{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:45:12Z","timestamp":1791639912715,"version":"4.3.4"},"reference-count":135,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T00:00:00Z","timestamp":1583280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1126032"],"award-info":[{"award-number":["1126032"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage therapeutic proteins based on the FN3 domain are beginning to use native fibronectin function as a point of differentiation. The small and simple structure of monomeric monobodies confers increased tissue distribution and reduced half-life, whilst the absence of disulphide bonds improves stability in cytosolic environments. Where multi-specificity is challenging with an antibody format that is prone to mis-pairing between chains, multiple FN3 domains in the fibronectin assembly already interact with a large number of molecules. As such, multiple monobodies engineered for interaction with therapeutic targets are being combined in a similar beads-on-a-string assembly which improves both efficacy and pharmacokinetics. Furthermore, full length fibronectin is able to fold into multiple conformations as part of its natural function and a greater understanding of how mechanical forces allow for the transition between states will lead to advanced applications that truly differentiate the FN3 domain as a therapeutic scaffold.<\/jats:p>","DOI":"10.3390\/cells9030610","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T10:46:08Z","timestamp":1583318768000},"page":"610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8978-3392","authenticated-orcid":false,"given":"Peter G.","family":"Chandler","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2943-9044","authenticated-orcid":false,"given":"Ashley M.","family":"Buckle","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.drudis.2015.09.004","article-title":"Challenges and opportunities for non-antibody scaffold drugs","volume":"20","author":"Phan","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hantschel, O. (2017). Monobodies as possible next-generation protein therapeutics\u2014A perspective. Swiss Med. Wkly., 147.","DOI":"10.4414\/smw.2017.14545"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1002\/pro.3148","article-title":"Monobodies and other synthetic binding proteins for expanding protein science","volume":"26","author":"Sha","year":"2017","journal-title":"Protein Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1006\/jmbi.1998.2238","article-title":"The fibronectin type III domain as a scaffold for novel binding proteins","volume":"284","author":"Koide","year":"1998","journal-title":"J. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/protein\/gzq097","article-title":"Adnectins: Engineered target-binding protein therapeutics","volume":"24","author":"Lipovsek","year":"2011","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1161\/01.ATV.0000223342.15969.7a","article-title":"Plasma fibronectin concentration: A risk factor for arterial thrombosis?","volume":"26","author":"Mosher","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.copbio.2005.06.005","article-title":"Engineered proteins as specific binding reagents","volume":"16","author":"Binz","year":"2005","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e306-e306","DOI":"10.1038\/emm.2017.35","article-title":"Affibody molecules as engineered protein drugs","volume":"49","author":"Frejd","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1016\/j.biochi.2010.03.010","article-title":"Biologic protease inhibitors as novel therapeutic agents","volume":"92","author":"Scott","year":"2010","journal-title":"Biochimie"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13036-015-0004-1","article-title":"Engineering pH responsive fibronectin domains for biomedical applications","volume":"9","author":"Heinzelman","year":"2015","journal-title":"J. Biol. Eng."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6632","DOI":"10.1073\/pnas.0700149104","article-title":"High-affinity single-domain binding proteins with a binary-code interface","volume":"104","author":"Koide","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jmb.2010.06.004","article-title":"Stability and CDR Composition Biases Enrich Binder Functionality Landscapes","volume":"401","author":"Hackel","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1134\/S0022093017060023","article-title":"Fibronectins: Structural-functional relationships","volume":"53","author":"Ivanova","year":"2017","journal-title":"J. Evol. Biochem. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1093\/protein\/gzu016","article-title":"Selection of high-affinity Centyrin FN3 domains from a simple library diversified at a combination of strand and loop positions","volume":"27","author":"Diem","year":"2014","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.str.2011.11.016","article-title":"Structures of Adnectin\/Protein Complexes Reveal an Expanded Binding Footprint","volume":"20","author":"Ramamurthy","year":"2012","journal-title":"Structure"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1073\/pnas.032665299","article-title":"Probing protein conformational changes in living cells by using designer binding proteins: Application to the estrogen receptor","volume":"99","author":"Koide","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.drudis.2009.06.007","article-title":"FN3: A new protein scaffold reaches the clinic","volume":"14","author":"Bloom","year":"2009","journal-title":"Drug Discov. Today"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/protein\/gzy018","article-title":"Synthetic 10FN3-based mono- and bivalent inhibitors of MDM2\/X function","volume":"31","author":"Lau","year":"2018","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1146\/annurev-cellbio-100109-104020","article-title":"Assembly of Fibronectin Extracellular Matrix","volume":"26","author":"Singh","year":"2010","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.jmb.2011.12.019","article-title":"Teaching an old scaffold new tricks: Monobodies constructed using alternative surfaces of the FN3 scaffold","volume":"415","author":"Koide","year":"2012","journal-title":"J. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5505","DOI":"10.1021\/bi500758u","article-title":"Converting a binding protein into a biosensing conformational switch using protein fragment exchange","volume":"53","author":"Zheng","year":"2014","journal-title":"Biochemistry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ymeth.2018.09.010","article-title":"Bispecific applications of non-immunoglobulin scaffold binders","volume":"154","author":"Hober","year":"2019","journal-title":"Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.yexcr.2011.02.013","article-title":"Introduction to current and future protein therapeutics: A protein engineering perspective","volume":"317","author":"Carter","year":"2011","journal-title":"Exp. Cell Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.coche.2018.01.004","article-title":"Emerging trends in bispecific antibody and scaffold protein therapeutics","volume":"19","author":"Verdino","year":"2018","journal-title":"Curr. Opin. Chem. Eng."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0092-8674(00)81002-8","article-title":"2.0 \u00c5 Crystal Structure of a Four-Domain Segment of Human Fibronectin Encompassing the RGD Loop and Synergy Region","volume":"84","author":"Leahy","year":"1996","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/B978-0-12-396962-0.00006-9","article-title":"Target-binding proteins based on the 10th human fibronectin type III domain (10Fn3)","volume":"503","author":"Koide","year":"2012","journal-title":"Methods Enzymol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1110\/ps.062498407","article-title":"Design, expression, and stability of a diverse protein library based on the human fibronectin type III domain","volume":"16","author":"Olson","year":"2007","journal-title":"Protein Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1021\/cb800069c","article-title":"mRNA display selection of a high-affinity, modification-specific phospho-i\u03bab\u03b1-binding fibronectin","volume":"3","author":"Olson","year":"2008","journal-title":"ACS Chem. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.neuron.2013.04.017","article-title":"Recombinant Probes for Visualizing Endogenous Synaptic Proteins in Living Neurons","volume":"78","author":"Gross","year":"2013","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1021\/acschembio.8b00513","article-title":"\u03b11-FANGs: Protein Ligands Selective for the \u03b1-Bungarotoxin Site of the \u03b11-Nicotinic Acetylcholine Receptor","volume":"13","author":"Nichols","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/protein\/gzu024","article-title":"Stabilization of the third fibronectin type III domain of human tenascin-C through minimal mutation and rational design","volume":"27","author":"Gilbreth","year":"2014","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9633","DOI":"10.1073\/pnas.0609901104","article-title":"Designing an extracellular matrix protein with enhanced mechanical stability","volume":"104","author":"Ng","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/978-1-4939-9869-2_10","article-title":"Strategies