{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:52:54Z","timestamp":1791553974550,"version":"4.3.4"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lysyl oxidase-like 2 (LOXL2) is a copper-dependent enzyme that is involved in collagen and elastin cross-linking in the tumor extracellular matrix (ECM) and contributes to tumor progression. Simtuzumab is a clinically evaluated humanized monoclonal antibody that binds to an allosteric binding site on LOXL2. Herein, we report radiolabeling and preliminary evaluation of simtuzumab labeled with zirconium-89 (89Zr, t1\/2: 3.3 days) for positron emission tomography (PET) imaging of LOXL2 in the ECM of tumors. Simtuzumab was conjugated with desferrioxamine (DFO) and labeled with 89Zr in &amp;gt;98% yield. Magnetic bead-based assay confirmed specific binding of [89Zr]Zr-DFO-simtuzumab to LOXL2. LOXL2 expression levels and cell binding of [89Zr]Zr-DFO-simtuzumab were assessed in MIA PaCa-2 and HepG2 cell lines. Western blot analysis indicated higher LOXL2 expression in MIA PaCa-2 cells compared with HepG2 cells. Cell binding assays revealed minimal binding (&amp;lt;0.5%) of [89Zr]Zr-DFO-simtuzumab in both cell lines, reflecting the lack of cell surface expression of LOXL2. Immunohistochemical (IHC) studies revealed primarily intracellular localization of LOXL2 in the MIA PaCa-2 xenograft model, with minimal expression in HepG2 xenografts in mice. microPET\/CT imaging studies in mice bearing MIA PaCa-2 xenografts demonstrated low but visible uptake of [89Zr]Zr-DFO-simtuzumab in tumors (6.2 \u00b1 1.3% ID\/g) at 96 h postinjection. Ex vivo biodistribution studies indicated higher uptake of the labeled conjugate in both xenograft tumor models relative to muscle, but no significant differences were observed in [89Zr]Zr-DFO-simtuzumab uptake in the two tumor models, consistent with the low ECM-associated LOXL2 in IHC staining. Overall, simtuzumab has been successfully labeled with [89Zr]Zr using DFO and characterized as a candidate immunoPET tracer for LOXL2. However, additional studies are needed to further validate the labeled conjugate in tumor models with high LOXL2 expression in the ECM and to confirm LOXL2-specific ECM imaging in vivo by PET.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00208","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T07:02:13Z","timestamp":1790578933000},"page":"2795-2805","source":"Crossref","is-referenced-by-count":0,"title":["Zirconium-89 Labeling\nand Preliminary Evaluation of\nSimtuzumab as a Candidate Positron Emission Tomography (PET) Imaging\nAgent for Human Lysyl Oxidase-like 2 (LOXL2) in the Extracellular\nMatrix of Solid Tumors"],"prefix":"10.1021","volume":"9","author":[{"given":"Graham","family":"Ragland","sequence":"first","affiliation":[{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 63607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atchimnaidu","family":"Siriki","sequence":"additional","affiliation":[{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 63607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaustab","family":"Ghosh","sequence":"additional","affiliation":[{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 63607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Thau","sequence":"additional","affiliation":[{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 63607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 63607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Feinberg","sequence":"additional","affiliation":[{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 63607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-2286","authenticated-orcid":true,"given":"Satish K.","family":"Chitneni","sequence":"additional","affiliation":[{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 63607"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"2026100909102504400_cit1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.abb.2013.12.022","article-title":"Human copper-dependent\namine oxidases","volume":"546","author":"Finney","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"issue":"18","key":"2026100909102504400_cit2","doi-asserted-by":"publisher","first-page":"3113","DOI":"10.1016\/j.bmcl.2018.07.001","article-title":"Inhibition\nof the LOX enzyme family\nmembers with old and new ligands. Selectivity analysis revisited","volume":"28","author":"Hajdu\u0301","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"issue":"6","key":"2026100909102504400_cit3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23063285","article-title":"Cleavage of\nLOXL1 by BMP1 and ADAMTS14 Proteases Suggests a Role for Proteolytic\nProcessing in the Regulation of LOXL1 Function","volume":"23","author":"Rosell-Garci\u0301a","year":"2022","journal-title":"Int. J. Mol. Sci."