[Research Articles] TCR {beta} chain-directed bispecific antibodies for the treatment of T cell cancers
Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen–targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies directed against T cell cancers require more selective targeting. Here, we describe an approach to target T cell cancers through T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique TCR β chain generated from 1 of 30 TCR β chain variable gene families (TRBV1 to TRBV30). We hypothesized that bispecific antibodies targeting a single TRBV family member expressed in malignant T cells could promote killing of these cancer cells, while preserving healthy T cells that express any of the other 29 possible TRBV family members. We addressed this hypothesis by demonstrating that bispecific antibodies targeting TRBV5-5 (α-V5) or TRBV12 (α-V12) specifically lyse relevant malignant T cell lines and patient-derived T cell leukemias in vitro. Treatment with these antibodies also resulted in major tumor regressions in mouse mod...
Source: Science Translational Medicine - Category: Biomedical Science Authors: Paul, S., Pearlman, A. H., Douglass, J., Mog, B. J., Hsiue, E. H.-C., Hwang, M. S., DiNapoli, S. R., Konig, M. F., Brown, P. A., Wright, K. M., Sur, S., Gabelli, S. B., Li, Y., Ghiaur, G., Pardoll, D. M., Papadopoulos, N., Bettegowda, C., Kinzler, K. W., Tags: Research Articles Source Type: research
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