for Increasing Protein Stability","volume":"Volume 2073","author":"Gerrard","year":"2020","journal-title":"Methods in Molecular Biology, Protein Nanotechnology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/protein\/gzr064","article-title":"Design of novel FN3 domains with high stability by a consensus sequence approach","volume":"25","author":"Jacobs","year":"2012","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_35","first-page":"563","article-title":"Engineering a targeted delivery platform using Centyrins","volume":"29","author":"Goldberg","year":"2016","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/protein\/gzv002","article-title":"Structural and dynamic properties that govern the stability of an engineered fibronectin type III domain","volume":"28","author":"Porebski","year":"2015","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cbpa.2009.04.627","article-title":"Engineered protein scaffolds as next-generation antibody therapeutics","volume":"13","author":"Gebauer","year":"2009","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/B978-0-12-394292-0.00014-X","article-title":"Engineering Fibronectin-Based Binding Proteins by Yeast Surface Display","volume":"Volume 523","author":"Keating","year":"2013","journal-title":"Methods in Enzymology, Methods in Protein Design"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1002\/cpch.39","article-title":"Generating FN3-Based Affinity Reagents through Phage Display","volume":"10","author":"Gorman","year":"2018","journal-title":"Curr. Protoc. Chem. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/S1074-5521(02)00187-4","article-title":"Directed Evolution of High-Affinity Antibody Mimics Using mRNA Display","volume":"9","author":"Xu","year":"2002","journal-title":"Chem. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/j.bbrc.2019.04.041","article-title":"Construction of small molecular CTLA4 analogs with CD80-binding affinity","volume":"513","author":"Liu","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4526","DOI":"10.1021\/acs.biochem.8b00408","article-title":"Engineering a Protein Binder Specific for p38\u03b1 with Interface Expansion","volume":"57","author":"Hussain","year":"2018","journal-title":"Biochemistry"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lewis, S.M., and Kuhlman, B.A. (2011). Anchored design of protein-protein interfaces. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020872"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.ymeth.2004.04.007","article-title":"Stability improvement of antibodies for extracellular and intracellular applications: CDR grafting to stable frameworks and structure-based framework engineering","volume":"34","author":"Ewert","year":"2004","journal-title":"Methods"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1126\/science.2451287","article-title":"Reshaping human antibodies: Grafting an antilysozyme activity","volume":"239","author":"Verhoeyen","year":"1988","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1093\/protein\/gzw046","article-title":"Circumventing the stability-function trade-off in an engineered FN3 domain","volume":"29","author":"Porebski","year":"2016","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"199","DOI":"10.4161\/mabs.2.2.11304","article-title":"Anti-tumor effect of CT-322 as an Adnectin inhibitor of vascular endothelial growth factor receptor-2","volume":"2","author":"Mamluk","year":"2010","journal-title":"mAbs"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s10637-014-0186-2","article-title":"Phase 2 study of CT-322, a targeted biologic inhibitor of VEGFR-2 based on a domain of human fibronectin, in recurrent glioblastoma","volume":"33","author":"Schiff","year":"2015","journal-title":"Investig. New Drugs"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/JCO.2010.32.2701","article-title":"Lessons from the adjuvant bevacizumab trial on colon cancer: What next?","volume":"29","author":"Lambrechts","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1038\/s41598-019-39776-0","article-title":"Enhancing bioactivity, physicochemical, and pharmacokinetic properties of a nano-sized, anti-VEGFR2 Adnectin, through PASylation technology","volume":"9","author":"Aghaabdollahian","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1007\/s10529-019-02731-0","article-title":"Extracellular production of recombinant N-glycosylated anti-VEGFR2 monobody in leaky Escherichia coli strain","volume":"41","author":"Ding","year":"2019","journal-title":"Biotechnol. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.7150\/thno.15169","article-title":"Ultrasound molecular imaging of the breast cancer neovasculature using engineered fibronectin scaffold ligands: A novel class of targeted contrast ultrasound agent","volume":"6","author":"Wilson","year":"2016","journal-title":"Theranostics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9021","DOI":"10.18632\/oncotarget.24078","article-title":"VEGFR2-specific FnCAR effectively redirects the cytotoxic activity of T cells and YT NK cells","volume":"9","author":"Kulemzin","year":"2018","journal-title":"Oncotarget"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1016\/j.jmb.2017.03.023","article-title":"Selective Targeting of SH2 Domain\u2013Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies","volume":"429","author":"Schmit","year":"2017","journal-title":"J. Mol. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"201906024","DOI":"10.1073\/pnas.1906024116","article-title":"Allosteric modulation of a human protein kinase with monobodies","volume":"116","author":"Zorba","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.str.2018.02.004","article-title":"Cork-in-Bottle Occlusion of Fluoride Ion Channels by Crystallization Chaperones","volume":"26","author":"McIlwain","year":"2018","journal-title":"Structure"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nrd.2016.268","article-title":"Strategies and challenges for the next generation of antibody-drug conjugates","volume":"16","author":"Beck","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/protein\/gzy013","article-title":"Adnectin\u2013drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors","volume":"31","author":"Carvajal","year":"2018","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Deonarain, M., Yahioglu, G., Stamati, I., Pomowski, A., Clarke, J., Edwards, B., Diez-Posada, S., and Stewart, A. (2018). Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours?. Antibodies, 7.","DOI":"10.3390\/antib7020016"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.4155\/bio-2018-0201","article-title":"Bioanalytical workflow for novel scaffold protein-drug conjugates: Quantitation of total Centyrin protein, conjugated Centyrin and free payload for Centyrin-drug conjugate in plasma and tissue samples using liquid chromatography-tandem mass spectrometry","volume":"10","author":"Shi","year":"2018","journal-title":"Bioanalysis"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5314","DOI":"10.1021\/acs.analchem.8b00411","article-title":"LC\/MS\/MS Bioanalysis of Protein-Drug Conjugates\u2014The Importance of Incorporating Succinimide Hydrolysis Products","volume":"90","author":"Shi","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1158\/1078-0432.CCR-18-1871","article-title":"A Novel Engineered Small Protein for Positron Emission Tomography Imaging of Human Programmed Death Ligand-1: Validation in Mouse Models and Human Cancer Tissues","volume":"25","author":"Natarajan","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1021\/acschembio.9b00113","article-title":"Targeted Protein Degradation through Cytosolic Delivery of Monobody Binders Using Bacterial Toxins","volume":"14","author":"Schmit","year":"2019","journal-title":"ACS Chem. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.jmb.2016.11.008","article-title":"RasIns: Genetically Encoded Intrabodies of Activated Ras Proteins","volume":"429","author":"Cetin","year":"2017","journal-title":"J. Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Ramakrishnan, S., Natarajan, A., Chan, C.T., Panesar, P.S., and Gambhir, S.S. (2019). Engineering of a novel subnanomolar affinity fibronectin III domain binder targeting human programmed death-ligand 1. Protein Eng. Des. Sel.","DOI":"10.1093\/protein\/gzz030"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.7150\/thno.24762","article-title":"Noninvasive imaging of the PD-1: PD-L1 immune checkpoint: Embracing nuclear medicine for the benefit of personalized immunotherapy","volume":"8","author":"Broos","year":"2018","journal-title":"Theranostics"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"529","DOI":"10.2967\/jnumed.117.199596","article-title":"Synthesis and Biologic Evaluation of a Novel 18 F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression","volume":"59","author":"Donnelly","year":"2018","journal-title":"J. Nucl. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1200\/JCO.2018.36.5_suppl.139","article-title":"Whole body PD-L1 PET in patients with NSCLC and melanoma","volume":"36","author":"Leung","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/978-1-4939-9654-4_20","article-title":"FN3 Protein Conjugates for Cancer Diagnosis and Imaging Studies","volume":"Volume 2033","author":"Massa","year":"2019","journal-title":"Methods in Molecular Biology, Bioconjugation"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1021\/acs.bioconjchem.7b00566","article-title":"Evaluation of a Centyrin-Based Near-Infrared Probe for Fluorescence-Guided Surgery of Epidermal Growth Factor Receptor Positive Tumors","volume":"28","author":"Mahalingam","year":"2017","journal-title":"Bioconjugate Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep01156","article-title":"PAPTi: A peptide aptamer interference toolkit for perturbation of protein-protein interaction networks","volume":"3","author":"Yeh","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/s41589-018-0099-z","article-title":"Facile target validation in an animal model with intracellularly expressed monobodies","volume":"14","author":"Gupta","year":"2018","journal-title":"Nat. Chem. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1021\/acscentsci.9b00127","article-title":"Broad-Spectrum Proteome Editing with an Engineered Bacterial Ubiquitin Ligase Mimic","volume":"5","author":"Ludwicki","year":"2019","journal-title":"ACS Cent. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"170066","DOI":"10.1098\/rsob.170066","article-title":"Targeting endogenous proteins for degradation through the affinity-directed protein missile system","volume":"7","author":"Fulcher","year":"2017","journal-title":"Open Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1517\/13543776.2015.1007954","article-title":"Fibronectin-based scaffold domain proteins that bind myostatin: A patent evaluation of WO2014043344","volume":"25","author":"Walker","year":"2015","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/bab.1762","article-title":"Fusion with an albumin-binding domain improves pharmacokinetics of an \u03b1v\u03b23-integrin binding fibronectin scaffold protein","volume":"66","author":"Gapizov","year":"2019","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1093\/protein\/gzv040","article-title":"Fusion to a highly stable consensus albumin binding domain allows for tunable pharmacokinetics","volume":"28","author":"Jacobs","year":"2015","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"eaat0882","DOI":"10.1126\/scitranslmed.aat0882","article-title":"Identification of biologic agents to neutralize the bicomponent leukocidins of Staphylococcus aureus","volume":"11","author":"Chan","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1093\/cvr\/cvz003","article-title":"Novel strategies to target proprotein convertase subtilisin kexin 9: Beyond monoclonal antibodies","volume":"115","author":"Seidah","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1001\/jama.2017.9924","article-title":"Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial","volume":"318","author":"Kazi","year":"2017","journal-title":"JAMA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1124\/jpet.114.214221","article-title":"Pharmacologic Profile of the Adnectin BMS-962476, a Small Protein Biologic Alternative to PCSK9 Antibodies for Low-Density Lipoprotein Lowering","volume":"350","author":"Mitchell","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"A1372","DOI":"10.1016\/S0735-1097(14)61372-3","article-title":"Ldl Cholesterol Reduction With Bms-962476, an Adnectin Inhibitor of Pcsk9: Results of a Single Ascending Dose Study","volume":"63","author":"Stein","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1124\/jpet.117.246652","article-title":"Generation and Characterization of a Novel Small Biologic Alternative to Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) Antibodies, DS-9001a, Albumin Binding Domain\u2013Fused Anticalin Protein","volume":"365","author":"Masuda","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1016\/S0735-1097(19)32320-4","article-title":"Low Density Lipoprotein Cholesterol Reduction and Safety With Lib003, an Anti-Proprotein Convertase Subtilisin\/Kexin Type 9 Fusion Protein: Results of a Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study","volume":"73","author":"Stein","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1016\/j.atherosclerosis.2019.06.019","article-title":"Safety, Tolerability And Ldl-C Reduction With A Novel Anti-Pcsk9 Recombinant Fusion Protein (Lib003): Results Of A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study","volume":"287","author":"Stein","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/S1474-4422(19)30200-5","article-title":"Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): A randomised, double-blind, placebo-controlled phase 2b trial","volume":"18","author":"Hanna","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"193","DOI":"10.4155\/bio.15.238","article-title":"LC-MS\/MS multiplexed assay for the quantitation of a therapeutic protein BMS-986089 and the target protein Myostatin","volume":"8","author":"Zhu","year":"2016","journal-title":"Bioanalysis"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"S94","DOI":"10.1016\/j.nmd.2016.06.036","article-title":"BMS-986089 is a high affinity anti-myostatin adnectin that increases muscle volume in three preclinical species","volume":"26","author":"Madireddi","year":"2016","journal-title":"Neuromuscul. Disord."