},{"issue":"25","key":"2026100909102504400_cit4","doi-asserted-by":"publisher","first-page":"22537","DOI":"10.1074\/jbc.M102352200","article-title":"Multiple bone morphogenetic protein 1-related mammalian\nmetalloproteinases process pro-lysyl oxidase at the correct physiological\nsite and control lysyl oxidase activation in mouse embryo fibroblast\ncultures","volume":"276","author":"Uzel","year":"2001","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2026100909102504400_cit5","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevImmunol.v24.i1.10","article-title":"The Scavenger Receptor\nCysteine-Rich (SRCR) domain:\nan ancient and highly conserved protein module of the innate immune\nsystem","volume":"24","author":"Sarrias","year":"2004","journal-title":"Crit. Rev. Immunol."},{"issue":"18","key":"2026100909102504400_cit6","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241814405","article-title":"LOXL2 in Cancer: A\nTwo-Decade Perspective","volume":"24","author":"Cano","year":"2023","journal-title":"Int. J. Mol. Sci."},{"issue":"3","key":"2026100909102504400_cit7","doi-asserted-by":"publisher","first-page":"C694","DOI":"10.1152\/ajpcell.00176.2023","article-title":"Lysyl oxidase\nlike-2 in fibrosis and cardiovascular disease","volume":"325","author":"Poe","year":"2023","journal-title":"Am. J. Physiol.-Cell Physiol."},{"issue":"2","key":"2026100909102504400_cit8","doi-asserted-by":"publisher","DOI":"10.1002\/adtp.201900119","article-title":"Lysyl Oxidase\nLike-2 (LOXL2): An Emerging Oncology Target","volume":"3","author":"Chopra","year":"2020","journal-title":"Adv. Ther-Germany"},{"issue":"2","key":"2026100909102504400_cit9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2020.188435","article-title":"LOXL2 in cancer: regulation, downstream\neffectors and novel roles","volume":"1874","author":"Wen","year":"2020","journal-title":"Biochim. Biophys.\nActa, Rev. Cancer"},{"issue":"3","key":"2026100909102504400_cit10","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.jhep.2005.02.052","article-title":"Abnormal deposition\nof collagen around hepatocytes in Wilson\u2019s disease is associated\nwith hepatocyte specific expression of lysyl oxidase and lysyl oxidase\nlike protein-2","volume":"43","author":"Vadasz","year":"2005","journal-title":"J. Hepatol."},{"key":"2026100909102504400_cit11","doi-asserted-by":"publisher","first-page":"3814","DOI":"10.1111\/febs.70418","article-title":"Decoding ECM\nremodeling: proteases as gatekeepers of Lysyl oxidase family-mediated\ncrosslinking","volume":"293","author":"Joshi","year":"2026","journal-title":"FEBS J."},{"issue":"5","key":"2026100909102504400_cit12","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.3892\/ijo.2019.4726","article-title":"Silencing of lysyl\noxidase-like 2 inhibits the migration, invasion\nand epithelial-to-mesenchymal transition of renal cell carcinoma cells\nthrough the Src\/FAK signaling pathway","volume":"54","author":"Hong","year":"2019","journal-title":"Int.\nJ. Oncol."},{"key":"2026100909102504400_cit13","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00284","article-title":"LOXL2 Expression Status Is Correlated\nWith Molecular Characterizations of Cervical Carcinoma and Associated\nWith Poor Cancer Survival via Epithelial-Mesenchymal Transition (EMT)\nPhenotype","volume":"10","author":"Cao","year":"2020","journal-title":"Front. Oncol."},{"issue":"10","key":"2026100909102504400_cit14","doi-asserted-by":"publisher","first-page":"2370","DOI":"10.1093\/carcin\/bgt241","article-title":"Lysyl\noxidase-like-2 promotes tumour angiogenesis and\nis a potential therapeutic target in angiogenic tumours","volume":"34","author":"Zaffryar-Eilot","year":"2013","journal-title":"Carcinogenesis"},{"issue":"27","key":"2026100909102504400_cit15","doi-asserted-by":"publisher","first-page":"42539","DOI":"10.18632\/oncotarget.9918","article-title":"Emerging role of\nLOXL2 in the promotion of pancreas\ncancer metastasis","volume":"7","author":"Park","year":"2106","journal-title":"Oncotarget"},{"issue":"21","key":"2026100909102504400_cit16","doi-asserted-by":"publisher","first-page":"5846","DOI":"10.1158\/0008-5472.CAN-16-3152","article-title":"Lysyl Oxidase-like Protein LOXL2 Promotes Lung Metastasis of Breast\nCancer","volume":"77","author":"Salvador","year":"2017","journal-title":"Cancer Res."