Bispecific antibodies targeting malignant T cells showed selectivity and efficacy in vitro and in vivo
Major Finding: Bispecific antibodies targeting malignant T cells showed selectivity and efficacy in vitro and in vivo.
Concept: T-cell cancers have not previously been able to be targeted with bispecific antibody treatments.
Impact: This work demonstrates how bispecific antibody treatments could be adapted to non–B-cell cancers.
The success of chimeric antigen receptor T-cell therapies and bispecific antibody treatments for B-cell malignancies owes in part to the fact that the resulting near-complete loss of healthy B cells observed due to targeting of surface antigens expressed on all B cells is clinically tolerable. In contrast, near-total T-cell depletion would produce clinically unacceptable immunosuppression. Recognizing that each T cell expresses only one of 30 possible T-cell receptor β chain variable (TRBV) families on its surface and that many T-cell cancers clonally express TRBV5 or TRBV12 families, Paul, Pearlman, Douglass, and colleagues hypothesized that it may be possible to target only a subset of T cells—including the malignant cells and some healthy T cells expressing the same TRBV—while sparing T cells expressing other TRBVs and thus preventing severe immunosuppression. To do this, bispecific antibodies expected to bring cytotoxic T cells into proximity with malignant T cells by targeting TRBV5-5 or TRBV12 (to bind cancerous T cells) and the T cell lineage–defining coreceptor CD3 (to bind other T cells) were generated. These bispecific antibodies were capable of selectively depleting target T cells from healthy human donors while sparing most other T cells in vitro. Further in vitro experiments showed that, mechanistically, the TRBV5-5– or TRBV12-targeting bispecific antibodies elicited cytokine (including IFNγ, TNFα, IL2, IL5, and GM-CSF) production by normal T cells exposed to malignant T cells expressing TRBV5-5 or TRBV12. Additionally, not only did these bispecific antibodies kill T-cell leukemia cell lines, but they also exhibited pronounced cytotoxicity toward patient-derived T-cell acute lymphoblastic leukemia cells in vitro. Finally, in vivo experiments using mouse xenograft models of T-cell leukemias demonstrated that these bispecific antibodies selectively killed malignant cells and extended survival. In summary, this work demonstrates the promise of using bispecific antibodies to target T-cell cancers, providing preclinical evidence to support continued investigation of this therapeutic modality.
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