In Search of Better Peptide-(Derived from PD-L2)-Based Immune Checkpoint Inhibitors
Boris Klebansky1, Marina Backer2, Vitaliy Gorbatyuk3
1BioPredict Inc., 4 Adele Ave., Demarest, NY 07627, USA.
Abstract:
Current anti-cancer immune checkpoint therapy relies on antibodies that primarily target the PD-1/PD-L1(-L2) negative regulatory pathway. Although very successful in some cases for certain cancers, these antibodies do not help most patients who, presumably, should benefit from this type of therapy. Therefore, an unmet clinical need for novel, more effective drugs targeting immune checkpoints remains. We have developed a series of high-potency peptide inhibitors interfering with PD-1/PD-L1(-L2) protein-protein interaction. Our best peptide inhibitors are 12 and 14 amino acids long and show sub-micromolar IC50 inhibitory activity in the in vitro assay. The positioning of the peptides within the PD-1 binding site is explored by extensive modeling. It is further supported by 2D NMR studies of PD-1/peptide complexes. These results reflect substantial progress in the development of immune checkpoint inhibitors using peptidomimetics.
Insights
Novel peptide inhibitors targeting the PD-1/PD-L1 pathway offer a promising new approach for cancer immunotherapy. These potent peptidomimetics show significant in vitro activity, addressing limitations of current antibody therapies.
Area of Science:
- Immunology
- Oncology
- Drug Discovery
Background:
- Current cancer immunotherapies often target the PD-1/PD-L1 pathway but are ineffective for many patients.
- A significant unmet need exists for novel immune checkpoint inhibitors with broader efficacy.
Purpose of the Study:
- To develop novel, high-potency peptide inhibitors targeting the PD-1/PD-L1(-L2) protein-protein interaction.
- To explore the mechanism of action and structural basis of these peptide inhibitors.
Main Methods:
- Development of peptide inhibitors with varying amino acid lengths.
- In vitro assays to determine inhibitory activity (IC50).
- Computational modeling and 2D NMR spectroscopy to study PD-1/peptide complex structures.
Main Results:
- Identified potent peptide inhibitors (12-14 amino acids) with sub-micromolar IC50 values.
- Extensive modeling and 2D NMR studies elucidated peptide positioning within the PD-1 binding site.
- Demonstrated substantial progress in developing peptidomimetic-based immune checkpoint inhibitors.
Conclusions:
- Peptide inhibitors represent a viable and promising alternative to antibody-based therapies for PD-1/PD-L1 immune checkpoint inhibition.
- These findings advance the development of novel cancer immunotherapies with potentially improved patient outcomes.
