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Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):E6506-14. doi: 10.1073/pnas.1519623112. Epub 2015 Nov 10.

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305; Department of Pathology, Stanford University Medical Center, Stanford, CA 94305;
2
Department of Radiology, Molecular Imaging Program at Stanford (MIPS), James H. Clark Center, Stanford, CA 94305; Department of Bioengineering, Materials Science and Engineering, Stanford University, Stanford, CA 94305;
3
Department of Radiology, Molecular Imaging Program at Stanford (MIPS), James H. Clark Center, Stanford, CA 94305;
4
Department of Molecular and Cellular Physiology, Stanford University Medical Center, Stanford, CA 94305;
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
6
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305; Department of Pathology, Stanford University Medical Center, Stanford, CA 94305; aaron.ring@yale.edu irv@stanford.edu.

Abstract

Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1-directed immunotherapy could be improved with smaller, nonantibody therapeutics, we used directed evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti-PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high-affinity PD-1 was effective in treating both small (50 mm(3)) and large tumors (150 mm(3)), whereas the activity of anti-PD-L1 antibodies was completely abrogated against large tumors. Furthermore, we found that high-affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1-positive and PD-L1-negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, nonantibody therapeutics for enhanced cancer immunotherapy and immune diagnostics.

KEYWORDS:

PD-1; PD-L1; PET imaging; cancer immunotherapy; protein engineering

PMID:
26604307
PMCID:
PMC4664306
DOI:
10.1073/pnas.1519623112
[Indexed for MEDLINE]
Free PMC Article
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