TCR-like human antibodies expressed on human CTLs mediate antibody affinity-dependent cytolytic activity

被引:65
作者
Chames, P
Willemsen, RA
Rojas, G
Dieckmann, D
Rem, L
Schuler, G
Bolhuis, RL
Hoogenboom, HR
机构
[1] Dyax SA, B-4000 Liege, Belgium
[2] Maastricht Univ, Dept Pathol, Maastricht, Netherlands
[3] Acad Hosp Rotterdam Dijkzigt, Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, Rotterdam, Netherlands
[4] Ctr Genet Engn & Biotechnol, Div Immunotechnol & Diagnost, Havana, Cuba
[5] Univ Erlangen Nurnberg, Dept Dermatol, D-8520 Erlangen, Germany
关键词
D O I
10.4049/jimmunol.169.2.1110
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页码:1110 / 1118
页数:9
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