Isolation and characterization of human recombinant antibodies endowed with the antigen-specific, major histocompatibility complex-restricted specificity of T cells directed toward the widely expressed tumor T-cell epitopes of the telomerase catalytic subunit.
The recent characterization of MHC-displayed tumor-associated antigensthat recognize effector cells of the immune system has created new perspectives for cancer therapy. Antibodies that recognize these tumor-associated MHC-peptide complexes with the same specificity as the T-cell antigen receptor will therefore be valuable tools for immunotherapy as well as for studying antigen presentation in human cancers. Most tumor-associated antigens are expressed in only one or a few tumor types; however, recently specific T-cell epitopes derived from the telomerase catalytic subunit (hTERT) that are widely expressed in many cancers were identified and shown to be recognized by CTLs derived from cancer patients. We selected a large nonimmune repertoire of phage Fab antibodies on recombinant human class I HLA-A2 complexes displaying two distinct antigenic T-cell epitopes derived from hTERT. We isolated a surprisingly large panel of high-affinity human recombinant Fab antibodies that exhibited peptide-specific, MHC-restricted binding characteristics of T cells. The analyzed Fabs not only recognize the cognate MHC-peptide complex in a recombinant soluble form but also the native complex as displayed on the surface of antigen-presenting cells and hTERT-expressing tumor cells. These findings demonstrate for the first time the ability to transform the unique fine specificity but low intrinsic affinity of TCRs on T cells into high-affinity soluble antibody molecules endowed with a T-cell antigen receptor-like specificity. These molecules may prove to be very important and widely applicable for monitoring the expression of specific MHC-peptide complexes on the surface of tumor and immune cells, for structure-function studies of TCR-peptide-MHC interactions, as well as for developing new targeting agents for immunotherapy.
Lev
Avital
A
Faculty of Biology, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel.
Denkberg
Galit
G
Cohen
Cyril J
CJ
Tzukerman
Maty
M
Skorecki
Karl L
KL
Chames
Patrick
P
Hoogenboom
Hennie R
HR
Reiter
Yoram
Y
D000818:Animals; D000918:Antibody Specificity; D000938:Antigen-Presenting Cells / Q000276:immunology; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D019098:Telomerase / Q000276:immunology*; D014162:Transfection
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D007128:Immunoglobulin Fragments; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D019098:Telomerase