{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:20:08Z","timestamp":1783592408283,"version":"3.55.0"},"reference-count":39,"publisher":"Bioscientifica","issue":"4","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":388,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003625","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["HR18C0012"],"award-info":[{"award-number":["HR18C0012"]}],"id":[{"id":"10.13039\/501100003625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Thyrogen, a recombinant human thyroid-stimulating hormone (rhTSH), has a short half-life in the bloodstream, which necessitates multiple doses during treatment. Therefore, we developed a new long-acting rhTSH using anti-serum albumin Fab-associated (SAFA) technology to validate its biological activity through in vitro assays, pharmacokinetic studies in healthy mice and pharmacodynamics studies in a thyroid-stimulating hormone (TSH)-suppressed mouse model. SAFA-TSH was produced using a Chinese hamster ovary expression system. To verify its biological activity, we generated Nthy-ori 3-1 cells stably overexpressing TSHR and measured the production of cyclic adenosine monophosphate (cAMP). In a rat study, slow-release triiodothyronine (T3) pellets were implanted 3 days before administering Thyrogen or SAFA-TSH to measure the amount of thyroxine (T4) release alone resulting from exogenous administration. SAFA-TSH increased cAMP production dose-dependently, but less effectively than Thyrogen at similar concentrations. SAFA-TSH required six times the dose of Thyrogen to achieve similar cAMP levels, likely due to differences in molecular weight and relative bioactivity. In a rat study, SAFA-TSH produced elevated thyroid hormone levels well after the decline in the response to Thyrogen. SAFA-TSH had significantly higher cumulative effects on T4 and free T4 levels compared with Thyrogen, as observed by a more than two-fold higher average area under the effect curve of 262.56 vs 118.89 \u03bcg \u00d7 h\/dL and 127.47 vs 60.75 \u03bcg \u00d7 h\/dL, respectively. SAFA technology created successful long-acting TSH that demonstrated bioactivity. These findings endorse the continued development of SAFA-TSH for clinical use, highlighting its potential as a significant advancement treating thyroid cancer patients.<\/jats:p>","DOI":"10.1530\/erc-24-0284","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T07:40:14Z","timestamp":1738741214000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["Development and validation of long-acting recombinant human TSH using SAFA technology"],"prefix":"10.1530","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1871-686X","authenticated-orcid":true,"given":"Daham","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine 1 , ,","place":["Seoul, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Jeong","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine 1 , ,","place":["Seoul, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Jeong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine 1 , ,","place":["Seoul, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0731-8439","authenticated-orcid":true,"given":"Yoon Hee","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine, Yonsei University College of Medicine 2 , ,","place":["Seoul, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunuk","family":"Zi","sequence":"additional","affiliation":[{"name":"AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University 3 , ,","place":["Chuncheon, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongsuk","family":"An","sequence":"additional","affiliation":[{"name":"AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University 3 , ,","place":["Chuncheon, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjoo","family":"Park","sequence":"additional","affiliation":[{"name":"AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University 3 , ,","place":["Chuncheon, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaekyu","family":"Han","sequence":"additional","affiliation":[{"name":"AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University 3 , ,","place":["Chuncheon, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Chi","sequence":"additional","affiliation":[{"name":"AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University 3 , ,","place":["Chuncheon, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-hoon","family":"Cha","sequence":"additional","affiliation":[{"name":"AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University 3 , ,","place":["Chuncheon, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9876-8370","authenticated-orcid":true,"given":"Eun Jig","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine 1 , ,","place":["Seoul, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"2026070905422705700_bib1","first-page":"271","article-title":"Glycoprotein hormone structure-function and analog design","volume":"54","author":"Boime","year":"1999","journal-title":"Recent Prog Horm Res"},{"key":"2026070905422705700_bib2","doi-asserted-by":"crossref","first-page":"T121","DOI":"10.1530\/ERC-21-0037","article-title":"Radioiodine treatment: an historical and future perspective","volume":"28","author":"Borges de Souza","year":"2021","journal-title":"Endocr Relat Cancer"},{"key":"2026070905422705700_bib3","doi-asserted-by":"crossref","DOI":"10.1016\/j.vetimm.2021.110322","article-title":"APB-F1, a long-acting feline granulocyte colony-stimulating factor fusion protein, created by exploiting FL335, a chimeric Fab specific for feline serum albumin","volume":"240","author":"Chi","year":"2021","journal-title":"Vet Immunol Immunopathol"},{"key":"2026070905422705700_bib4","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1210\/jc.2003-031027","article-title":"Recombinant human thyrotropin stimulation of fluoro-D-glucose positron emission tomography uptake in well-differentiated