},{"issue":"11","key":"2026100909102504400_cit17","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.572","article-title":"An activity-based\nbioprobe differentiates a\nnovel small molecule inhibitor from a LOXL2 antibody and provides\nrenewed promise for anti-fibrotic therapeutic strategies","volume":"11","author":"Findlay","year":"2021","journal-title":"Clin. Transl. Med."},{"issue":"9","key":"2026100909102504400_cit18","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/nm.2208","article-title":"Allosteric\ninhibition of lysyl oxidase-like-2 impedes\nthe development of a pathologic microenvironment","volume":"16","author":"Barry-Hamilton","year":"2010","journal-title":"Nat. Med."},{"issue":"9","key":"2026100909102504400_cit19","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1136\/gutjnl-2016-312473","article-title":"Selective targeting of lysyl oxidase-like 2 (LOXL2)\nsuppresses hepatic fibrosis progression and accelerates its reversal","volume":"66","author":"Ikenaga","year":"2017","journal-title":"Gut"},{"issue":"2","key":"2026100909102504400_cit20","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1002\/hep.30237","article-title":"Simtuzumab for Primary Sclerosing Cholangitis:\nPhase 2 Study Results With Insights on the Natural History of the\nDisease","volume":"69","author":"Muir","year":"2019","journal-title":"Hepatology"},{"issue":"3","key":"2026100909102504400_cit21","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1634\/theoncologist.2017-0024","article-title":"A Phase II Randomized,\nDouble-Blind, Placebo-Controlled Study of Simtuzumab or Placebo in\nCombination with Gemcitabine for the First-Line Treatment of Pancreatic\nAdenocarcinoma","volume":"22","author":"Benson","year":"2017","journal-title":"Oncologist"},{"issue":"5","key":"2026100909102504400_cit22","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1002\/hep.32204","article-title":"Cirrhosis regression\nis associated with improved clinical\noutcomes in patients with nonalcoholic steatohepatitis","volume":"75","author":"Sanyal","year":"2022","journal-title":"Hepatology"},{"issue":"27","key":"2026100909102504400_cit23","doi-asserted-by":"publisher","first-page":"20964","DOI":"10.1074\/jbc.M109.094136","article-title":"Modulation\nof lysyl oxidase-like\n2 enzymatic activity by an allosteric antibody inhibitor","volume":"285","author":"Rodriguez","year":"2010","journal-title":"J. Biol. Chem."},{"issue":"3","key":"2026100909102504400_cit24","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1634\/theoncologist.2016-0479","article-title":"A Phase II,\nRandomized, Double-Blind,\nPlacebo-Controlled Study of Simtuzumab in Combination with FOLFIRI\nfor the Second-Line Treatment of Metastatic KRAS Mutant Colorectal\nAdenocarcinoma","volume":"22","author":"Hecht","year":"2017","journal-title":"Oncologist"},{"issue":"3","key":"2026100909102504400_cit25","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2014.32.3_suppl.554","article-title":"Phase I and IIa\nstudies of simtuzumab alone and in\ncombination with FOLFIRI in patients with advanced solid tumors","volume":"32","author":"LoRusso","year":"2014","journal-title":"J. Clin. Oncol."},{"issue":"12","key":"2026100909102504400_cit26","doi-asserted-by":"publisher","first-page":"4541","DOI":"10.1158\/0008-5472.CAN-07-6345","article-title":"Lysyl oxidase-like\n2 as a new poor prognosis marker of squamous cell carcinomas","volume":"68","author":"Peinado","year":"2008","journal-title":"Cancer Res."},{"key":"2026100909102504400_cit27","doi-asserted-by":"publisher","first-page":"2699","DOI":"10.2147\/OTT.S164056","article-title":"Clinical relevance\nof lysyl oxidase-like 2 and functional\nmechanisms in glioma","volume":"11","author":"Du","year":"2018","journal-title":"OncoTargets Ther."},{"issue":"1","key":"2026100909102504400_cit28","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-015-0609-9","article-title":"Targeting lysyl oxidase\nfor molecular imaging in breast cancer","volume":"17","author":"Wuest","year":"2015","journal-title":"Breast\nCancer Res."