TriTACs, a Novel Class of T-Cell–Engaging Protein Constructs Designed for the Treatment of Solid Tumors
Richard J. Austin, Bryan D. Lemon, Wade H. Aaron, Manasi Barath, Patricia Culp, Robert B. DuBridge, Luke Evnin, Adrie Jones, Anand Panchal, Purbasa Patnaik, Vanitha Ramakrishnan, Sony Sotelo Rocha, Pui Seto, Kenneth G. Sexton, Kathryn L. Strobel, Russell Wall, Stephen Yu, Timothy Z. Yu, Che‐Leung Law, Patrick A. Baeuerle, Holger Wesche
Abstract
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. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic 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.