Journal Article
. 2015 Nov; 112(47):E6506-14.
doi: 10.1073/pnas.1519623112.

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

Roy L Maute 1 Sydney R Gordon 1 Aaron T Mayer 2 Melissa N McCracken 1 Arutselvan Natarajan 3 Nan Guo Ring 1 Richard Kimura 3 Jonathan M Tsai 1 Aashish Manglik 4 Andrew C Kruse 5 Sanjiv S Gambhir 2 Irving L Weissman 6 Aaron M Ring 6 
  • PMID: 26604307
  •     33 References
  •     118 citations


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.

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ACS Chem Biol, 2020 May 01; 15(6). PMID: 32352272    Free PMC article.
CD47 prevents the elimination of diseased fibroblasts in scleroderma.
Tristan Lerbs, Lu Cui, +7 authors, Gerlinde Wernig.
JCI Insight, 2020 Aug 21; 5(16). PMID: 32814713    Free PMC article.
Evaluating a Single Domain Antibody Targeting Human PD-L1 as a Nuclear Imaging and Therapeutic Agent.
Katrijn Broos, Quentin Lecocq, +9 authors, Karine Breckpot.
Cancers (Basel), 2019 Jun 27; 11(6). PMID: 31234464    Free PMC article.
A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma Model.
Zhibing Lin, Yan Zhang, +4 authors, Rongxiu Li.
Mol Ther Oncolytics, 2019 Aug 07; 14. PMID: 31384666    Free PMC article.
Tumor-Directed Blockade of CD47 with Bispecific Antibodies Induces Adaptive Antitumor Immunity.
Elie Dheilly, Stefano Majocchi, +9 authors, Krzysztof Masternak.
Antibodies (Basel), 2018 Jan 03; 7(1). PMID: 31544856    Free PMC article.
Image-guided mathematical modeling for pharmacological evaluation of nanomaterials and monoclonal antibodies.
Prashant Dogra, Joseph D Butner, +12 authors, Zhihui Wang.
Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2020 Apr 22; 12(5). PMID: 32314552    Free PMC article.
89Zr-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs.
Elly L van der Veen, Danique Giesen, +3 authors, Marjolijn N Lub-de Hooge.
J Immunother Cancer, 2020 Oct 07; 8(2). PMID: 33020241    Free PMC article.
Positron Emission Tomography for Response Evaluation in Microenvironment-Targeted Anti-Cancer Therapy.
Noboru Oriuchi, Shigeyasu Sugawara, Tohru Shiga.
Biomedicines, 2020 Sep 26; 8(9). PMID: 32972006    Free PMC article.
Application and Prospects of Molecular Imaging in Immunotherapy.
Weiqing Wang, Zhenhua Gao, +4 authors, Xue Meng.
Cancer Manag Res, 2020 Oct 17; 12. PMID: 33061627    Free PMC article.
Quantifying PD-L1 Expression to Monitor Immune Checkpoint Therapy: Opportunities and Challenges.
Sridhar Nimmagadda.
Cancers (Basel), 2020 Nov 04; 12(11). PMID: 33137949    Free PMC article.
PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model.
Neta Rosenzweig, Raz Dvir-Szternfeld, +9 authors, Michal Schwartz.
Nat Commun, 2019 Jan 30; 10(1). PMID: 30692527    Free PMC article.
Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology.
Hyun Tae Lee, Sang Hyung Lee, Yong-Seok Heo.
Molecules, 2019 Mar 29; 24(6). PMID: 30917623    Free PMC article.
SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.
Siwen Hu-Lieskovan, Srabani Bhaumik, +14 authors, Holden T Maecker.
J Immunother Cancer, 2020 Dec 04; 8(2). PMID: 33268350    Free PMC article.
An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2.
Takuya Tada, Chen Fan, +7 authors, Nathaniel R Landau.
Cell Rep, 2020 Dec 17; 33(12). PMID: 33326798    Free PMC article.
Multimodal Molecular Imaging of the Tumour Microenvironment.
Claudia Foray, Cristina Barca, +7 authors, Bastian Zinnhardt.
Adv Exp Med Biol, 2020 Feb 08; 1225. PMID: 32030648
Noninvasive Imaging of Cancer Immunotherapy.
Omar Abousaway, Taha Rakhshandehroo, +2 authors, Mohammad Rashidian.
Nanotheranostics, 2021 Jan 05; 5(1). PMID: 33391977    Free PMC article.
Peptide-Based Nanomaterials for Tumor Immunotherapy.
Lingyun Li, Bing Ma, Weizhi Wang.
Molecules, 2021 Jan 06; 26(1). PMID: 33396754    Free PMC article.
Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles.
Zhaohan Wei, Xiaoqiong Zhang, +13 authors, Xiangliang Yang.
Nat Commun, 2021 Jan 21; 12(1). PMID: 33469052    Free PMC article.
Computer-aided design of PVR mutants with enhanced binding affinity to TIGIT.
Xiaowen Zhou, Jiangfeng Du, +12 authors, Yanfeng Gao.
Cell Commun Signal, 2021 Feb 10; 19(1). PMID: 33557880    Free PMC article.
Tumor Burden and Immunotherapy: Impact on Immune Infiltration and Therapeutic Outcomes.
Samuel I Kim, Christopher R Cassella, Katelyn T Byrne.
Front Immunol, 2021 Feb 19; 11. PMID: 33597954    Free PMC article.
In Vivo Evaluation and Dosimetry Estimate for a High Affinity Affibody PET Tracer Targeting PD-L1.
Daniel J Rubins, Xiangjun Meng, +16 authors, Jeffrey L Evelhoch.
Mol Imaging Biol, 2020 Oct 25; 23(2). PMID: 33098025
Combination of vasculature targeting, hypofractionated radiotherapy, and immune checkpoint inhibitor elicits potent antitumor immune response and blocks tumor progression.
Stefano Pierini, Abhishek Mishra, +10 authors, Andrea Facciabene.
J Immunother Cancer, 2021 Feb 11; 9(2). PMID: 33563772    Free PMC article.
Imaging-based Biomarkers for Predicting and Evaluating Cancer Immunotherapy Response.
Minghao Wu, Yanyan Zhang, +3 authors, Zhaoxiang Ye.
Radiol Imaging Cancer, 2019 Nov 29; 1(2). PMID: 33778682    Free PMC article.
First immunotherapeutic CAR-T cells against the immune checkpoint protein HLA-G.
François Anna, Elodie Bole-Richard, +9 authors, Julien Caumartin.
J Immunother Cancer, 2021 Mar 20; 9(3). PMID: 33737343    Free PMC article.
Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy.
Siqi Chen, Seigmund W T Lai, Christine E Brown, Mingye Feng.
Front Immunol, 2021 Apr 02; 12. PMID: 33790906    Free PMC article.
Blocking of the PD-1/PD-L1 interaction by a novel cyclic peptide inhibitor for cancer immunotherapy.
Wenjie Zhai, Xiuman Zhou, +8 authors, Yanfeng Gao.
Sci China Life Sci, 2020 Aug 02; 64(4). PMID: 32737851
Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy.
Jing Liu, Zhihao Zhao, +7 authors, Youqing Shen.
Nat Commun, 2021 Apr 25; 12(1). PMID: 33893275    Free PMC article.
Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture.
Jan P Bogen, Stefania C Carrara, +3 authors, Harald Kolmar.
Front Immunol, 2021 May 28; 12. PMID: 34040611    Free PMC article.
Alternative and New Radiopharmaceutical Agents for Lung Cancer.
Silvi Telo, Letizia Calderoni, +3 authors, Stefano Fanti.
Curr Radiopharm, 2019 Dec 24; 13(3). PMID: 31868150    Free PMC article.
Preclinical development and characterisation of 99mTc-NM-01 for SPECT/CT imaging of human PD-L1.
Nicholas Cl Wong, Yina Cai, +4 authors, Felix M Mottaghy.
Am J Nucl Med Mol Imaging, 2021 Jul 09; 11(3). PMID: 34234994    Free PMC article.
Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer.
Yu Rebecca Miao, Kaushik N Thakkar, +15 authors, Amato J Giaccia.
Clin Cancer Res, 2021 May 21; 27(15). PMID: 34011561    Free PMC article.
Novel oncolytic adenovirus expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitor activates multiple immune effector populations leading to enhanced tumor killing in vitro, in vivo and with patient-derived tumor organoids.
Firas Hamdan, Erkko Ylösmäki, +18 authors, Vincenzo Cerullo.
J Immunother Cancer, 2021 Aug 08; 9(8). PMID: 34362830    Free PMC article.
In Vivo Cell Tracking Using PET: Opportunities and Challenges for Clinical Translation in Oncology.
Laura M Lechermann, Doreen Lau, +2 authors, Ferdia A Gallagher.
Cancers (Basel), 2021 Aug 28; 13(16). PMID: 34439195    Free PMC article.
Molecular Imaging and the PD-L1 Pathway: From Bench to Clinic.
