{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:18:52Z","timestamp":1783574332372,"version":"3.55.0"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Inhibrx, Inc."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Respir Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alpha-1 antitrypsin deficiency (AATD) is a genetic disease resulting in decreased circulating functional levels of alpha-1 antitrypsin (AAT), an important protease inhibitor that protects tissue, particularly the lungs, from protease-mediated degradation. Individuals with AATD-associated emphysema have historically been treated with plasma-derived AAT, requiring weekly infusions. A recombinant AAT-Fc fusion protein, efdoralprin alfa, is currently being studied in clinical trials. Here, we sought to delineate a normal range of functional AAT (fAAT) that can be used to assess how effectively therapies restore fAAT to the normal range.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Self-reported healthy individuals from Massachusetts were recruited to serve as donors to delineate a reference interval (RI), with requirements for \u2265\u200975% of individuals to be White. The Mayo Clinic analyzed blood samples from each donor to confirm wildtype Pi*MM phenotype and assess total AAT protein levels using the A1ALC test and a Siemens nephelometry assay, respectively. Samples were assessed for fAAT at BioAgilytix using a validated anti-neutrophil elastase capacity assay with WHO International AAT standards. Verification cohorts were recruited from geographically distinct regions (Florida and California) to confirm that the Massachusetts cohort was representative of the broader population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 237 individual donors in the RI cohort, 211 with confirmed wildtype Pi*MM phenotype were used to calculate the RI. The central 95% range (2.5th percentile to 97.5th percentile) of fAAT concentration was 23.8\u201342.4 \u00b5M, with 23.8 \u00b5M designated as the lower limit of normal (LLN). Although one of the Florida verification cohorts was not included because of inability to verify sample-handling procedures, the LLN determined from the RI cohort was in alignment with the other two verification cohorts. In addition, the lower bound for total AAT protein from the RI cohort was 106\u00a0mg\/dL. This value was consistent with two larger published datasets, supporting the representativeness of the RI cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The fAAT RI and LLN delineated by this study can be applied directly to clinical trials to evaluate the pharmacodynamic effect of AATD therapies, and, in conjunction with clinical trial pharmacokinetic data, can be used to support dosing decisions for patients with AATD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12931-026-03705-3","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:03:21Z","timestamp":1783573401000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Delineating a reference interval for functional alpha-1 antitrypsin in the serum of healthy Pi*MM donors using an anti-neutrophil elastase capacity assay"],"prefix":"10.1186","volume":"27","author":[{"given":"Keith David","family":"Merdek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dobrin","family":"Draganov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Laura","family":"Sargentini-Maier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Thibault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Kalabus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Ramani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carson","family":"Veldstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"3705_CR1","doi-asserted-by":"crossref","unstructured":"Seixas S, Marques PI. Known mutations at the cause of alpha-1 antitrypsin deficiency an updated overview of serpina1 variation spectrum. Appl Clin Genet. 2021;14:173\u201394.","DOI":"10.2147\/TACG.S257511"},{"issue":"7","key":"3705_CR2","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1016\/j.medcli.2023.10.014","volume":"162","author":"F Das\u00ed","year":"2024","unstructured":"Das\u00ed F. Alpha-1 antitrypsin deficiency. Med Clin (Barc). 2024;162(7):336\u201342.","journal-title":"Med Clin (Barc)"},{"issue":"7","key":"3705_CR3","doi-asserted-by":"publisher","first-page":"507","DOI":"10.3949\/ccjm.83a.16031","volume":"83","author":"JK Stoller","year":"2016","unstructured":"Stoller JK. Alpha-1 antitrypsin deficiency: An underrecognized, treatable cause of COPD. Cleve Clin J Med. 2016;83(7):507\u201314.","journal-title":"Cleve Clin J Med"},{"issue":"3","key":"3705_CR4","first-page":"668","volume":"3","author":"RA Sandhaus","year":"2016","unstructured":"Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis. 2016;3(3):668\u201382.","journal-title":"Chronic Obstr Pulm Dis"},{"issue":"3","key":"3705_CR5","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1111\/resp.13774","volume":"25","author":"J Dummer","year":"2020","unstructured":"Dummer J, Dobler CC, Holmes M, et al. Diagnosis and treatment of lung disease associated with alpha one-antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand. Respirology. 