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Carcinoembryonic Antigen (CEA)-specific T-Cell Activation in Colon Carcinoma Induced by Anti-CD3xAnti-CEA Bispecific Diabodies and B7xAnti-CEA Bispecific Fusion Proteins¹

MRC Centre for Protein Engineering, Cambridge CB2 2QH, United Kingdom [P. H., R. H., G. W.]; Department I of Internal Medicine [O. M., M. S., J. W., V. D., H. B.] and Institute of Neurophysiology [B. F., L. Q.], University of Cologne, 50924 Cologne, Germany; and Institut Curie, 75248 Paris Cedex 05, France [O. C.]

Two bispecific recombinant molecules, an anti-CD3xanti-carcino-embryogenic antigen (CEA) diabody and a B7xanti-CEA fusion protein, were tested for their capacity to specifically activate T cells in the presence of CEA-expressing colon carcinoma cells. T-cell activation by the anti-CD3xanti-CEA diabody required close contact to CEA-positive cells and resulted in diabody-mediated cytotoxicity against the target cells. Additionally, CD28-mediated costimulation in combination with anti-CD3xanti-CEA diabodies induced activation of autologous T cells in CEA-positive primary colon carcinoma specimens, as determined by flow cytometry. The high specificity of the bispecific diabody approach could be further enhanced by the use of B7xanti-CEA fusion proteins because the costimulatory CD28-signaling to the T cells strictly depended on the expression of CEA on the target cells.

We demonstrate that displaying engagement sites for the T-cell antigens CD3 and CD28 on the surface of colon carcinoma cells is a suitable way to activate and retarget T cells in a highly tumor-specific manner. For clinical purposes, B7xanti-tumor-associated antigen (TAA) fusion proteins, which are equally effective but more specific compared with anti-CD28 monoclonal anti-bodies, thus may improve the tumor specificity of anti-CD3xanti-TAA bispecific antibodies. Furthermore, B7-negative tumors can be converted into B7-positive tumors by B7xanti-TAA fusion proteins without the need for B7 gene transfer to the malignant cells.

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