biology
Cell Mediated Immunity Immune system
Cytomegalovirus Immunology
Cytotoxicity Human leukocyte antigen
Fibroblasts Human betaherpesvirus 5
HLA Antibody
Infection Antibodies
Lymphoblastoid Transplantation
Lymphocytes Cell Receptors
Morbidity
Mortality
Peptides
Phage Display
Polygenic
Polymorphic
Receptor
Treatment Modality
Viral

Semantics

Type Source Name
disease MESH infection
disease MESH viral infections
disease MESH cancers
pathway REACTOME HCMV Infection
disease MESH Dissociation
disease MESH renal
disease MESH lymphadenopathy
disease MESH pneumonia
disease MESH hepatitis
disease MESH colitis
disease MESH ulcers
disease MESH retinitis
disease MESH polyradiculopathy
drug DRUGBANK Ganciclovir
drug DRUGBANK Valganciclovir
drug DRUGBANK L-Valine
drug DRUGBANK Foscarnet
drug DRUGBANK Cidofovir
drug DRUGBANK Letermovir
drug DRUGBANK L-Leucine
drug DRUGBANK Indoleacetic acid
disease MESH diagnosis
drug DRUGBANK Isopropyl beta-D-thiogalactopyranoside
drug DRUGBANK Amino acids
drug DRUGBANK Honey
disease MESH squamous carcinoma
drug DRUGBANK Streptomycin
drug DRUGBANK L-Glutamine
drug DRUGBANK Myricetin
drug DRUGBANK Edetic Acid
drug DRUGBANK Trypsin
drug DRUGBANK BIA
drug DRUGBANK Coenzyme M
drug DRUGBANK Dimethyl sulfoxide
disease MESH EBV infection
disease MESH tic
disease MESH melanoma
pathway KEGG Melanoma
disease MESH immuno
drug DRUGBANK Diethylstilbestrol
disease MESH Cell line authentication
drug DRUGBANK Cefaclor
drug DRUGBANK Activated charcoal
disease MESH infectious diseases
disease MESH Kaposi sarcoma
disease MESH hematological malignancies
disease MESH AIDS
disease MESH death
drug DRUGBANK Ranitidine
drug DRUGBANK Cefazolin
disease MESH vaccinia
drug DRUGBANK L-Aspartic Acid
drug DRUGBANK Aspartame
drug DRUGBANK L-Phenylalanine
drug DRUGBANK Esomeprazole
disease MESH biopsy
disease MESH adenocarcinoma
disease MESH congenital
disease MESH cytomegalovirus infection
disease MESH adverse drug reaction
pathway KEGG Chronic myeloid leukemia
disease MESH leukemia

Original Article

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