thyroid carcinoma","volume":"89","author":"Chin","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905422705700_bib5","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.bbrc.2020.03.133","article-title":"Structural basis of serum albumin recognition by SL335, an antibody Fab extending the serum half-life of protein therapeutics","volume":"526","author":"Cho","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"2026070905422705700_bib6","doi-asserted-by":"crossref","first-page":"791","DOI":"10.3803\/EnM.2022.1533","article-title":"Recent changes in the incidence of thyroid cancer in Korea between 2005 and 2018: analysis of Korean national data","volume":"37","author":"Choi","year":"2022","journal-title":"Endocrinol Metab"},{"key":"2026070905422705700_bib7","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1089\/thy.2007.0331","article-title":"Review on the occasion of a decade of recombinant human TSH: prospects and novel uses","volume":"18","author":"Duntas","year":"2008","journal-title":"Thyroid"},{"key":"2026070905422705700_bib8","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1089\/thy.2013.0119","article-title":"Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice","volume":"24","author":"Estrada","year":"2014","journal-title":"Thyroid"},{"key":"2026070905422705700_bib9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1530\/EJE-08-0151","article-title":"Exploring the use of recombinant human TSH in the diagnosis of central hypothyroidism","volume":"159","author":"Filipsson","year":"2008","journal-title":"Eur J Endocrinol"},{"key":"2026070905422705700_bib10","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1046\/j.1365-2265.2003.01830.x","article-title":"Recombinant human TSH testing is a valuable tool for differential diagnosis of congenital hypothyroidism during L-thyroxine replacement","volume":"59","author":"Fugazzola","year":"2003","journal-title":"Clin Endocrinol"},{"key":"2026070905422705700_bib11","doi-asserted-by":"crossref","first-page":"R133","DOI":"10.1530\/EJE-19-0149","article-title":"MANAGEMENT OF ENDOCRINE DISEASE: The role of rhTSH in the management of differentiated thyroid cancer: pros and cons","volume":"181","author":"Giovanella","year":"2019","journal-title":"Eur J Endocrinol"},{"key":"2026070905422705700_bib12","doi-asserted-by":"crossref","first-page":"R47","DOI":"10.1530\/EJE-14-0608","article-title":"Recombinant human TSH and radioactive iodine therapy in the management of benign multinodular goiter","volume":"172","author":"Graf","year":"2015","journal-title":"Eur J Endocrinol"},{"key":"2026070905422705700_bib13","doi-asserted-by":"crossref","first-page":"79","DOI":"10.4274\/mirt.88598","article-title":"Is very high thyroid stimulating hormone level required in differentiated thyroid cancer for ablation success?","volume":"25","author":"Hasbek","year":"2016","journal-title":"Mol Imaging Radionuclide Ther"},{"key":"2026070905422705700_bib14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"key":"2026070905422705700_bib15","first-page":"3877","article-title":"A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer","volume":"84","author":"Haugen","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905422705700_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.cyto.2023.156413","article-title":"Albumin-binding recombinant human IL-18BP ameliorates macrophage activation syndrome and atopic dermatitis via direct IL-18 inactivation","volume":"172","author":"Jang","year":"2023","journal-title":"Cytokine"},{"key":"2026070905422705700_bib17","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.imlet.2019.01.009","article-title":"Intact bioactivities and improved pharmacokinetic of the SL335-IFN-\u03b2-1a fusion protein that created by genetic fusion of SL335, a human anti-serum albumin fab, and human interferon-\u03b2","volume":"207","author":"Ji","year":"2019","journal-title":"Immunol Lett"},{"key":"2026070905422705700_bib18","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.imlet.2015.11.013","article-title":"Isolation of human anti-serum albumin Fab antibodies with an extended serum-half life","volume":"169","author":"Kang","year":"2016","journal-title":"Immunol Lett"},{"key":"2026070905422705700_bib19","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.imlet.2017.02.008","article-title":"Optimal expression of a Fab-effector fusion protein in Escherichia coli by removing the cysteine residues responsible for an interchain disulfide bond of a Fab molecule","volume":"184","author":"Kang","year":"2017","journal-title":"Immunol Lett"},{"key":"2026070905422705700_bib20","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2023.1132172","article-title":"Long-acting recombinant human follicle-stimulating hormone (SAFA-FSH) enhances spermatogenesis","volume":"14","author":"Kim","year":"2023","journal-title":"Front Endocrinol"},{"key":"2026070905422705700_bib21","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1158\/1055-9965.EPI-21-1440","article-title":"Epidemiology of thyroid cancer","volume":"31","author":"Kitahara","year":"2022","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"2026070905422705700_bib22","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1210\/endo.138.6.5189","article-title":"Regulation by thyroid-stimulating hormone of sodium\/iodide symporter gene expression and protein levels in FRTL-5 cells","volume":"138","author":"Kogai","year":"1997","journal-title":"Endocrinology"},{"key":"2026070905422705700_bib23","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0133852","article-title":"The cut-off level of recombinant human TSH-stimulated thyroglobulin in the follow-up of patients with differentiated thyroid cancer","volume":"10","author":"Kowalska","year":"2015","journal-title":"PLoS One"},{"key":"2026070905422705700_bib24","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1210\/jc.2008-1747","article-title":"Assessment