TriTACs, a novel class of T cell-engaging protein constructs designed for the treatment of solid tumors.

T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T cell receptor. While high response rates were observed with T cell engagers specific for CD19, CD20 or BCMA in patients with hematological cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T cell engager format, called TriTAC (for Trispecific T cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting) TriTAC in clinical development for patients with metastatic castration resistant prostate cancer.