| Autor: |
Paul, Suman, Pearlman, Alexander H., Douglass, Jacqueline, Mog, Brian J., Hsiue, Emily Han-Chung, Hwang, Michael S., DiNapoli, Sarah R., Konig, Maximilian F., Brown, Patrick A., Wright, Katharine M., Sur, Surojit, Gabelli, Sandra B., Li, Yana, Ghiaur, Gabriel, Pardoll, Drew M., Papadopoulos, Nickolas, Bettegowda, Chetan, Kinzler, Kenneth W., Zhou, Shibin, Vogelstein, Bert |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 3/10/2021, Vol. 13 Issue 584, p1-16, 16p |
| Abstrakt: |
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. 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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