Cytokine TRAIL death receptor agonists: design strategies and clinical prospects

The development of therapeutic bispecific antibodies and hybrid proteins is one of the most urgent biomedical technologies with obvious clinical prospects. At the same time, advanced strategies of molecular design of drugs with new properties are coming to the forefront. The tumour necrosis factor-related apoptosis inducing ligand (TRAIL) receptor pathways are important components of the immune system involved in the immune surveillance and selective elimination of transformed cells. TRAIL-based proteins are therefore promising drug candidates for the treatment of malignant tumours and autoimmune diseases. In the first series of clinical trials, drugs targeting the death receptors DR4 or DR5, did not show significant anti-cancer activity. This is due to the TRAIL resistance mechanisms that tumours evolve to evade the efficient induction of apoptotic signalling. However, a wide range of novel TRAIL death receptor-targeted formulations are currently being developed, mainly to improve stability, enhance death receptor clustering and involve additional tumour targets. Over the past decade, several dozens of multi-targeted fusion proteins with either TRAIL protein or DR5-specific agonistic monoclonal antibodies have been developed to improve therapeutic efficacy. These include fusions with either short peptide tags or large functional proteins, as well as antibody fragments targeting molecular pathways involved in angiogenesis or proliferative signalling such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), programmed death-ligand 1 (PD-L1), <i>etc</i>. Collectively, these multimodal proteins enhance the activation of extrinsic and intrinsic apoptotic pathways in transformed cells, as well as affect the tumour microenvironment. This comprehensive review systematizes the bispecific and multivalent fusion proteins and conjugates targeting TRAIL death receptors, analyze the molecular mechanisms by which they overcome tumour resistance to TRAIL, and assess their clinical prospects.<br>The bibliography includes 236 references.