Definition

An engineered toxin body (ETB) composed of biparatopic heavy chain variable domains (VHHs) targeting the human T-cell-expressed receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; CTLA4; CD152), fused to the enzymatically active, de-immunized, ribosome-inactivating cytotoxic payload Shiga-like toxin-A subunit (SLTA), with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration of ETB targeting CTLA-4 MT-8421, the antibody fragments specifically target and bind to two non-overlapping epitopes on CTLA-4-expressing T regulatory cells (Tregs) in the tumor microenvironment (TME). Upon internalization, the SLTA moiety is released and acts as an N-glycosidase, which binds to and cleaves an adenine nucleobase in the 28S RNA component of the 60S subunit of ribosomes and prevents ribosome activity. This inhibits protein synthesis and leads to apoptosis in CTLA-4-expressing Tregs in the TME. The depletion of the immune suppressive Tregs in the TME may enhance a cytotoxic T-lymphocyte (CTL)-mediated immune response against cancer cells. CTLA-4, an inhibitory receptor and member of the immunoglobulin superfamily (IgSF), is overexpressed by Tregs in the TME and plays a key role in the downregulation of the immune system.