Structural and biological characterization of pAC65, a macrocyclic peptide that blocks PD-L1 with equivalent potency
Ismael Rodriguez1, Justyna Kocik-Krol1, Lukasz Skalniak1
1Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, Krakow, 30-387, Poland.
Abstract:
Recent advances in immuno-oncology have opened up new and impressive treatment options for cancer. Notwithstanding, overcoming the limitations of the current FDA-approved therapies with monoclonal antibodies (mAbs) that block the PD-1/PD-L1 pathway continues to lead to the testing of multiple approaches and optimizations. Recently, a series of macrocyclic peptides have been developed that exhibit binding strengths to PD-L1 ranging from sub-micromolar to micromolar. In this study, we present the most potent non-antibody-based PD-1/PD-L1 interaction inhibitor reported to date. The structural and biological characterization of this macrocyclic PD-L1 targeting peptide provides the rationale for inhibition of both PD-1/PD-L1 and CD80/PD-L1 complexes. The IC50 and EC50 values obtained in PD-L1 binding assays indicate that the pAC65 peptide has potency equivalent to the current FDA-approved mAbs and may have similar activity to the BMS986189 peptide, which entered the clinical trial and has favorable safety and pharmacokinetic data. The data presented here delineate the generation of similar peptides with improved biological activities and applications not only in the field of cancer immunotherapy but also in other disorders related to the immune system.
Insights
Researchers developed a potent macrocyclic peptide that inhibits PD-1/PD-L1 interactions, offering a novel non-antibody immunotherapy for cancer. This peptide shows promise for treating various immune system disorders.
Area of Science:
- Immunology
- Oncology
- Drug Discovery
Background:
- Current immuno-oncology therapies using monoclonal antibodies (mAbs) targeting the PD-1/PD-L1 pathway face limitations.
- Development of macrocyclic peptides offers alternative strategies for modulating immune responses.
Discussion:
- This study introduces a novel macrocyclic peptide inhibitor of PD-1/PD-L1 interactions, demonstrating potent binding affinities.
- Structural and biological characterization supports the inhibition of PD-1/PD-L1 and CD80/PD-L1 complexes.
- The peptide exhibits potency comparable to FDA-approved mAbs and a clinically evaluated peptide (BMS986189).
Key Insights:
- The developed peptide is the most potent non-antibody-based inhibitor of PD-1/PD-L1 interactions reported to date.
- The peptide's efficacy in binding assays suggests potential for similar therapeutic activity as existing antibody therapies.
- The findings highlight the potential of macrocyclic peptides in cancer immunotherapy.
Outlook:
- Further development of similar peptides could lead to improved biological activities and broader applications.
- These peptides may serve as alternative treatments for cancer immunotherapy.
- Potential applications extend to other immune system-related disorders beyond cancer.
