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

Abstract

Backvround: Chimeric T cell recptors with specificity for defined tumor associated antigens are valuable tools to target T cells to tumor cells. The function of these receptors in the presence of soluble antigen, however, is crucial because the tumor associated antigen is often shed into the serum of cancer patients. Methods: For this reason we have generated a chimeric T cell receptor with specificity for the membrane bound form of the carcinoembryonic antigen (CEA). This receptor (humBW431/26-CH2/3-T) is composed of a humanized single chain antibody (humBW431/26), that was fused to the Fc domains (CH2/3) of the human lgG1 and the signaling unit of the Fc~R1 receptor t chain ('/). Results: After transfection this chimeric receptor converted MD45 T cells to specificity for CEA+ tumor cells. Only immobilized, especially membrane-bound CEA, could crosslink the chimeric receptor resulting in cellular activation with IL-2 release and cytolytic activity towards CEA+ tumor cells. Cellular activation by membrane bound antigen was also efficient in the presence of high amounts of soluble CEA (up to 25 lag/ml whereas an anti-idiotypic antibody could completely block T cell activation even at low concentrations (0,1 lag/ml). Conclusion: Our data demonstrate, that the chimeric T cell receptor humBW431/26-CH2/3-y has selective specificity for membrane-bound CEA and that targeting of tumor cells by chimeric T cell receptors can be performed even in the presence of high amounts of soluble antigen.