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Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy.
- Source :
- Acta Pharmaceutica Sinica B; Mar2024, Vol. 14 Issue 3, p1150-1165, 16p
- Publication Year :
- 2024
-
Abstract
- Aside from antibodies, peptides show great potential as immune checkpoint inhibitors (ICIs) due to several advantages, such as better tumor penetration and lower cost. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1 (FGL1). Here, we found that LAG-3 expression was higher than programmed cell death protein 1 (PD-1) in multiple human cancers by TCGA databases, and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning, which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-II. Subsequently, d -amino acids were introduced to substitute the N- and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1, which restores T cell function in vitro and inhibits tumor growth in vivo. Further, a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1 blocking peptide OPBP-1(8–12), which activates T cell with enhanced proliferation and IFN- γ production. More importantly, LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response. In conclusion, we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function, and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response. The LFP-D1 peptide specifically blocks the interaction between LAG-3 and FGL1, and LFOP peptide provides a biological rationale for co-blockade LAG-3/FGL1 and PD-1/PD-L1 pathway as an effective cancer immunotherapeutic strategy when combined with radiotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 22113835
- Volume :
- 14
- Issue :
- 3
- Database :
- Supplemental Index
- Journal :
- Acta Pharmaceutica Sinica B
- Publication Type :
- Academic Journal
- Accession number :
- 175874341
- Full Text :
- https://doi.org/10.1016/j.apsb.2023.12.011