Cancer Immunology, Immunotherapy

, Volume 51, Issue 10, pp 565–573

A functional recombinant single-chain T cell receptor fragment capable of selectively targeting antigen-presenting cells

  • Malka Epel
  • Joshua D. Ellenhorn
  • Don J. Diamond
  • Yoram Reiter
Original Article

DOI: 10.1007/s00262-002-0312-4

Cite this article as:
Epel, M., Ellenhorn, J.D., Diamond, D.J. et al. Cancer Immunol Immunother (2002) 51: 565. doi:10.1007/s00262-002-0312-4

Abstract.

Specificity in the immune system is dictated and regulated by specific recognition of peptide/major histocompatibility complexes (MHC) by the T cell receptor (TCR). Such peptide/MHC complexes are a desirable target for novel approaches in immunotherapy because of their highly restricted fine specificity. Recently a potent anti-human p53 CD8+ cytotoxic T lymphocyte (CTL) response has been developed in HLA-A2 transgenic mice after immunization with peptides corresponding to HLA-A2 motifs from human p53. An α/β T-cell receptor was cloned from such CTL which exhibited a moderately high affinity to the human p53149–157 peptide. In this report, we investigated the possibility of using a recombinant tumor-specific TCR for antigen-specific elimination of cells that express the specific MHC-peptide complex. To this end, we constructed a functional single-chain Fv fragment from the cloned TCR and fused it to a very potent cytotoxic molecule, a truncated form of Pseudomonas exotoxin A (PE38). The p53 TCR scFv-P38 fusion protein was generated by in vitro refolding from bacterially-expressed inclusion bodies, and was found to be functional by its ability to bind antigen-presenting cells (APC) which express the specific p53-derived peptide. Moreover, we have shown that the p53-specific TCR scFv-PE38 molecule specifically kills APC in a peptide-dependent manner. These results represent the first time that a TCR-derived recombinant single-chain Fv fragment has been used as a targeting moiety to deliver a cytotoxic effector molecule to cells and has been able to mediate the efficient killing of the particular cell population that expresses the specific MHC/peptide complex. Similarly to antibody-based targeting approaches, TCR with tumor cell specificity represent attractive candidates for generating new, very specific targeting moieties for various modes of cancer immunotherapy.

Cancer-specific targeting Single-chain Fv T-cell receptor

Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • Malka Epel
    • 1
  • Joshua D. Ellenhorn
    • 2
  • Don J. Diamond
    • 3
  • Yoram Reiter
    • 1
  1. 1.Faculty of Biology, Technion-Israel Institute of Technology, Technion City, Room 333, Haifa 32000, Israel
  2. 2.Division of General and Oncologic Surgery, Beckman Research Institute of the City of Hope and City of Hope National Medical Center, Duarte, California 91010, USA
  3. 3.Laboratory of Vaccine Research, Beckman Research Institute of the City of Hope and City of Hope National Medical Center, Duarte, California 91010, USA