Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy

Area of Science:

• Immunology
• Oncology
• Peptide Therapeutics

Background:

• Peptides offer advantages over antibodies as immune checkpoint inhibitors (ICIs), including better tumor penetration and lower cost.
• Lymphocyte-activation gene 3 (LAG-3) is a key immune checkpoint that, upon interaction with fibrinogen-like protein-1 (FGL1), can lead to T cell dysfunction.
• LAG-3 expression is elevated in several human cancers compared to Programmed cell death protein 1 (PD-1).

Purpose of the Study:

• To develop novel peptide-based immune checkpoint inhibitors targeting the LAG-3/FGL1 interaction.
• To engineer a bispecific peptide combining LAG-3 and PD-1 inhibition for enhanced antitumor immunity.
• To evaluate the efficacy of the bispecific peptide in combination with radiotherapy.

Main Methods:

• Phage display bio-panning was used to identify a peptide (LFP-6) that binds to LAG-3 and blocks LAG-3/FGL1 interaction.
• Peptide LFP-6 was modified with d-amino acids to create a proteolysis-resistant version (LFP-D1).
• A bispecific peptide (LFOP) was constructed by conjugating LFP-D1 with a PD-1/PD-L1 blocking peptide (OPBP-1(8-12)).

Main Results:

• LFP-D1 demonstrated the ability to restore T cell function in vitro and inhibit tumor growth in vivo.
• The bispecific peptide LFOP enhanced T cell proliferation and Interferon-gamma (IFN-γ) production.
• Combination therapy with LFOP and radiotherapy significantly increased T cell infiltration in tumors and boosted systemic antitumor immune responses.

Conclusions:

• A novel peptide inhibitor of the LAG-3/FGL1 interaction was successfully developed, capable of restoring T cell function.
• The engineered bispecific peptide LFOP effectively targets both LAG-3/FGL1 and PD-1/PD-L1 pathways.
• The combination of LFOP and radiotherapy presents a promising strategy for enhancing antitumor immune responses and improving cancer treatment outcomes.