TCR beta chain-directed bispecific antibodies for the treatment of T cell cancers

T cell-mediated immunotherapies have great potential but are limited by the paucity of shared cancer-specific targets. As an alternative, targets with minimal overlap with non-essential healthy cells have been evaluated. This approach has been successfully used to treat B cell cancers, and immunotherapeutic agents directed against the pan-B cell marker CD19 have produced astounding clinical results. Though such therapies result in the near complete loss of healthy B cells, this depletion is well tolerated by patients. Unfortunately, analogous targeting of pan-T cell markers would not be tolerated by patients with T cell cancers because of the resultant severe and unacceptable immunosuppression. Here we describe an approach to target T cell cancers through targeting of specific subsets of T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique T cell receptor beta chain generated from one of thirty TCR beta chain variable gene families (TRBV1 to TRBV30). Immune attack on the single TRBV family member expressed in a T cell cancer can destroy these cancer cells while preserving healthy T cells that express any of the other 29 possible TRBV family members, thereby maintaining a functioning immune system. We demonstrate that bispecific antibodies targeting TRBV5-5 (anti-V5) and TRBV12 (anti-V12) redirect healthy T cells to specifically lyse TRBV5-5+ and TRBV12+ malignant T cell lines and patient-derived T cell leukemias in vitro. We further show that anti-V5 or anti-V12 destroys malignant cells and improves survival in mouse models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting strategy that preserves enough healthy T cells to maintain cellular immunity.