The failure of ligand-dependent inhibitors of TREM-1 and TREM-2 in clinical trials, despite promising preclinical data, suggests a need for alternative therapeutic strategies. A new perspective published in Frontiers in Immunology proposes that ligand-independent mechanisms of action may overcome these challenges.
Challenges with Ligand-Dependent Inhibition
TREM-1 and TREM-2 are multiligand receptors involved in inflammatory and immune responses. TREM-1, primarily expressed on neutrophils and macrophages, amplifies inflammation, while TREM-2 can act as both a negative and positive regulator of inflammation. Current approaches to inhibiting these receptors often involve ligand-dependent inhibitors, such as decoy receptors, peptides, or antagonistic monoclonal antibodies, which aim to block the interaction between the receptor and its ligands.
However, these ligand-dependent strategies face several challenges. First, preclinical studies may not fully capture the complexity of ligand interactions in humans, where multiple known and unknown ligands compete for receptor binding. Second, decoy peptides may exhibit off-target effects due to ligand promiscuity. Third, pan-TREM-1 or TREM-2 inhibitors may affect cells with different roles in disease pathogenesis, potentially leading to unintended consequences. For example, LR12, a peptide inhibitor of TREM-1, failed to meet its primary endpoint in a Phase IIb sepsis trial, despite demonstrating safety in humans.
Ligand-Independent Inhibition as a Solution
Ligand-independent inhibition strategies offer a potential solution to these challenges. These strategies target the interactions between receptor subunits, such as TREM-1 and DAP-12, disrupting downstream signaling regardless of ligand binding. For example, the TREM-1 inhibitory peptide GF9 disrupts the interaction between TREM-1 and DAP-12, preventing the formation of DAP-12 homooligomers and blocking transmembrane signaling. Similarly, peptide IA9 inhibits TREM-2 in a ligand-independent manner.
In addition to bypassing ligand competition, ligand-independent inhibitors can also be designed for targeted delivery to specific cell types. For example, macrophage-targeted formulations of GF9 have shown efficacy in suppressing TREM-1-mediated macrophage activation and ameliorating inflammatory diseases in animal models. This targeted approach can minimize off-target effects and maximize therapeutic efficacy.
Broader Implications for Multiligand Receptors
The challenges and potential solutions discussed for TREM-1 and TREM-2 may also apply to other multiligand receptors, such as toll-like receptors (TLRs), receptor for advanced glycation end products (RAGE), CD36, and scavenger receptors. Like TREM-1 and TREM-2, these receptors interact with multiple ligands and have been implicated in various diseases. Ligand-independent inhibition strategies may offer a more effective and targeted approach to modulating their activity.
Conclusion
Ligand-independent inhibition represents a promising alternative strategy for targeting TREM-1, TREM-2, and other multiligand receptors in human disease. By addressing the multiplicity and promiscuity of ligands, as well as the differential roles played by these receptors on different cells, this approach may mitigate the risk of clinical failure and improve the odds of developing novel and effective therapies.