of the incremental value of recombinant thyrotropin stimulation before 2-[18F]-Fluoro-2-deoxy-D-glucose positron emission tomography\/computed tomography imaging to localize residual differentiated thyroid cancer","volume":"94","author":"Leboulleux","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905422705700_bib25","doi-asserted-by":"crossref","first-page":"448","DOI":"10.3349\/ymj.2023.0457","article-title":"Minimally invasive open bilateral total thyroidectomy using unilateral neck incision in thyroid cancer: preliminary surgical and quality of life outcomes","volume":"65","author":"Lee","year":"2024","journal-title":"Yonsei Med J"},{"key":"2026070905422705700_bib26","doi-asserted-by":"crossref","first-page":"348","DOI":"10.3349\/ymj.2023.0266","article-title":"No change in complications following thyroidectomy despite increase in thyroid cancer surgeries: a meta-regression analysis","volume":"65","author":"Lee","year":"2024","journal-title":"Yonsei Med J"},{"key":"2026070905422705700_bib27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1159\/000371512","article-title":"Differences in physicians' and patients' perception of acute hypothyroid symptoms induced by thyroid hormone withdrawal in thyroid cancer patients: a multicenter survey in Korea","volume":"4","author":"Lim","year":"2015","journal-title":"Eur Thyroid J"},{"key":"2026070905422705700_bib28","doi-asserted-by":"crossref","DOI":"10.1530\/ETJ-21-0046","article-title":"2022 ETA Consensus Statement: what are the indications for post-surgical radioiodine therapy in differentiated thyroid cancer?","volume":"11","author":"Pacini","year":"2022","journal-title":"Eur Thyroid J"},{"key":"2026070905422705700_bib29","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1210\/jc.2005-1651","article-title":"Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study","volume":"91","author":"Pacini","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905422705700_bib30","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1210\/en.2012-2010","article-title":"Carbohydrate-mediated polyethylene glycol conjugation of TSH improves its pharmacological properties","volume":"154","author":"Park","year":"2013","journal-title":"Endocrinology"},{"key":"2026070905422705700_bib31","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1097\/RLU.0000000000005022","article-title":"Comparison of recombinant human thyroid-stimulating hormone and thyroid hormone withdrawal for 131 I therapy in patients with intermediate- to high-risk thyroid cancer: a systematic review and meta-analysis","volume":"49","author":"Park","year":"2024","journal-title":"Clin Nucl Med"},{"key":"2026070905422705700_bib32","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.1210\/jc.2012-1616","article-title":"Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges","volume":"97","author":"Persani","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905422705700_bib33","doi-asserted-by":"crossref","first-page":"R44","DOI":"10.1530\/EC-18-0515","article-title":"The diagnosis and management of central hypothyroidism in 2018","volume":"8","author":"Persani","year":"2019","journal-title":"Endocr Connections"},{"key":"2026070905422705700_bib34","first-page":"924","article-title":"TSH signal transduction in thyroid cells of Nthy-ori 3-1 line","volume":"24","author":"Piotrowska","year":"2011","journal-title":"Post\u0119py Nauk Med"},{"key":"2026070905422705700_bib35","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3803\/EnM.2023.1896","article-title":"Adequate dose of levothyroxine for thyroid-stimulating hormone suppression after total thyroidectomy in patients with differentiated thyroid cancer","volume":"39","author":"Ryu","year":"2024","journal-title":"Endocrinol Metab"},{"key":"2026070905422705700_bib36","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1089\/thy.2006.16.267","article-title":"Thyroid-stimulating hormone-stimulated fused positron emission tomography\/computed tomography in the evaluation of recurrence in 131I-negative papillary thyroid carcinoma","volume":"16","author":"Saab","year":"2006","journal-title":"Thyroid"},{"key":"2026070905422705700_bib37","first-page":"1514","article-title":"Outcomes of thyrotropin alfa versus levothyroxine withdrawal-aided radioiodine therapy for distant metastasis of papillary thyroid cancer","volume":"31","author":"Simoes-Pereira","year":"2021","journal-title":"Thyroid"},{"key":"2026070905422705700_bib38","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1210\/endo-128-1-341","article-title":"Biological activity and metabolic clearance of a recombinant human thyrotropin produced in Chinese hamster ovary cells","volume":"128","author":"Thotakura","year":"1991","journal-title":"Endocrinology"},{"key":"2026070905422705700_bib39","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jconrel.2019.02.016","article-title":"Current strategies in extending half-lives of therapeutic proteins","volume":"301","author":"Zaman","year":"2019","journal-title":"J Contr Release"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/32\/4\/ERC-24-0284.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/32\/4\/ERC-24-0284.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-24-0284\/144936\/erc-24-0284.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-24-0284\/144936\/erc-24-0284.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T09:42:40Z","timestamp":1783590160000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/32\/4\/e240284\/25902\/Development-and-validation-of-long-acting"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,5]]},"references-count":39,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-24-0284","relation":{},"ISSN":["1479-6821","1351-0088"],"issn-type":[{"value":"1479-6821","type":"electronic"},{"value":"1351-0088","type":"print"}],"subject":[],"published":{"date-parts":[[2025,2,5]]},"article-number":"e240284"}}