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"S95","DOI":"10.1016\/j.nmd.2016.06.037","article-title":"BMS-986089: A novel adnectin protein that dose dependently lowers free myostatin and increases muscle volume and lean body mass","volume":"26","author":"Jacobsen","year":"2016","journal-title":"Neuromuscul. Disord."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Wagner, K.R., Wong, B.L., Byrne, B.J., Tian, C., Jacobsen, L.K., Tirucherai, G.S., Rabbia, M., Kletzl, H., Dukart, J., and Ong, R. (2019, January 4\u201310). A Phase 1b\/2 Study of the Anti-Myostatin Adnectin RG6206 (BMS-986089) in Ambulatory Boys with Duchenne Muscular Dystrophy: A 72-Week Treatment Update (P1.6-062). Proceedings of the 71st Annual Meeting of the American-Academy-of-Neurology (AAN), Philadelphia, PA, USA. Abstract P1.6-062.","DOI":"10.1212\/WNL.92.15_supplement.P1.6-062"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1158\/1535-7163.MCT-12-1107","article-title":"Multivalent scaffold proteins as superagonists of TRAIL receptor 2-induced apoptosis","volume":"12","author":"Swers","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2019.04.006","article-title":"A review of bispecific antibodies and antibody constructs in oncology and clinical challenges","volume":"201","author":"Suurs","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1080\/19420862.2018.1424611","article-title":"Fc\u03b3RII-binding Centyrins mediate agonism and antibody-dependent cellular phagocytosis when fused to an anti-OX40 antibody","volume":"10","author":"Zhang","year":"2018","journal-title":"mAbs"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1016\/j.ymthe.2017.07.009","article-title":"Adnectin-Based Design of Chimeric Antigen Receptor for T Cell Engineering","volume":"25","author":"Han","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1182\/blood.V128.22.2127.2127","article-title":"A Novel Bcma-Specific, Centyrin-Based CAR-T Product for the Treatment of Multiple Myeloma","volume":"128","author":"Hermanson","year":"2016","journal-title":"Blood"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Smith, J.B., Codde, R., Tan, Y., Barnett, B.E., Hermanson, D., Rengarajan, S., Ostertag, E.M., and Shedlock, D.J. (2017, January 2\u20135). Abstract A071: PSMA-specific CARTyrin T-stem cell memory therapy eliminates solid tumor in subcutaneous prostate cancer model. Proceedings of the AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, Orlando, FL, USA. Abstract A071.","DOI":"10.1158\/1538-7445.PRCA2017-A071"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Gregory, T.K., Berdeja, J.G., Patel, K.K., Ali, S.A., Cohen, A.D., Costello, C., Ostertag, E.M., de Silva, N., Shedlock, D.J., and Resler, M. (2018, January 14\u201318). Abstract CT130: Clinical trial of P-BCMA-101 T stem cell memory (Tscm) CAR-T cells in relapsed\/refractory (r\/r) multiple myeloma (MM). Proceedings of the Annual Meeting of the American-Association-for-Cancer-Research (AACR), Chicago, IL, USA. Abstract CT130.","DOI":"10.1158\/1538-7445.AM2018-CT130"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3184-3184","DOI":"10.1182\/blood-2019-129562","article-title":"Phase 2 Study of the Response and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed\/Refractory (r\/r) Multiple Myeloma (MM) (PRIME)","volume":"134","author":"Costello","year":"2019","journal-title":"Blood"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1021\/acs.biochem.9b00037","article-title":"Human Antibody Bispecifics through Phage Display Selection","volume":"58","author":"Luthra","year":"2019","journal-title":"Biochemistry"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s10456-012-9294-9","article-title":"Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing\u2019s sarcoma A673-xenograft growth and normalize tumor vascular architecture","volume":"15","author":"Ackermann","year":"2012","journal-title":"Angiogenesis"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"38","DOI":"10.4161\/mabs.3.1.14168","article-title":"A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor","volume":"3","author":"Emanuel","year":"2011","journal-title":"mAbs"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e00508-17","DOI":"10.1128\/AAC.00508-17","article-title":"Discovery and Characterization of a Novel CD4-Binding Adnectin with Potent Anti-HIV Activity","volume":"61","author":"Wensel","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e00421-18","DOI":"10.1128\/JVI.00421-18","article-title":"A Novel gp41-Binding Adnectin with Potent Anti-HIV Activity Is Highly Synergistic when Linked to a CD4-Binding Adnectin","volume":"92","author":"Wensel","year":"2018","journal-title":"J. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.tibtech.2010.03.007","article-title":"Multivalent antibodies: When design surpasses evolution","volume":"28","author":"Cuesta","year":"2010","journal-title":"Trends Biotechnol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Karnell, J.L., Albulescu, M., Drabic, S., Wang, L., Moate, R., Baca, M., Oganesyan, V., Gunsior, M., Thisted, T., and Yan, L. (2019). A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Sci. Transl. Med., 11.","DOI":"10.1126\/scitranslmed.aar6584"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1107\/S1744309113022847","article-title":"Fibronectin type III domains engineered to bind CD40L: Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of two complexes","volume":"69","author":"Oganesyan","year":"2013","journal-title":"Acta Crystallogr. Sect. F"},{"key":"#cr-split#-ref_107.1","unstructured":"Coyle, A., Baca, M., Thisted, T., Drabic, S., Grinberg, L., Novarra, S., Oganesyan, V., Herbst, R., and Spencer, D.K. (2013). CD40L-Specific TN3-Derived Scaffolds and Methods of Use Thereof"},{"key":"#cr-split#-ref_107.2","doi-asserted-by":"crossref","unstructured":"(57) WO 2013\/055745 A2 2013. (No. 10,000,553), U.S. Patent.","DOI":"10.1016\/S1464-2859(13)70235-9"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Albulescu, M., Gunsior, M., Li, J., Bush, J., Godwood, A., Miday, R., Grant, E., Howe, D., Faggioni, R., and Roskos, L. (2017). SAT0249 Safety, pharmacokinetics, pharmacodynamics and inhibition of T-cell dependent antibody response (TDAR) with MEDI4920, a novel, engineered CD40 ligand (CD40L) antagonist: Results of a first-time-in-human study. Proceedings of the Poster Presentations, European League Against Rheumatism.","DOI":"10.1136\/annrheumdis-2017-eular.3468"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Nicholson, S.M., Casey, K.A., Gunsior, M., Drabic, S., Iverson, W., Cook, H., Scott, S., O\u2019Day, T., Karanth, S., and Dixit, R. (2019). The enhanced immunopharmacology of VIB4920, a novel Tn3 fusion protein and CD40L antagonist, and assessment of its safety profile in cynomolgus monkeys. Br. J. Pharmacol.","DOI":"10.1111\/bph.14897"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13058-019-1116-1","article-title":"MEDI3039, a novel highly potent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 2 agonist, causes regression of orthotopic tumors and inhibits outgrowth of metastatic triple-negative breast cancer","volume":"21","author":"Greer","year":"2019","journal-title":"Breast Cancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"12656","DOI":"10.1021\/bi701215e","article-title":"Fibronectin Type III Domain Based Monobody with High Avidity","volume":"46","author":"Duan","year":"2007","journal-title":"Biochemistry"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.str.2003.11.024","article-title":"Tuning the Mechanical Stability of Fibronectin Type III Modules through Sequence Variations","volume":"12","author":"Craig","year":"2004","journal-title":"Structure"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1074\/jbc.272.3.1718","article-title":"Cryptic self-association sites in type III modules of fibronectin","volume":"272","author":"Ingham","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1073\/pnas.1616408114","article-title":"Biophysical properties of the clinical-stage antibody landscape","volume":"114","author":"Jain","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/prot.22577","article-title":"Structure of the EMMPRIN N-terminal domain 1: Dimerization via \u03b2-strand swapping","volume":"77","author":"Luo","year":"2009","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0014-5793(04)00304-7","article-title":"Domain swapping of a llama VHH domain builds a crystal-wide \u03b2-sheet structure","volume":"564","author":"Spinelli","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1006\/jmbi.1999.2816","article-title":"Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC","volume":"290","author":"Ultsch","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1002\/jps.24393","article-title":"Technical