title: The Monospecificity of Novel Anti-HLA-E Monoclonal Antibodies Enables Reliable Immunodiagnosis, Immunomodulation of HLA-E, and Upregulation of CD8+ T Lymphocytes.
abstract: In human cancers, over-expression of HLA-E is marked by gene expression. However, immunolocalization of HLA-E on tumor cells is impeded by the HLA-Ia reactivity of commercial anti-HLA-E monoclonal antibodies (MAbs). So there was a clear need to develop monospecific anti-HLA-E MAbs for reliable immunodiagnosis of HLA-E, particularly considering the prognostic relevance of HLA-E in human cancer. HLA-E overexpression is correlated with disease progression and poor survival of patients, both of which are attributed to the suppression of anti-tumor activity of cytotoxic T cells mediated by HLA-E. The suppression mechanism involves the binding of HLA-E-specific amino acids located on the α1 and α2 helices of HLA-E to the inhibitory receptors (CD94/NKG2a) on CD8+ T lymphocytes. An anti-HLA-E MAb that recognizes these HLA-E-specific sequences can not only be a monospecific MAb with potential for specific immunolocalization of HLA-E but can also block the sequences from interacting with the CD94/NKG2a receptors. We therefore developed several clones that secrete such HLA-E-specific MAbs; then we assessed the ability of the MAbs to bind to the amino acid sequences interacting with the CD94/NKG2a receptors by inhibiting them from binding to HLA-E with peptides that inhibit receptor binding. Elucidation of the immunomodulatory capabilities of these monospecific MAbs showed that they can induce proliferation of CD8+ T cells with or without co-stimulation. These novel MAbs can serve a dual role in combating cancer by blocking interaction of HLA-E with CD94/NKG2a and by promoting proliferation of both non-activated and activated CD8+ cytotoxic αβ T cells.
authors.affiliation: Terasaki Foundation Laboratory , Los Angeles, California.
authors.forename: Mepur H
authors.initials: MH
authors.lastname: Ravindranath
authors.affiliation: Terasaki Foundation Laboratory , Los Angeles, California.
authors.forename: Paul I
authors.initials: PI
authors.lastname: Terasaki
authors.affiliation: Terasaki Foundation Laboratory , Los Angeles, California.
authors.forename: Tho
authors.initials: T
authors.lastname: Pham
authors.affiliation: Terasaki Foundation Laboratory , Los Angeles, California.
authors.forename: Vadim
authors.initials: V
authors.lastname: Jucaud
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005500:Follow-Up Studies; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007159:Immunologic Tests; D056747:Immunomodulation; D007694:Killer Cells, Natural / Q000276:immunology; D008545:Melanoma / Q000175:diagnosis* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008807:Mice, Inbred BALB C; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010446:Peptide Fragments / Q000276:immunology*; D011379:Prognosis; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D015854:Up-Regulation; D000097625:HLA-E Antigens
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D000097625:HLA-E Antigens