2020;25(3):321\u201335.","journal-title":"Respirology"},{"issue":"1","key":"3705_CR6","first-page":"1","volume":"12","author":"DN Pfeffer","year":"2025","unstructured":"Pfeffer DN, Dhakne R, El Massad O, et al. Improving the likelihood of identifying alpha-1 antitrypsin deficiency among patients with COPD: A novel predictive model using real-world data. Chronic Obstr Pulm Dis. 2025;12(1):1\u201311.","journal-title":"Chronic Obstr Pulm Dis"},{"issue":"2","key":"3705_CR7","first-page":"190","volume":"8","author":"S Gurevich","year":"2021","unstructured":"Gurevich S, Daya A, Da Silva C, Girard C, Rahaghi F. Improving screening for alpha-1 antitrypsin deficiency with direct testing in the pulmonary function testing laboratory. Chronic Obstr Pulm Dis. 2021;8(2):190\u20137.","journal-title":"Chronic Obstr Pulm Dis"},{"key":"3705_CR8","doi-asserted-by":"crossref","unstructured":"Foil KE. Variants of SERPINA1 and the increasing complexity of testing for alpha-1 antitrypsin deficiency. Ther Adv Chronic Dis. 2021;12_suppl:20406223211015954.","DOI":"10.1177\/20406223211015954"},{"issue":"21","key":"3705_CR9","doi-asserted-by":"publisher","first-page":"5132","DOI":"10.3390\/jcm10215132","volume":"10","author":"B Ruiz-Duque","year":"2021","unstructured":"Ruiz-Duque B, Ba\u00f1uls L, Reinoso-Arija R, et al. Methodologies for the determination of blood alpha1 antitrypsin levels: A systematic review. J Clin Med. 2021;10(21):5132.","journal-title":"J Clin Med"},{"key":"3705_CR10","doi-asserted-by":"crossref","unstructured":"Sinden NJ, Koura F, Stockley RA. The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote. BMC Pulm Med. 2014;14:132.","DOI":"10.1186\/1471-2466-14-132"},{"issue":"2","key":"3705_CR11","doi-asserted-by":"publisher","first-page":"2101410","DOI":"10.1183\/13993003.01410-2021","volume":"59","author":"AN Franciosi","year":"2022","unstructured":"Franciosi AN, Fraughen D, Carroll TP, McElvaney NG. Alpha-1 antitrypsin deficiency: Clarifying the role of the putative protective threshold. Eur Respir J. 2022;59(2):2101410.","journal-title":"Eur Respir J"},{"issue":"6","key":"3705_CR12","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1080\/10408363.2018.1482256","volume":"55","author":"Y Ozarda","year":"2018","unstructured":"Ozarda Y, Sikaris K, Streichert T, Macri J. Distinguishing reference intervals and clinical decision limits - A Review by the IFCC Committee on Reference Intervals and Decision Limits. Crit Rev Clin Lab Sci. 2018;55(6):420\u201331.","journal-title":"Crit Rev Clin Lab Sci"},{"key":"3705_CR13","unstructured":"Clinical and Laboratory Standards Institute. EP28-A3c. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline. 3rd ed. October 2010."},{"key":"3705_CR14","unstructured":"National Institute for Biological Standards and Control (NIBSC). WHO International Standard: 1st International Standard for Alpha-1-Antitrypsin, Plasma-Derived; NIBSC code: 05\/162; Instructions for Use (version 2.1, dated 27\/10\/2009). Potters Bar: Hertfordshire; 2009."},{"issue":"3","key":"3705_CR15","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1309\/AJCPMEEJK32ACYFP","volume":"138","author":"LJ Donato","year":"2012","unstructured":"Donato LJ, Jenkins SM, Smith C, Katzmann JA, Snyder MR. Reference and interpretive ranges for \u03b1(1)-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin Pathol. 2012;138(3):398\u2013405.","journal-title":"Am J Clin Pathol"},{"issue":"4","key":"3705_CR16","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1378\/chest.12-0564","volume":"143","author":"JA Bornhorst","year":"2013","unstructured":"Bornhorst JA, Greene DN, Ashwood ER, Grenache DG. \u03b11-antitrypsin phenotypes and associated serum protein concentrations in a large clinical population. Chest. 2013;143(4):1000\u20138.","journal-title":"Chest"},{"issue":"3","key":"3705_CR17","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1378\/chest.100.3.703","volume":"100","author":"ML Brantly","year":"1991","unstructured":"Brantly ML, Wittes JT, Vogelmeier CF, Hubbard RC, Fells GA, Crystal RG. Use of a highly purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient alpha 1-antitrypsin phenotypes. Chest. 1991;100(3):703\u20138.","journal-title":"Chest"},{"issue":"8","key":"3705_CR18","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.3390\/ph18081165","volume":"18","author":"A Engelmaier","year":"2025","unstructured":"Engelmaier A, Zimmermann M, Butterweck HA, Weber A. Bioanalytical method validations of three alpha1-antitrypsin measurement methods required for clinical sample analysis. Pharmaceuticals (Basel). 2025;18(8):1165.","journal-title":"Pharmaceuticals (Basel)"}],"container-title":["Respiratory Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12931-026-03705-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12931-026-03705-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12931-026-03705-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:03:26Z","timestamp":1783573406000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12931-026-03705-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":18,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3705"],"URL":"https:\/\/doi.org\/10.1186\/s12931-026-03705-3","relation":{},"ISSN":["1465-993X"],"issn-type":[{"value":"1465-993X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]},"assertion":[{"value":"25 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This clinical study has been reviewed and approved by an Institutional\/Independent Review Board (IRB) and\/or Independent Ethics Committee (IEC) in accordance with requirements of local governing regulatory agencies, including the Department of Health and Human Services (DHHS) and Food and Drug Administration (FDA) Codes of Federal Regulations, on the Protection of Human Subjects (45 CFR Part 46 and 2\u00a0L CFR Part 56, respectively). Informed consent was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"KDM, DD, YK, MLSM, NT, and ML are employees of Sanofi and may hold company stock or stock options. JK and CV are employees of Inhibrx Biosciences, Inc., a former affiliate of Inhibrx, Inc., and may hold stock or stock options in Inhibrx Biosciences, Inc. JK also reports a patent titled \u201cEffective Dosage of Recombinant Serpin-Fc Fusion Protein for Use in a Method of Treating AAT Deficiency in a Subject\u201d pending to Inhibrx, Inc. VR is a former employee of Inhibrx Biosciences, Inc., a former affiliate of Inhibrx, Inc., and is currently employed at Celerion.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"278"}}