Research ArticleCancer

TCR β chain–directed bispecific antibodies for the treatment of T cell cancers

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Science Translational Medicine  10 Mar 2021:
Vol. 13, Issue 584, eabd3595
DOI: 10.1126/scitranslmed.abd3595

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Specific bispecific antibodies

A major challenge in efforts to develop immunotherapies for T cell cancers is the need to protect healthy T cells while eliminating malignant T cells. Here, Paul et al. developed bispecific antibodies targeting 1 of 30 T cell receptor β chain variable regions, hypothesizing that targeting the β chain expressed by malignant T cells would avoid collateral damage to T cells expressing one of the other 29 β chains. The authors showed that bispecific antibodies recognizing malignant T cell receptor β chains promoted killing of malignant T cells and preservation of healthy T cells in vitro and in mouse models in vivo. These findings support the development of T cell receptor–specific approaches to target T cell cancers.

Abstract

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 models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting approach that preserves enough healthy T cells to maintain cellular immunity.

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