A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA.
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 gamma-signaling chain of the human Fc epsilon RI receptor constituting a completely humanized chimeric receptor. After transfection, the humBW431/26 scFv-CH2CH3-gamma 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 micrograms/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.
Hombach
A
A
Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Germany.
Koch
D
D
Sircar
R
R
Heuser
C
C
Diehl
V
V
Kruis
W
W
Pohl
C
C
Abken
H
H
D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007128:Immunoglobulin Fragments; D007376:Interleukin-2 / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002272:Carcinoembryonic Antigen; D007128:Immunoglobulin Fragments; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell