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

Affiliations

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.

PMID: 26604307
33 References
118 citations

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.

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References
B7-H1 (PD-L1) on T cells is required for T-cell-mediated conditioning of dendritic cell maturation. Oezcan Talay, Ching-Hung Shen, Lieping Chen, Jianzhu Chen. Proc Natl Acad Sci U S A, 2009 Feb 10; 106(8). PMID: 19202065 Free PMC article.
Small-animal PET imaging of human epidermal growth factor receptor positive tumor with a 64Cu labeled affibody protein. Zheng Miao, Gang Ren, +2 authors, Hongguang Liu, Lei Jiang, Zhen Cheng. less Bioconjug Chem, 2010 Apr 21; 21(5). PMID: 20402512
Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. Kazuyoshi Takeda, Yuko Kojima, +7 authors, Mark J Smyth. less J Immunol, 2010 Apr 20; 184(10). PMID: 20400706
The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors. Carol M Lee, Ian F Tannock. BMC Cancer, 2010 Jun 08; 10. PMID: 20525277 Free PMC article.
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. Julie R Brahmer, Charles G Drake, +17 authors, Suzanne L Topalian. less J Clin Oncol, 2010 Jun 03; 28(19). PMID: 20516446 Free PMC article. Highly Cited.
The PD-1 pathway in tolerance and autoimmunity. Loise M Francisco, Peter T Sage, Arlene H Sharpe. Immunol Rev, 2010 Jul 20; 236. PMID: 20636820 Free PMC article. Highly Cited. Review.
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. Kaori Sakuishi, Lionel Apetoh, +3 authors, Ana C Anderson. less J Exp Med, 2010 Sep 08; 207(10). PMID: 20819927 Free PMC article. Highly Cited.
Hallmarks of cancer: the next generation. Douglas Hanahan, Robert A Weinberg. Cell, 2011 Mar 08; 144(5). PMID: 21376230 Highly Cited. Review.
Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Seng-Ryong Woo, Meghan E Turnis, +18 authors, Dario A A Vignali. less Cancer Res, 2011 Dec 22; 72(4). PMID: 22186141 Free PMC article. Highly Cited.
The determinants of tumour immunogenicity. Thomas Blankenstein, Pierre G Coulie, Eli Gilboa, Elizabeth M Jaffee. Nat Rev Cancer, 2012 Mar 02; 12(4). PMID: 22378190 Free PMC article. Highly Cited. Review.
The blockade of immune checkpoints in cancer immunotherapy. Drew M Pardoll. Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437870 Free PMC article. Highly Cited. Review.
Antibody therapy of cancer. Andrew M Scott, Jedd D Wolchok, Lloyd J Old. Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437872 Highly Cited. Review.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. Suzanne L Topalian, F Stephen Hodi, +27 authors, Mario Sznol. less N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658127 Free PMC article. Highly Cited.
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. Julie R Brahmer, Scott S Tykodi, +23 authors, Jon M Wigginton. less N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658128 Free PMC article. Highly Cited.
Structure and interactions of the human programmed cell death 1 receptor. Xiaoxiao Cheng, Vaclav Veverka, +16 authors, Simon J Davis. less J Biol Chem, 2013 Feb 19; 288(17). PMID: 23417675 Free PMC article. Highly Cited.
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. Omid Hamid, Caroline Robert, +23 authors, Antoni Ribas. less N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724846 Free PMC article. Highly Cited.
Nivolumab plus ipilimumab in advanced melanoma. Jedd D Wolchok, Harriet Kluger, +21 authors, Mario Sznol. less N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724867 Free PMC article. Highly Cited.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada. less J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981 Free PMC article. Highly Cited.
DNA targeting specificity of RNA-guided Cas9 nucleases. Patrick D Hsu, David A Scott, +11 authors, Feng Zhang. less Nat Biotechnol, 2013 Jul 23; 31(9). PMID: 23873081 Free PMC article. Highly Cited.
Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody. Aaron M Ring, Aashish Manglik, +4 authors, Brian K Kobilka. less Nature, 2013 Sep 24; 502(7472). PMID: 24056936 Free PMC article. Highly Cited.
A novel engineered anti-CD20 tracer enables early time PET imaging in a humanized transgenic mouse model of B-cell non-Hodgkins lymphoma. Arutselvan Natarajan, Benjamin J Hackel, Sanjiv Sam Gambhir. Clin Cancer Res, 2013 Oct 08; 19(24). PMID: 24097872
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. Liufu Deng, Hua Liang, +4 authors, Yang-Xin Fu. less J Clin Invest, 2014 Jan 03; 124(2). PMID: 24382348 Free PMC article. Highly Cited.
Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. Lei Lu, Xiaobing Xu, +3 authors, Xuan Wang. less J Transl Med, 2014 Feb 08; 12. PMID: 24502656 Free PMC article.
PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. Zhiqiang Guo, Xin Wang, +3 authors, Dali Cheng, Zhijun Xia, Meng Luan, Shulan Zhang. less PLoS One, 2014 Mar 04; 9(2). PMID: 24586709 Free PMC article. Highly Cited.
PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors. Alena Gros, Paul F Robbins, +13 authors, Steven A Rosenberg. less J Clin Invest, 2014 Mar 29; 124(5). PMID: 24667641 Free PMC article. Highly Cited.
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Roy S Herbst, Jean-Charles Soria, +19 authors, F Stephen Hodi. less Nature, 2014 Nov 28; 515(7528). PMID: 25428504 Free PMC article. Highly Cited.
Nivolumab in previously untreated melanoma without BRAF mutation. Caroline Robert, Georgina V Long, +25 authors, Paolo A Ascierto. less N Engl J Med, 2014 Nov 18; 372(4). PMID: 25399552 Highly Cited.
Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Naiyer A Rizvi, Julien Mazières, +27 authors, Suresh S Ramalingam. less Lancet Oncol, 2015 Feb 24; 16(3). PMID: 25704439 Free PMC article. Highly Cited.
Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. Robert J Motzer, Brian I Rini, +12 authors, Hans J Hammers. less J Clin Oncol, 2014 Dec 03; 33(13). PMID: 25452452 Free PMC article. Highly Cited.
SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. Jens M Chemnitz, Richard V Parry, +2 authors, Kim E Nichols, Carl H June, James L Riley. less J Immunol, 2004 Jul 09; 173(2). PMID: 15240681 Highly Cited.
Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Yoshiko Iwai, Masayoshi Ishida, +3 authors, Nagahiro Minato. less Proc Natl Acad Sci U S A, 2002 Sep 10; 99(19). PMID: 12218188 Free PMC article. Highly Cited.
FcγRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1/PD-L1 Axis. Rony Dahan, Emanuela Sega, +3 authors, Jeffrey V Ravetch. less Cancer Cell, 2015 Sep 17; 28(3). PMID: 26373277 Highly Cited.
The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. David Yin-Wei Lin, Yoshimasa Tanaka, +7 authors, David N Garboczi. less Proc Natl Acad Sci U S A, 2008 Feb 22; 105(8). PMID: 18287011 Free PMC article. Highly Cited.

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A humanized antibody for imaging immune checkpoint ligand PD-L1 expression in tumors. Samit Chatterjee, Wojciech G Lesniak, +6 authors, Sridhar Nimmagadda. less Oncotarget, 2016 Feb 06; 7(9). PMID: 26848870 Free PMC article. Highly Cited.
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Weiping Zou, Jedd D Wolchok, Lieping Chen. Sci Transl Med, 2016 Mar 05; 8(328). PMID: 26936508 Free PMC article. Highly Cited. Review.
Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Jonathan T Sockolosky, Michael Dougan, +5 authors, K Christopher Garcia. less Proc Natl Acad Sci U S A, 2016 Apr 20; 113(19). PMID: 27091975 Free PMC article. Highly Cited.
Quantitative CD3 PET Imaging Predicts Tumor Growth Response to Anti-CTLA-4 Therapy. Benjamin M Larimer, Eric Wehrenberg-Klee, Alexander Caraballo, Umar Mahmood. J Nucl Med, 2016 May 28; 57(10). PMID: 27230929 Free PMC article.
Inhibitors of programmed cell death 1 (PD-1): a patent review (2010-2015). Tryfon Zarganes-Tzitzikas, Markella Konstantinidou, +5 authors, Alexander Dömling. less Expert Opin Ther Pat, 2016 Jul 02; 26(9). PMID: 27367741 Free PMC article.
High-Resolution PET Imaging with Therapeutic Antibody-based PD-1/PD-L1 Checkpoint Tracers. Michael Hettich, Friederike Braun, +2 authors, Gabriele Niedermann. less Theranostics, 2016 Jul 23; 6(10). PMID: 27446497 Free PMC article. Highly Cited.
PD-L1 Detection in Tumors Using [(64)Cu]Atezolizumab with PET. Wojciech G Lesniak, Samit Chatterjee, +4 authors, Sridhar Nimmagadda. less Bioconjug Chem, 2016 Jul 28; 27(9). PMID: 27458027 Free PMC article.
Molecular Imaging of Immunotherapy Targets in Cancer. Emily B Ehlerding, Christopher G England, Douglas G McNeel, Weibo Cai. J Nucl Med, 2016 Jul 30; 57(10). PMID: 27469363 Free PMC article. Review.
Structural basis of anti-PD-L1 monoclonal antibody avelumab for tumor therapy. Kefang Liu, Shuguang Tan, +11 authors, George F Gao. less Cell Res, 2016 Aug 31; 27(1). PMID: 27573173 Free PMC article.
Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant. Roberta Pascolutti, Xianqiang Sun, +4 authors, Andrew C Kruse. less Structure, 2016 Sep 13; 24(10). PMID: 27618663 Free PMC article.
Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Shuguang Tan, Danqing Chen, +9 authors, George F Gao. less Protein Cell, 2016 Nov 07; 7(12). PMID: 27815822 Free PMC article. Review.
Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging. Aaron T Mayer, Arutselvan Natarajan, +5 authors, Sanjiv S Gambhir. less J Nucl Med, 2016 Dec 17; 58(4). PMID: 27980047 Free PMC article.
Rapid PD-L1 detection in tumors with PET using a highly specific peptide. Samit Chatterjee, Wojciech G Lesniak, +8 authors, Sridhar Nimmagadda. less Biochem Biophys Res Commun, 2016 Dec 28; 483(1). PMID: 28025143 Free PMC article.
Noninvasive monitoring of cancer therapy induced activated T cells using [18F]FB-IL-2 PET imaging. S V Hartimath, O Draghiciu, +5 authors, E F J de Vries. less Oncoimmunology, 2017 Feb 16; 6(1). PMID: 28197364 Free PMC article.
Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy. Eszter Lázár-Molnár, Lisa Scandiuzzi, +7 authors, Steven C Almo. less EBioMedicine, 2017 Feb 25; 17. PMID: 28233730 Free PMC article.
Evaluation of response to immune checkpoint inhibitors: Is there a role for positron emission tomography? Matteo Bauckneht, Roberta Piva, +2 authors, Silvia Morbelli. less World J Radiol, 2017 Mar 17; 9(2). PMID: 28298962 Free PMC article.
Non-invasive assessment of murine PD-L1 levels in syngeneic tumor models by nuclear imaging with nanobody tracers. Katrijn Broos, Marleen Keyaerts, +7 authors, Nick Devoogdt. less Oncotarget, 2017 Apr 15; 8(26). PMID: 28410210 Free PMC article.
Nuclear Molecular Imaging Strategies in Immune Checkpoint Inhibitor Therapy. Kasper F Guldbrandsen, Helle W Hendel, Seppo W Langer, Barbara M Fischer. Diagnostics (Basel), 2017 Apr 22; 7(2). PMID: 28430133 Free PMC article. Review.
Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response. Benjamin M Larimer, Eric Wehrenberg-Klee, +5 authors, Umar Mahmood. less Cancer Res, 2017 May 04; 77(9). PMID: 28461564 Free PMC article. Highly Cited.
Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab. Shuguang Tan, Kefang Liu, +4 authors, Jianxun Qi. less Protein Cell, 2017 May 11; 9(1). PMID: 28488247 Free PMC article.
PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Sydney R Gordon, Roy L Maute, +10 authors, Irving L Weissman. less Nature, 2017 May 18; 545(7655). PMID: 28514441 Free PMC article. Highly Cited.
Combination therapy of cancer with cancer vaccine and immune checkpoint inhibitors: A mathematical model. Xiulan Lai, Avner Friedman. PLoS One, 2017 May 26; 12(5). PMID: 28542574 Free PMC article.
Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Mizuki Nishino, Nikhil H Ramaiya, Hiroto Hatabu, F Stephen Hodi. Nat Rev Clin Oncol, 2017 Jun 28; 14(11). PMID: 28653677 Free PMC article. Highly Cited. Review.
Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Hyun Tae Lee, Ju Yeon Lee, +6 authors, Yong-Seok Heo. less Sci Rep, 2017 Jul 19; 7(1). PMID: 28717238 Free PMC article.
Combination therapy for melanoma with BRAF/MEK inhibitor and immune checkpoint inhibitor: a mathematical model. Xiulan Lai, Avner Friedman. BMC Syst Biol, 2017 Jul 21; 11(1). PMID: 28724377 Free PMC article.
Preclinical immunoPET/CT imaging using Zr-89-labeled anti-PD-L1 monoclonal antibody for assessing radiation-induced PD-L1 upregulation in head and neck cancer and melanoma. Masahiro Kikuchi, David A Clump, +6 authors, Robert L Ferris. less Oncoimmunology, 2017 Aug 16; 6(7). PMID: 28811971 Free PMC article.
Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors. Sabrina Rossi, Luca Toschi, +3 authors, Egesta Lopci. less Eur J Nucl Med Mol Imaging, 2017 Aug 18; 44(13). PMID: 28815334 Review.
Identification and characterization of a novel Sso7d scaffold-based binder against Notch1. Tenzin Gocha, Balaji M Rao, Ramanuj DasGupta. Sci Rep, 2017 Sep 22; 7(1). PMID: 28931897 Free PMC article.
PD-L1 is an activation-independent marker of brown adipocytes. Jessica R Ingram, Michael Dougan, +12 authors, Hidde L Ploegh. less Nat Commun, 2017 Sep 25; 8(1). PMID: 28935898 Free PMC article.
Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies. Mengnan He, Yan Chai, +6 authors, George F Gao. less Oncotarget, 2017 Oct 06; 8(40). PMID: 28978021 Free PMC article.
High-affinity human PD-L1 variants attenuate the suppression of T cell activation. Zhaoduan Liang, Ye Tian, +5 authors, Yi Li. less Oncotarget, 2017 Nov 29; 8(51). PMID: 29179441 Free PMC article.
Seeing is believing: anti-PD-1/PD-L1 monoclonal antibodies in action for checkpoint blockade tumor immunotherapy. Shuguang Tan, Catherine W-H Zhang, George F Gao. Signal Transduct Target Ther, 2017 Dec 22; 1. PMID: 29263905 Free PMC article.
The Positive Relationship Between γH2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma. Atsushi Osoegawa, Hitomi Hiraishi, +6 authors, Kenji Sugio. less In Vivo, 2017 Dec 25; 32(1). PMID: 29275316 Free PMC article.
Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with 89Zr in Human Lymphoma Xenografts. Jason T Yoon, Mark S Longtine, Bernadette V Marquez-Nostra, Richard L Wahl. J Nucl Med, 2018 Jan 20; 59(8). PMID: 29348316 Free PMC article.
Combination therapy for cancer with oncolytic virus and checkpoint inhibitor: A mathematical model. Avner Friedman, Xiulan Lai. PLoS One, 2018 Feb 09; 13(2). PMID: 29420595 Free PMC article.
The Immunoimaging Toolbox. Aaron T Mayer, Sanjiv S Gambhir. J Nucl Med, 2018 May 26; 59(8). PMID: 29794226 Free PMC article. Review.
Constrained Combinatorial Libraries of Gp2 Proteins Enhance Discovery of PD-L1 Binders. Max A Kruziki, Vidur Sarma, Benjamin J Hackel. ACS Comb Sci, 2018 May 26; 20(7). PMID: 29799714 Free PMC article.
Defining and Understanding Adaptive Resistance in Cancer Immunotherapy. Tae Kon Kim, Roy S Herbst, Lieping Chen. Trends Immunol, 2018 May 29; 39(8). PMID: 29802087 Free PMC article. Highly Cited. Review.
High-affinity PD-1 molecules deliver improved interaction with PD-L1 and PD-L2. Yanyan Li, Zhaoduan Liang, +9 authors, Yi Li. less Cancer Sci, 2018 Jun 12; 109(8). PMID: 29890018 Free PMC article.
Antigen-Presenting Cell-Intrinsic PD-1 Neutralizes PD-L1 in cis to Attenuate PD-1 Signaling in T Cells. Yunlong Zhao, Devin L Harrison, +3 authors, Yuran Song, Jie Ji, Jun Huang, Enfu Hui. less Cell Rep, 2018 Jul 12; 24(2). PMID: 29996099 Free PMC article.
Noninvasive imaging of the PD-1:PD-L1 immune checkpoint: Embracing nuclear medicine for the benefit of personalized immunotherapy. Katrijn Broos, Quentin Lecocq, +3 authors, Karine Breckpot. less Theranostics, 2018 Jul 22; 8(13). PMID: 30026866 Free PMC article. Review.
Peptide-Based 68Ga-PET Radiotracer for Imaging PD-L1 Expression in Cancer. Ravindra A De Silva, Dhiraj Kumar, +7 authors, Sridhar Nimmagadda. less Mol Pharm, 2018 Jul 25; 15(9). PMID: 30037229 Free PMC article.
A systematic review of the cost and cost-effectiveness studies of immune checkpoint inhibitors. Vivek Verma, Tanja Sprave, +4 authors, Charles R Thomas. less J Immunother Cancer, 2018 Nov 25; 6(1). PMID: 30470252 Free PMC article. Highly Cited. Systematic Review.
Imaging of Precision Therapy for Lung Cancer: Current State of the Art. Hyesun Park, Lynette M Sholl, +2 authors, Hiroto Hatabu, Mark M Awad, Mizuki Nishino. less Radiology, 2019 Aug 07; 293(1). PMID: 31385753 Free PMC article. Review.
Discovery of low-molecular weight anti-PD-L1 peptides for cancer immunotherapy. Hao Liu, Zhen Zhao, +7 authors, Kun Cheng. less J Immunother Cancer, 2019 Oct 24; 7(1). PMID: 31640814 Free PMC article.
CD4+ and CD8a+ PET imaging predicts response to novel PD-1 checkpoint inhibitor: studies of Sym021 in syngeneic mouse cancer models. Lotte K Kristensen, Camilla Fröhlich, +8 authors, Andreas Kjaer. less Theranostics, 2019 Nov 23; 9(26). PMID: 31754392 Free PMC article.
A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery. Shaogeng Tang, Peter S Kim. Proc Natl Acad Sci U S A, 2019 Nov 16; 116(49). PMID: 31727844 Free PMC article.
The CC' loop of IgV domains of the immune checkpoint receptors, plays a key role in receptor:ligand affinity modulation. Shankar V Kundapura, Udupi A Ramagopal. Sci Rep, 2019 Dec 18; 9(1). PMID: 31844079 Free PMC article.
Predictive biomarkers for immune checkpoint blockade and opportunities for combination therapies. Hongxing Shen, Eddy Shih-Hsin Yang, +4 authors, Lewis Zhichang Shi. less Genes Dis, 2020 Feb 12; 6(3). PMID: 32042863 Free PMC article. Review.
A Novel Engineered Small Protein for Positron Emission Tomography Imaging of Human Programmed Death Ligand-1: Validation in Mouse Models and Human Cancer Tissues. Arutselvan Natarajan, Chirag B Patel, +3 authors, Sanjiv S Gambhir. less Clin Cancer Res, 2018 Oct 31; 25(6). PMID: 30373750 Free PMC article.
Imaging of Cancer Immunotherapy: Current Approaches and Future Directions. Mizuki Nishino, Hiroto Hatabu, F Stephen Hodi. Radiology, 2018 Nov 21; 290(1). PMID: 30457485 Free PMC article. Review.
Peptide-based PET quantifies target engagement of PD-L1 therapeutics. Dhiraj Kumar, Ala Lisok, +15 authors, Sridhar Nimmagadda. less J Clin Invest, 2018 Nov 21; 129(2). PMID: 30457978 Free PMC article.
Fragment-based screening of programmed death ligand 1 (PD-L1). Evan Perry, Jonathan J Mills, +8 authors, Stephen Fesik. less Bioorg Med Chem Lett, 2019 Feb 08; 29(6). PMID: 30728114 Free PMC article.
Site-Specific Immuno-PET Tracer to Image PD-L1. Haley L Wissler, Emily B Ehlerding, +11 authors, Rongsheng E Wang. less Mol Pharm, 2019 Mar 16; 16(5). PMID: 30875232 Free PMC article.
How to schedule VEGF and PD-1 inhibitors in combination cancer therapy? Xiulan Lai, Avner Friedman. BMC Syst Biol, 2019 Mar 22; 13(1). PMID: 30894166 Free PMC article.
Computational Redesign of PD-1 Interface for PD-L1 Ligand Selectivity. Rojan Shrestha, Sarah C Garrett, Steven C Almo, Andras Fiser. Structure, 2019 Apr 02; 27(5). PMID: 30930066 Free PMC article.
Lentiviral Vector-Based Dendritic Cell Vaccine Suppresses HIV Replication in Humanized Mice. Thomas D Norton, Anjie Zhen, +3 authors, Nathaniel R Landau. less Mol Ther, 2019 Apr 10; 27(5). PMID: 30962161 Free PMC article.
Bispecific CD3-HAC carried by E1A-engineered mesenchymal stromal cells against metastatic breast cancer by blocking PD-L1 and activating T cells. Yuanyuan Yang, Xiaolong Zhang, +11 authors, Dongsheng Xiong. less J Hematol Oncol, 2019 Apr 27; 12(1). PMID: 31023384 Free PMC article.
Photoacoustic imaging as a tool to probe the tumour microenvironment. Emma Brown, Joanna Brunker, Sarah E Bohndiek. Dis Model Mech, 2019 Jul 25; 12(7). PMID: 31337635 Free PMC article. Review.
Development of [18F]FPy-WL12 as a PD-L1 Specific PET Imaging Peptide. Wojciech G Lesniak, Ronnie C Mease, +7 authors, Sridhar Nimmagadda. less Mol Imaging, 2019 Jun 13; 18. PMID: 31187691 Free PMC article.
Modeling Oncolytic Viral Therapy, Immune Checkpoint Inhibition, and the Complex Dynamics of Innate and Adaptive Immunity in Glioblastoma Treatment. Kathleen M Storey, Sean E Lawler, Trachette L Jackson. Front Physiol, 2020 Mar 21; 11. PMID: 32194436 Free PMC article.
Advances in molecular imaging of immune checkpoint targets in malignancies: current and future prospect. Yang Du, Yinhua Jin, +3 authors, Wei Sun, Junjie Fang, Jianjun Zheng, Jie Tian. less Eur Radiol, 2018 Dec 07; 29(8). PMID: 30506221 Free PMC article. Review.
TNF-α inhibitor reduces drug-resistance to anti-PD-1: A mathematical model. Xiulan Lai, Wenrui Hao, Avner Friedman. PLoS One, 2020 Apr 21; 15(4). PMID: 32310956 Free PMC article.
Concurrent Injection of Unlabeled Antibodies Allows Positron Emission Tomography Imaging of Programmed Cell Death Ligand 1 Expression in an Orthotopic Pancreatic Tumor Model. Jun Zhao, Xiaoxia Wen, +4 authors, Chun Li. less ACS Omega, 2020 Apr 28; 5(15). PMID: 32337408 Free PMC article.
Engineering of a novel subnanomolar affinity fibronectin III domain binder targeting human programmed death-ligand 1. Sindhuja Ramakrishnan, Arutselvan Natarajan, +2 authors, Sanjiv S Gambhir. less Protein Eng Des Sel, 2019 Oct 16; 32(5). PMID: 31612217 Free PMC article.
ImmunoPET: Concept, Design, and Applications. Weijun Wei, Zachary T Rosenkrans, +3 authors, Weibo Cai. less Chem Rev, 2020 Mar 24; 120(8). PMID: 32202104 Free PMC article. Review.
In vivo Imaging Technologies to Monitor the Immune System. Claire E McCarthy, Jordan M White, Nerissa T Viola, Heather M Gibson. Front Immunol, 2020 Jun 26; 11. PMID: 32582173 Free PMC article. Review.
Recombinant Expression and Purification of Extracellular Domain of the Programmed Cell Death Protein Receptor. Adish Zhansaya, Mukantayev Kanatbek, +6 authors, Ramankulov Yerlan. less Rep Biochem Mol Biol, 2020 Jun 26; 8(4). PMID: 32582792 Free PMC article.
mRNA Display Discovery of a Novel Programmed Death Ligand 1 (PD-L1) Binding Peptide (a Peptide Ligand for PD-L1). Golnaz Kamalinia, Brian J Engel, +6 authors, Richard W Roberts. less 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. less 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. less 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. less 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. less 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. less Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2020 Apr 22; 12(5). PMID: 32314552 Free PMC article. Review.
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. less 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. Review.
Application and Prospects of Molecular Imaging in Immunotherapy. Weiqing Wang, Zhenhua Gao, +4 authors, Xue Meng. less Cancer Manag Res, 2020 Oct 17; 12. PMID: 33061627 Free PMC article. Review.
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. Review.
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. less 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. Review.
SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery. Siwen Hu-Lieskovan, Srabani Bhaumik, +14 authors, Holden T Maecker. less 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. less 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. less Adv Exp Med Biol, 2020 Feb 08; 1225. PMID: 32030648 Review.
Noninvasive Imaging of Cancer Immunotherapy. Omar Abousaway, Taha Rakhshandehroo, +2 authors, Mohammad Rashidian. less Nanotheranostics, 2021 Jan 05; 5(1). PMID: 33391977 Free PMC article. Review.
Peptide-Based Nanomaterials for Tumor Immunotherapy. Lingyun Li, Bing Ma, Weizhi Wang. Molecules, 2021 Jan 06; 26(1). PMID: 33396754 Free PMC article. Review.
Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles. Zhaohan Wei, Xiaoqiong Zhang, +13 authors, Xiangliang Yang. less 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. less 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. Review.
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. less 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. less 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, Yuwei Zhang, Ying Liu, Mingjie Wu, Zhaoxiang Ye. less Radiol Imaging Cancer, 2019 Nov 29; 1(2). PMID: 33778682 Free PMC article. Review.
First immunotherapeutic CAR-T cells against the immune checkpoint protein HLA-G. François Anna, Elodie Bole-Richard, +9 authors, Julien Caumartin. less 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. Review.
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. less 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. less 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. less 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. less Curr Radiopharm, 2019 Dec 24; 13(3). PMID: 31868150 Free PMC article. Review.
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. less 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. less 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. less 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, Bala Attili, Luigi Aloj, Ferdia A Gallagher. less Cancers (Basel), 2021 Aug 28; 13(16). PMID: 34439195 Free PMC article. Review.
Molecular Imaging and the PD-L1 Pathway: From Bench to Clinic. David Leung, Samuel Bonacorsi, +2 authors, Ralph Adam Smith, Wolfgang Weber, Wendy Hayes. less Front Oncol, 2021 Sep 10; 11. PMID: 34497758 Free PMC article. Review.
Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics. Dhiraj Kumar, Akhilesh Mishra, +15 authors, Sridhar Nimmagadda. less 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. less 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. less 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. less 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. less 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. Review.
Molecular Immune Targeted Imaging of Tumor Microenvironment. Taha Rakhshandehroo, Bryan Ronain Smith, +2 authors, Neeta Pandit-Taskar. less Nanotheranostics, 2022 Mar 01; 6(3). PMID: 35223381 Free PMC article. Review.
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. less J Hematol Oncol, 2022 Mar 14; 15(1). PMID: 35279217 Free PMC article. Review.
Imaging immunity in patients with cancer using positron emission tomography. Fiona Hegi-Johnson, Stacey Rudd, +9 authors, Michael P MacManus. less NPJ Precis Oncol, 2022 Apr 09; 6(1). PMID: 35393508 Free PMC article. Review.
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. less 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 Review.

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