Generation of a highly versatile TCR bispecific scaffold optimized for targeting tumor-specific peptide-HLA antigens

Abstract

ABSTRACT Redirection of T lymphocytes toward cancer cells has been one of the most promising treatment concepts in oncology developed over the past years and leading to multiple regulatory approvals for both adoptive cell therapy (ACT) and T-cell-engaging bispecific (TEB) molecules. However, progress has been achieved predominantly in hematological indications by aiming at so-called lineage antigens (i.e. CD19, CD20, BCMA). Targeting of peptide-HLA antigens (pHLA) has been proposed as a strategy to overcome the paucity of suitable surface antigens in solid cancers, yet the technical hurdle to specifically address this class of low copy and highly promiscuous antigens has so far hampered its use in a broader patient population. We here describe the successful development of TCER (T-Cell-Engaging Receptor), a novel and highly versatile class of T-cell receptor (TCR)-based TEB with optimized in vivo efficacy, tolerability, plasma half-life, and stability characteristics for a broad use targeting pHLA in oncology and beyond.