nature.com

A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA - Gene Therapy

  • ️Abken, H
  • ️Fri Feb 05 1999
  • Brief Communication
  • Published: 05 February 1999

Gene Therapy volume 6, pages 300–304 (1999)Cite this article

Abstract

Chimeric T cell receptors with specificity for tumor-associated antigens are successfully used to target T cells to tumor cells. The efficacy of this approach, however, is reduced by soluble antigen that is frequently present in high serum concentrations. To overcome this situation, we constructed an anti-CEA chimeric receptor whose extracellular moiety is composed of a humanized single chain antibody fragment (scFv) derived from the anti-CEA mAb BW431/26 and the CH2/CH3 constant domains of human IgG. The intracellular moiety consists of the γ-signaling chain of the human FcεRI receptor constituting a com- pletely humanized chimeric receptor. After transfection, the humBW431/26 scFv-CH2CH3-γ receptor is expressed as a homodimer on the surface of MD45 T cells. Co-incubation with CEA+ tumor cells specifically activates grafted MD45 T cells indicated by IL-2 secretion and cytolytic activity against CEA+ tumor cells. Notably, the efficacy of receptor-mediated activation is not affected by soluble CEA up to 25 μg/ml demonstrating the usefulness of this chimeric receptor for specific cellular activation by membrane-bound CEA even in the presence of high concentrations of CEA, as found in patients during progression of the disease.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 6 print issues and online access

$259.00 per year

only $43.17 per issue

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Gross G, Eshhar Z . Endowing T cells with antibody specificity using chimeric T cell receptors FASEB J 1992 6: 3370–3378

    Article  CAS  Google Scholar 

  2. Eshhar Z, Waks T, Gross G, Schindler DG . Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the γ or ζ subunits of the immunoglobulin and T cell receptors Proc Natl Acad Sci USA 1993 90: 720–724

    Article  CAS  Google Scholar 

  3. Hwu P et al. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain J Exp Med 1993 178: 361–366

    Article  CAS  Google Scholar 

  4. Moritz D, Wels W, Mattern J, Groner B . Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2-expressing tumor cells Proc Natl Acad Sci USA 1994 91: 4318–4322

    Article  CAS  Google Scholar 

  5. Hwu P et al. In vivo activity of T cells redirected with chimeric antibody/T cell receptor genes Cancer Res 1995 55: 3369–3373

    CAS  Google Scholar 

  6. Eshhar Z et al. The T-body approach: potential for cancer immunotherapy Semin Immunopathol 1996 18: 199–209

    Article  CAS  Google Scholar 

  7. Abken H, Hombach A, Reinhold U, Ferrone S . Can combined T cell and antibody-based immunotherapy outsmart tumor cells? Immunol Today 1998 19: 2–5

    Article  CAS  Google Scholar 

  8. Gross G et al. Chimeric T cell receptors specific to a B-lymphoma idiotype: a model for tumor immunotherapy Biochem Soc Transact 1995 23: 1079–1083

    Article  CAS  Google Scholar 

  9. Fletcher RH . Carcinoembryonic antigen Ann Intern Med 1986 104: 66–73

    Article  CAS  Google Scholar 

  10. Bosslet K et al. Immunohistochemical localization and molecular characteristics of three monoclonal antibody-defined epitopes detectable on carcinoembryonic antigen (CEA) Int J Cancer 1985 36: 75–84

    Article  CAS  Google Scholar 

  11. Murakami M et al. Binding reactivity of monoclonal anti-carcinoembryonic antigen (CEA) antibodies with cell membrane-bound CEA and with free CEA in solution Immunol Invest 1996 25: 23–35

    Article  CAS  Google Scholar 

  12. Kaulen H et al. Humanized anti-carcinoembryonic antigen antibody: strategies to enhance human tumor cell killing Year Immunol 1993 7: 106–109

    CAS  PubMed  Google Scholar 

  13. Bruynk A, Seemann G, Bosslet K . Charcterization of a humanized bispecific monoclonal antibody for cancer therapy Br J Cancer 1993 67: 436–440

    Article  Google Scholar 

  14. Shu L, Qi SF, Schlom J, Kashmiri SVS . Secretion of a single-gene encoded immunoglobulin from myeloma cells Proc Natl Acad Sci USA 1993 90: 7995–7999

    Article  CAS  Google Scholar 

  15. Pohl C et al. CD30-specific AB1-AB2-AB3 internal image antibody network: potential use as anti-idiotype vaccine against Hodgkin’s lymphoma Int J Cancer 1993 54: 418–425

    Article  CAS  Google Scholar 

  16. Blomberg K, Ulfstedt AC . Fluorescent europium chelates as target cell markers in the assessment of natural killer cell cytotoxicity J Immunol Meth 1993 160: 27–34

    Article  CAS  Google Scholar 

  17. Moertel CG et al. The pre-operative carcinoembryonic antigen test in the diagnosis, staging, and prognosis of colorectal cancer Cancer 1986 58: 603–610

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Köln, Germany

    A Hombach, D Koch, R Sircar, C Heuser, V Diehl & H Abken

  2. Evangelisches Krankenhaus Köln-Kalk, Köln, Germany

    W Kruis & C Pohl

Authors

  1. A Hombach

    You can also search for this author in PubMed Google Scholar

  2. D Koch

    You can also search for this author in PubMed Google Scholar

  3. R Sircar

    You can also search for this author in PubMed Google Scholar

  4. C Heuser

    You can also search for this author in PubMed Google Scholar

  5. V Diehl

    You can also search for this author in PubMed Google Scholar

  6. W Kruis

    You can also search for this author in PubMed Google Scholar

  7. C Pohl

    You can also search for this author in PubMed Google Scholar

  8. H Abken

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Hombach, A., Koch, D., Sircar, R. et al. A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA. Gene Ther 6, 300–304 (1999). https://doi.org/10.1038/sj.gt.3300813

Download citation

  • Received: 24 April 1998

  • Accepted: 16 September 1998

  • Published: 05 February 1999

  • Issue Date: 01 February 1999

  • DOI: https://doi.org/10.1038/sj.gt.3300813

Keywords