Using extension-based mRNA display to design antibody-like proteinogenic peptides for human PD-L1
Justin N Ong1,2, Brian J Grindel1, Scott A Rankin3
1Deparment of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Protein Science : a Publication of the Protein Society
|August 25, 2025
Summary
Researchers developed small, protein-based drugs (peptides) that effectively target human programmed death-ligand 1 (hPD-L1). These new peptides offer a more scalable and cost-effective alternative to current antibody therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Peptide drugs often require expensive modifications for efficacy and stability.
- Current peptide drug production faces scalability challenges.
Purpose of the Study:
- To engineer small, linear, proteinogenic peptides targeting human programmed death-ligand 1 (hPD-L1).
- To achieve antibody-like affinity and stability for hPD-L1 binding peptides.
- To explore cost-effective and scalable alternatives to antibody therapeutics.
Main Methods:
- Utilized mRNA display affinity maturation to select high-affinity peptides.
- Characterized peptide binding affinity and selectivity for hPD-L1.
- Assessed peptide stability in human serum and binding to cancer cells.
Main Results:
- Identified SPAM2 and SPAM3 peptides with high affinity (250-300 pM dissociation constants) for hPD-L1.
- Demonstrated selectivity for hPD-L1 and competition with known ligand binding sites.
- Confirmed peptide stability in human serum and high-affinity binding to glioma cells.
Conclusions:
- Affinity maturation is effective for enhancing biophysical properties of linear peptides.
- Engineered peptides SPAM2 and SPAM3 show translational potential for hPD-L1 targeted therapies.
- Developed peptides offer a promising, scalable alternative to antibody-based treatments.