},{"issue":"16","key":"2026100909102504400_cit29","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28166041","article-title":"Accelerator-Based\nProduction of Scandium Radioisotopes\nfor Applications in Prostate Cancer: Toward Building a Pipeline for\nRapid Development of Novel Theranostics","volume":"28","author":"Meier","year":"2023","journal-title":"Molecules"},{"issue":"8","key":"2026100909102504400_cit30","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/onc.2014.23","article-title":"Lysyl oxidase-like\n2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression\nand early metastasis colonization","volume":"34","author":"Canesin","year":"2015","journal-title":"Oncogene"},{"issue":"1","key":"2026100909102504400_cit31","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-30923-4","article-title":"The prediction value\nof LOXL-2 in the clinical pathology and prognosis of cancers: A meta-analysis\nand bioinformatics analysis","volume":"16","author":"Yang","year":"2026","journal-title":"Sci. Rep."},{"issue":"96","key":"2026100909102504400_cit32","doi-asserted-by":"publisher","DOI":"10.3791\/52521","article-title":"The bioconjugation and radiosynthesis of 89Zr-DFO-labeled antibodies","author":"Zeglis","year":"2015","journal-title":"J. Visualized Exp."},{"issue":"15","key":"2026100909102504400_cit33","doi-asserted-by":"publisher","first-page":"3561","DOI":"10.1158\/1078-0432.CCR-14-1051","article-title":"Desmoplasia\nin Primary Tumors and Metastatic Lesions of Pancreatic\nCancer","volume":"21","author":"Whatcott","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"2026100909102504400_cit34","doi-asserted-by":"publisher","DOI":"10.1016\/j.crphar.2021.100014","article-title":"Reversal\nof TGF-beta-induced epithelial-mesenchymal\ntransition in hepatocellular carcinoma by sorafenib, a VEGFR-2 and\nRaf kinase inhibitor","volume":"2","author":"Modi","year":"2021","journal-title":"Curr. Res. Pharmacol.\nDrug Discovery"},{"issue":"16","key":"2026100909102504400_cit35","doi-asserted-by":"publisher","first-page":"26066","DOI":"10.18632\/oncotarget.15257","article-title":"Pre-clinical evaluation\nof small molecule LOXL2 inhibitors in breast cancer","volume":"8","author":"Chang","year":"2017","journal-title":"Oncotarget"},{"issue":"1","key":"2026100909102504400_cit36","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00544-0","article-title":"Extracellular\nmatrix and its therapeutic potential\nfor cancer treatment","volume":"6","author":"Huang","year":"2021","journal-title":"Signal Transduction Targeted\nTher."},{"issue":"18","key":"2026100909102504400_cit37","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202300331","article-title":"Lysyl Oxidases as Targets\nfor Cancer Therapy and Diagnostic Imaging","volume":"18","author":"Lo\u0308ser","year":"2023","journal-title":"ChemMedChem"},{"issue":"7","key":"2026100909102504400_cit38","doi-asserted-by":"publisher","first-page":"3613","DOI":"10.1021\/acs.molpharmaceut.3c00232","article-title":"SPECT Imaging\nof Lysyl Oxidase-like 2 in a Model of Idiopathic Pulmonary Fibrosis","volume":"20","author":"Vizier","year":"2023","journal-title":"Mol. Pharmaceutics"},{"issue":"14","key":"2026100909102504400_cit39","doi-asserted-by":"publisher","first-page":"4249","DOI":"10.1158\/0008-5472.CAN-15-2813","article-title":"Tumor Cell Invasion\nCan. Be Blocked by Modulators of Collagen Fibril Alignment That Control\nAssembly of the Extracellular Matrix","volume":"76","author":"Grossman","year":"2016","journal-title":"Cancer\nRes."},{"issue":"15","key":"2026100909102504400_cit40","doi-asserted-by":"publisher","first-page":"5745","DOI":"10.7150\/thno.100116","article-title":"Collagen type I PET\/MRI\nenables evaluation of treatment response\nin pancreatic cancer in pre-clinical and first-in-human translational\nstudies","volume":"14","author":"Esfahani","year":"2024","journal-title":"Theranostics"},{"issue":"1","key":"2026100909102504400_cit41","doi-asserted-by":"publisher","DOI":"10.1038\/s44303-024-00053-z","article-title":"Clinical applications of fibroblast\nactivation protein\ninhibitor positron emission tomography (FAPI-PET)","volume":"2","author":"Mori","year":"2024","journal-title":"npj Imaging"}],"container-title":["ACS Pharmacology &amp; Translational\nScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsptsci.6c00208","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/10\/2795\/68672357\/acsptsci.6c00208.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/10\/2795\/68672357\/acsptsci.6c00208.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:31:37Z","timestamp":1791552697000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article\/9\/10\/2795\/5439691\/Zirconium-89-Labeling-and-Preliminary-Evaluation"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,9,28]]},"published-print":{"date-parts":[[2026,10,9]]}},"URL":"https:\/\/doi.org\/10.1021\/acsptsci.6c00208","relation":{},"ISSN":["2575-9108"],"issn-type":[{"value":"2575-9108","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}