Decision-Making with Higher Order Structure Data: Starting a New Dialogue","volume":"104","author":"Gabrielson","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1002\/jctb.5682","article-title":"Higher-order structure and conformational change in biopharmaceuticals","volume":"93","author":"Orphanou","year":"2018","journal-title":"J. Chem. Technol. Biotechnol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1002\/prot.24502","article-title":"C-terminal \u03b2-strand swapping in a consensus-derived fibronectin Type III scaffold","volume":"82","author":"Teplyakov","year":"2014","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1002\/prot.24517","article-title":"N-terminal \u03b2-strand swapping in a consensus-derived alternative scaffold driven by stabilizing hydrophobic interactions","volume":"82","author":"Luo","year":"2014","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1007\/s13361-018-1966-2","article-title":"Conformational Assessment of Adnectin and Adnectin-Drug Conjugate by Hydrogen\/Deuterium Exchange Mass Spectrometry","volume":"29","author":"Huang","year":"2018","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.jmb.2008.06.051","article-title":"Picomolar Affinity Fibronectin Domains Engineered Utilizing Loop Length Diversity, Recursive Mutagenesis, and Loop Shuffling","volume":"381","author":"Hackel","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/978-1-4614-3229-6_9","article-title":"Implications of 3D domain swapping for protein folding, misfolding and function","volume":"747","author":"Rousseau","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.jmb.2016.02.016","article-title":"Ensemble Modeling and Intracellular Aggregation of an Engineered Immunoglobulin-Like Domain","volume":"428","author":"Trainor","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0167-7012(03)00111-8","article-title":"Inhibition of fibronectin binding of some bacterial cells by subtle pH increase within the physiological range","volume":"55","author":"Ito","year":"2003","journal-title":"J. Microbiol. Methods"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"11090","DOI":"10.1074\/jbc.M111.319764","article-title":"Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9","volume":"287","author":"Liang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_128","first-page":"1","article-title":"An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence","volume":"10","author":"Lee","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1038\/s41565-019-0568-x","article-title":"A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain","volume":"14","author":"Retamal","year":"2019","journal-title":"Nat. Nanotechnol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1021\/cb900284c","article-title":"Rational conversion of affinity reagents into label-free sensors for peptide motifs by designed allostery","volume":"5","author":"Huang","year":"2010","journal-title":"ACS Chem. Biol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"7631","DOI":"10.1021\/acs.analchem.9b00445","article-title":"Wavelength-Dependent Fluorescent Immunosensors via Incorporation of Polarity Indicators near the Binding Interface of Antibody Fragments","volume":"91","author":"Islam","year":"2019","journal-title":"Anal. Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/978-1-4939-6940-1_2","article-title":"Construction of Allosteric Protein Switches by Alternate Frame Folding and Intermolecular Fragment Exchange","volume":"Volume 1596","author":"Ha","year":"2017","journal-title":"Synthetic Protein Switches: Methods and Protocols"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1021\/ar960017f","article-title":"Design by Directed Evolution","volume":"31","author":"Arnold","year":"1998","journal-title":"Acc. Chem. Res."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1146\/annurev.iy.12.040194.002245","article-title":"Making Antibodies by Phage Display Technology","volume":"12","author":"Winter","year":"1994","journal-title":"Annu. Rev. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/610\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:03:55Z","timestamp":1760173435000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,4]]},"references-count":135,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["cells9030610"],"URL":"https:\/\/doi.org\/10.3390\/cells9030610","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202001.0206.v1","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,4]]}}}