Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging
Open accessAbstract
Significance: Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) are key targets in the treatment of cancer, but current antibody-based drugs against this pathway have inherent drawbacks that may limit their effectiveness. We used directed evolution with yeast display to engineer a nonantibody biologic based on the ectodomain of PD-1. High-affinity PD-1 was more effective than anti–PD-L1 antibodies in the treatment of mouse tumor models and could additionally be used as a PET imaging tracer to noninvasively assess the PD-L1 expression status of tumors. This engineered protein thus represents an agent useful for clinical translation and highlights the paradigm of small protein biologics for future drug development.
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pdl1_inp_1 bound PD-L1 worse than HAC PD-1 (KD = 110 pM) but better than WT PD-1 (KD = 3.9 μM).
“worse than HAC PD-1 (KD = 110 pM) (38) but better than WT PD-1 (KD = 3.9 μM) (38).”
From Scaffolding protein functional sites using deep learning (2022) · cites this paper as [38]
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“Taking ALX-148 for example, generated via yeast display and directed evolution, its binding affinity has been enhanced to 11 pM (72), whereas hu5F9-G4, generated from hybridomas, binds with CD47 at an affinity of 8 nM, 2 magnitudes lower than ALX-148 (73).”
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- Authors
- Maute, R. L., Gordon, S. R., Mayer, A. T., McCracken, M. N., Natarajan, A., Ring, N. G., Kimura, R., Tsai, J. M., Manglik, A., Kruse, A. C., Gambhir, S. S., Weissman, I. L., & Ring, A. M.
- Affiliations
- Stanford Medicine (US)
- Harvard University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-11-10
- Volume
- 112
- Issue
- 47
- Pages
- E6506-14
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4664306
- OpenAlex
- W2129482327
- Cited by
- 347
- References
- 6
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 23 · 2023: 43 · 2022: 42 · 2021: 45 · 2020: 43 · 2019: 37 · 2018: 33 · 2017: 25 · 2016: 22 · 2015: 1 · 2013: 1
- FWCI
- 11.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Virginia and D.K. Ludwig Fund for Cancer Research (1)
- HHS | NIH | National Cancer Institute (P50A114747, T32CA09151)
- Canary Foundation (2)
- HHS | NIH | National Institute of General Medical Sciences (GM07365)
- Cancer Research Institute (3)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Keywords
- PD-1, PD-L1, immune checkpoint blockade, competitive antagonists, directed evolution, yeast surface display, tumor penetration, Fc effector functions, tumor-infiltrating T cells, immuno-PET, cancer immunotherapy, CT26 cells, tumor size dependence
- MeSH terms
- Amino Acid Sequence, Animals, Disease Models, Animal, Humans, Immunotherapy, Lymphocyte Depletion, Mice, Inbred BALB C, Molecular Sequence Data, Neoplasms, Protein Binding, T-Lymphocytes, Protein Engineering, Directed Molecular Evolution, Cell Line, Tumor, Positron-Emission Tomography, Mutant Proteins, Programmed Cell Death 1 Receptor
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