TREM-1 and TREM-2 as Therapeutic Targets: Clinical Challenges and Perspectives

Growing evidence indicate that triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, plays a pivotal role and represent an emerging target for therapeutic intervention in the pathogenesis of many human diseases and disorders, including cancer, sepsis, inflammatory bowel disease, retinopathy, rheumatoid arthritis, systemic sclerosis, brain and spinal cord injuries, and other inflammation-associated pathologies. However, despite promising preclinical data and safety in humans, the first clinical inhibitor of TREM-1 (peptide LR12 or nangibotide) failed to reach significance for the primary endpoint in phase IIb sepsis trial. Here, based on the multiplicity of TREM-1 ligands, I hypothesize that the ligand-dependent mechanism of action of LR12 rather than TREM-1 inhibition per se is the reason of failure in late clinical trials. Similar reasoning can be used to explain why an antagonistic monoclonal antibody against TREM-2, another multiligand receptor, failed recently in phase Ia/b oncology trials due to lack of efficacy, despite success in animal models. In light of this hypothesis, I discuss the failure of inhibitors for these and other multiligand receptors (e.g., toll-like receptors, TLRs; receptor for advanced glycation end products, RAGE) in the clinical setting, risk of failure of those in development, and how this risk can be mitigated in the future by the use of ligand-independent inhibition strategies.