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TCR-Like HumanAntibodies Expressedon Human CTLs MediateAntibodyAffinity-DependentCytolytic Activity Patrick ChamesRalph A. WillemsenGertrudis Rojas2002 год

TCR-Like Human Antibodies Expressed on Human CTLs Mediate Antibody Affinity-Dependent Cytolytic Activity
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Аннотация: The permanent genetic programming via gene transfer of autologous T cells with cell surface receptors directed toward tumor-related Ags holds great promise for the development of more-specific tumor therapies. In this study we have explored the use of Abs directed to MHC-peptide complexes (or TCR-like Abs) to engraft CTLs with exquisite specificity for cancer cells. First, we affinity matured in vitro a previously selected TCR-like Ab, Fab-G8, which is highly specific for the peptide melanoma-associated Ag-A1 presented by the HLA-A1 molecule. A combination of L chain shuffling, H chain-targeted mutagenesis, and in vitro selection of phage display libraries yielded a Fab-G8 Ab derivative, Fab-Hyb3, with an 18-fold improved affinity yet identical peptide fine specificity. Fab-G8 and Fab-Hyb3 were expressed on primary human T lymphocytes as cell surface-anchored Fab, demonstrating that T cells expressing the high-affinity Fab-Hyb3 molecule eradicate tumor cells much more effectively. Furthermore, the gain in ligand-binding affinity resulted in a 2-log improvement in the detection of peptide/MHC complexes on melanoma-associated Ag-A1 peptide-loaded cells. In summary, an affinity-matured Ab specifically recognizing a cancer-related peptide/MHC complex was generated and used to improve the tumor cell killing capacity of human T cells. This strategy, based on engraftment of T cells with in vitro engineered Abs, is an attractive alternative to the laborious, and in many cases unsuccessful, generation of highly potent tumor-specific T lymphocytes.
Год издания: 2002
Авторы: Patrick Chames, Ralph A. Willemsen, Gertrudis Rojas, Detlef Dieckmann, Louise Rem, Gerold Schuler, R. L. H. Bolhuis, Hennie R. Hoogenboom
Издательство: American Association of Immunologists
Источник: The Journal of Immunology
Ключевые слова: Monoclonal and Polyclonal Antibodies Research, CAR-T cell therapy research, T-cell and B-cell Immunology
Другие ссылки: The Journal of Immunology (HTML)
CiteSeer X (The Pennsylvania State University) (PDF)
CiteSeer X (The Pennsylvania State University) (HTML)
PubMed (HTML)