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mRNA Display Discovery of a Novel Programmed Death Ligand 1 (PD-L1) Binding Peptide (a Peptide Ligand for PD-L1)
Golnaz Kamalinia1, Brian J Engel2, Anupallavi Srinivasamani3
1Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States.
Abstract:
Programmed death ligand 1 (PD-L1) is a critical immune checkpoint ligand whose overexpression on tumor cells provides a mechanism of escape from immune surveillance. The interaction between PD-L1 and PD-1 on T cell lymphocytes suppresses both T cell activation and effector function and is engaged by cancers to dampen antitumor immunity. Here, we used mRNA display to engineer an 18-residue linear peptide that binds to human PD-L1. This peptide, which we term SPAM (signal peptide-based affinity maturated ligand), is nonhomologous to known PD-L1 binding peptides and mAbs, with dissociation constants (KD) of 119 and 67 nM for unglycosylated and glycosylated human PD-L1, respectively. The SPAM peptide is highly selective for human PD-L1 and shows no significant binding to either mouse PD-L1 or human PD-L2. Competition binding assays indicate that the SPAM peptide binding site overlaps with the binding site of PD-1 as well as therapeutic anti-PD-L1 antibodies. Taken together, these results suggest that the SPAM peptide specifically binds to human PD-L1 and could potentially serve as a PD-L1 affinity agent and PD-L1/PD-1 pathway modulator.
Insights
Researchers engineered SPAM, a novel peptide targeting human Programmed Death Ligand 1 (PD-L1). This peptide selectively binds PD-L1, offering potential for modulating the PD-1/PD-L1 immune checkpoint pathway.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Programmed death ligand 1 (PD-L1) is a key immune checkpoint.
- Overexpression of PD-L1 on tumors facilitates immune evasion.
- The PD-L1/PD-1 interaction inhibits T cell responses against cancer.
Purpose of the Study:
- To engineer a novel peptide binder for human PD-L1.
- To characterize the binding affinity and selectivity of the engineered peptide.
- To explore the potential of the peptide as a PD-L1/PD-1 pathway modulator.
Main Methods:
- mRNA display technology was employed for peptide engineering.
- Binding affinity was determined using dissociation constant (KD) measurements.
- Selectivity was assessed against related proteins and across species.
Main Results:
- An 18-residue linear peptide, termed SPAM, was successfully engineered.
- SPAM exhibits high affinity for human PD-L1 (KD of 119 nM and 67 nM).
- The peptide demonstrates high selectivity for human PD-L1 over mouse PD-L1 and human PD-L2.
Conclusions:
- SPAM specifically binds to human PD-L1.
- The binding site of SPAM overlaps with PD-1 and known anti-PD-L1 antibodies.
- SPAM represents a potential PD-L1 affinity agent for modulating the immune checkpoint pathway.