David Leung, Samuel Bonacorsi, +2 authors, Wendy Hayes.
Front Oncol, 2021 Sep 10; 11. PMID: 34497758    Free PMC article.
Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics.
Dhiraj Kumar, Akhilesh Mishra, +15 authors, Sridhar Nimmagadda.
Proc Natl Acad Sci U S A, 2021 Sep 12; 118(37). PMID: 34508005    Free PMC article.
High-resolution positron emission microscopy of patient-derived tumor organoids.
Syamantak Khan, June Ho Shin, +5 authors, Guillem Pratx.
Nat Commun, 2021 Oct 09; 12(1). PMID: 34620852    Free PMC article.
Folding in Place: Design of β-Strap Motifs to Stabilize the Folding of Hairpins with Long Loops.
Alexis D Richaud, Guangkuan Zhao, Samir Hobloss, Stéphane P Roche.
J Org Chem, 2021 Sep 10; 86(19). PMID: 34499510    Free PMC article.
Engineering a variant of IL-17RA with high binding affinity to IL-17A for optimized immunotherapy.
Fatemeh Armaghan, Zahra Hajihassan.
Biotechnol Rep (Amst), 2021 Nov 13; 32. PMID: 34765462    Free PMC article.
Preclinical Evaluation of 89Zr-Df-IAB22M2C PET as an Imaging Biomarker for the Development of the GUCY2C-CD3 Bispecific PF-07062119 as a T Cell Engaging Therapy.
Kevin P Maresca, Jianqing Chen, +19 authors, Timothy J McCarthy.
Mol Imaging Biol, 2021 Jun 19; 23(6). PMID: 34143379    Free PMC article.
Engineered extracellular vesicles for concurrent Anti-PDL1 immunotherapy and chemotherapy.
Yundi Chen, Lixue Wang, +6 authors, Yuan Wan.
Bioact Mater, 2021 Nov 26; 9. PMID: 34820569    Free PMC article.
[Construction and evaluation of dual-effect cord blood natural killer cells expressing highaffinity PD-1 and chimeric antigen CD19 receptor].
H Zhong, Q Zou, +6 authors, Q Zou.
Nan Fang Yi Ke Da Xue Xue Bao, 2022 Jan 12; 41(12). PMID: 35012922    Free PMC article.
Combination therapy for mCRPC with immune checkpoint inhibitors, ADT and vaccine: A mathematical model.
Nourridine Siewe, Avner Friedman.
PLoS One, 2022 Jan 12; 17(1). PMID: 35015785    Free PMC article.
The Diagnosis and Management of Immune Checkpoint Inhibitor Cardiovascular Toxicity: Myocarditis and Beyond.
Dan Gilon, Zaza Iakobishvili, David Leibowitz.
Vaccines (Basel), 2022 Feb 27; 10(2). PMID: 35214762    Free PMC article.
Molecular Immune Targeted Imaging of Tumor Microenvironment.
Taha Rakhshandehroo, Bryan Ronain Smith, +2 authors, Neeta Pandit-Taskar.
Nanotheranostics, 2022 Mar 01; 6(3). PMID: 35223381    Free PMC article.
Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
Mengling Wu, Qianrui Huang, +4 authors, Yong Xia.
J Hematol Oncol, 2022 Mar 14; 15(1). PMID: 35279217    Free PMC article.
Imaging immunity in patients with cancer using positron emission tomography.
Fiona Hegi-Johnson, Stacey Rudd, +9 authors, Michael P MacManus.
NPJ Precis Oncol, 2022 Apr 09; 6(1). PMID: 35393508    Free PMC article.
Yeast Surface Display for Protein Engineering: Library Generation, Screening, and Affinity Maturation.
Byong H Kang, Brianna M Lax, K Dane Wittrup.
Methods Mol Biol, 2022 Apr 29; 2491. PMID: 35482183
Engineering a High-Affinity PD-1 Peptide for Optimized Immune Cell-Mediated Tumor Therapy.
Yilei Chen, Hongxing Huang, +5 authors, Hua Wang.
Cancer Res Treat, 2021 Aug 07; 54(2). PMID: 34352997    Free PMC article.
Macrophage-mediated anti-tumor immunity against high-risk neuroblastoma.
Xao X Tang, Hiroyuki Shimada, Naohiko Ikegaki.
Genes Immun, 2022 May 08;. PMID: 35525858
Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities.
Tae Kon Kim, Esten N Vandsemb, Roy S Herbst, Lieping Chen.
Nat Rev Drug Discov, 2022 Jun 15;. PMID: 35701637