{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:46:26Z","timestamp":1787237186924,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T00:00:00Z","timestamp":1727395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Center for Protein Therapeutics at the University of Buffalo","award":["GM114179"],"award-info":[{"award-number":["GM114179"]}]},{"name":"Center for Protein Therapeutics at the University of Buffalo","award":["GM146097"],"award-info":[{"award-number":["GM146097"]}]},{"name":"Center for Protein Therapeutics at the University of Buffalo","award":["AI138195"],"award-info":[{"award-number":["AI138195"]}]},{"name":"Center for Protein Therapeutics at the University of Buffalo","award":["R01CA246785"],"award-info":[{"award-number":["R01CA246785"]}]},{"name":"Center for Protein Therapeutics at the University of Buffalo","award":["R01CA256928"],"award-info":[{"award-number":["R01CA256928"]}]},{"name":"Center for Protein Therapeutics at the University of Buffalo","award":["R01CA275967"],"award-info":[{"award-number":["R01CA275967"]}]},{"name":"National Institute of General Medical Sciences","award":["GM114179"],"award-info":[{"award-number":["GM114179"]}]},{"name":"National Institute of General Medical Sciences","award":["GM146097"],"award-info":[{"award-number":["GM146097"]}]},{"name":"National Institute of General Medical Sciences","award":["AI138195"],"award-info":[{"award-number":["AI138195"]}]},{"name":"National Institute of General Medical Sciences","award":["R01CA246785"],"award-info":[{"award-number":["R01CA246785"]}]},{"name":"National Institute of General Medical Sciences","award":["R01CA256928"],"award-info":[{"award-number":["R01CA256928"]}]},{"name":"National Institute of General Medical Sciences","award":["R01CA275967"],"award-info":[{"award-number":["R01CA275967"]}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["GM114179"],"award-info":[{"award-number":["GM114179"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["GM146097"],"award-info":[{"award-number":["GM146097"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI138195"],"award-info":[{"award-number":["AI138195"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01CA246785"],"award-info":[{"award-number":["R01CA246785"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01CA256928"],"award-info":[{"award-number":["R01CA256928"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01CA275967"],"award-info":[{"award-number":["R01CA275967"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Cancer Institute","award":["GM114179"],"award-info":[{"award-number":["GM114179"]}]},{"name":"National Cancer Institute","award":["GM146097"],"award-info":[{"award-number":["GM146097"]}]},{"name":"National Cancer Institute","award":["AI138195"],"award-info":[{"award-number":["AI138195"]}]},{"name":"National Cancer Institute","award":["R01CA246785"],"award-info":[{"award-number":["R01CA246785"]}]},{"name":"National Cancer Institute","award":["R01CA256928"],"award-info":[{"award-number":["R01CA256928"]}]},{"name":"National Cancer Institute","award":["R01CA275967"],"award-info":[{"award-number":["R01CA275967"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Objective: This study aimed to investigate the effect of molecular size on the pulmonary pharmacokinetics (PK) of proteins following systemic and local administration in wild-type mice. Methods: A non-cross-reactive antibody trastuzumab, and F(ab\u2032)2, Fab, and scFv fragments of this antibody were used for the investigation. Proteins were injected intravenously or via intratracheal instillation, and PK was measured in plasma, lungs, trachea, bronchi, and bronchoalveolar lavage (BAL) using ELISA. Concentrations in BAL were urea normalized. Results: Following systemic administration, the biodistribution coefficient (BC) for lungs, trachea, bronchi, and BAL was 11%, 11%, 15%, and 2% for the antibody; 15%, 7%, 13%, and 8% for F(ab\u2032)2; 25%, 17%, 28%, and 46% for Fab; and 14%, 1%, 2%, and 50% for scFv. The antibody exposure in BAL was ~50-fold lower than plasma and ~5\u20137-fold lower than lung tissues. A tissue-dependent BC vs. molecular size relationship was observed, where distribution in tissues was the highest for Fab (50 kDa), and scFv demonstrated the highest distribution in the BAL. PK data generated following local administration were quite variable; however, local dosing resulted in BAL exposures that were 10\u2013100-fold higher than those achieved after systemic dosing for all proteins. The BAL antibody concentrations were 100\u20131000-fold higher than plasma concentrations initially, which normalized by day 14. For most proteins, local dosing resulted in higher lung concentrations than trachea and bronchi, opposite to what was observed after systemic dosing. Conclusions: The PK data presented here provide an unprecedented quantitative insight into the effect of molecular size on the pulmonary disposition of proteins following systemic and local administration.<\/jats:p>","DOI":"10.3390\/pharmaceutics16101259","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T09:16:10Z","timestamp":1727428570000},"page":"1259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pulmonary Pharmacokinetics of Antibody and Antibody Fragments Following Systemic and Local Administration in Mice"],"prefix":"10.3390","volume":"16","author":[{"given":"Prabhas","family":"Jagdale","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3717-0233","authenticated-orcid":false,"given":"Ashwni","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0723-6206","authenticated-orcid":false,"given":"Dhaval K.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Usmani, S.S., Bedi, G., Samuel, J.S., Singh, S., Kalra, S., Kumar, P., Ahuja, A.A., Sharma, M., Gautam, A., and Raghava, G.P. (2017). THPdb: Database of FDA-approved peptide and protein therapeutics. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181748"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrd2399","article-title":"Protein therapeutics: A summary and pharmacological classification","volume":"7","author":"Leader","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1073\/pnas.76.1.106","article-title":"Expression in Escherichia coli of chemically synthesized genes for human insulin","volume":"76","author":"Goeddel","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1080\/1744666X.2018.1468753","article-title":"Immunogenicity of biologic therapies: Causes and consequences","volume":"14","author":"Boehncke","year":"2018","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.pharmthera.2013.10.008","article-title":"Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis","volume":"141","author":"Royce","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lyly, A., Laulajainen-Hongisto, A., Gevaert, P., Kauppi, P., and Toppila-Salmi, S. (2020). Monoclonal antibodies and airway diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249477"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.bsheal.2021.02.001","article-title":"An update to monoclonal antibody as therapeutic option against COVID-19","volume":"3","author":"Deb","year":"2021","journal-title":"Biosaf. Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3957","DOI":"10.1007\/s00253-022-11989-w","article-title":"Anti-bacterial monoclonal antibodies: Next generation therapy against superbugs","volume":"106","author":"Wang","year":"2022","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1152\/japplphysiol.00362.2005","article-title":"Epithelial lining fluid solute concentrations in chronic obstructive lung disease patients and normal subjects","volume":"99","author":"Effros","year":"2005","journal-title":"J. Appl. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Schamberger, A.C., Schiller, H.B., Fernandez, I.E., Sterclova, M., Heinzelmann, K., Hennen, E., Hatz, R., Behr, J., Va\u0161\u00e1kov\u00e1, M., and Mann, M. (2016). Glutathione peroxidase 3 localizes to the epithelial lining fluid and the extracellular matrix in interstitial lung disease. Sci. Rep., 6.","DOI":"10.1038\/srep29952"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S-4","DOI":"10.1089\/dia.2007.0228","article-title":"Inhalation, deposition, and fate of insulin and other therapeutic proteins","volume":"9","author":"Brain","year":"2007","journal-title":"Diabetes Technol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/s10928-021-09772-x","article-title":"Two-pore physiologically based pharmacokinetic model validation using whole-body biodistribution of trastuzumab and different-size fragments in mice","volume":"48","author":"Li","year":"2021","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.xphs.2020.05.025","article-title":"Whole-body pharmacokinetics of antibody in mice determined using enzyme-linked immunosorbent assay and derivation of tissue interstitial concentrations","volume":"110","author":"Chang","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s10928-007-9065-1","article-title":"Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice","volume":"34","author":"Garg","year":"2007","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.addr.2006.07.015","article-title":"Pulmonary administration of therapeutic proteins using an immunoglobulin transport pathway","volume":"58","author":"Bitonti","year":"2006","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"L679","DOI":"10.1152\/ajplung.00205.2003","article-title":"Mechanisms of alveolar protein clearance in the intact lung","volume":"286","author":"Hastings","year":"2004","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1007\/s11095-005-9226-0","article-title":"Expression and transport functionality of FcRn within rat alveolar epithelium: A study in primary cell culture and in the isolated perfused lung","volume":"23","author":"Sakagami","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/19420862.2015.1111497","article-title":"Influence of molecular size on tissue distribution of antibody fragments","volume":"8","author":"Li","year":"2016","journal-title":"MAbs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1513\/pats.200409-049TA","article-title":"The lungs as a portal of entry for systemic drug delivery","volume":"1","author":"Patton","year":"2004","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/rr58","article-title":"The lung as a route for systemic delivery of therapeutic proteins and peptides","volume":"2","author":"Armand","year":"2001","journal-title":"Respir. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1056\/NEJMoa2107934","article-title":"Early Treatment for COVID-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab","volume":"385","author":"Gupta","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1124\/dmd.119.087809","article-title":"Effect of Size on Solid Tumor Disposition of Protein Therapeutics","volume":"47","author":"Li","year":"2019","journal-title":"Drug Metab. Dispos."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1258\/002367707779399400","article-title":"A novel and simple method for endotracheal intubation of mice","volume":"41","author":"Spoelstra","year":"2007","journal-title":"Lab. Anim."},{"key":"ref_24","first-page":"e55398","article-title":"Bronchoalveolar Lavage of Murine Lungs to Analyze Inflammatory Cell Infiltration","volume":"123","author":"Job","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1208\/s12248-021-00647-0","article-title":"Pharmacokinetics of Monoclonal Antibody and Antibody Fragments in the Mouse Eye following Systemic Administration","volume":"23","author":"Bussing","year":"2021","journal-title":"AAPS J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"89","DOI":"10.12793\/tcp.2019.27.3.89","article-title":"Non-compartmental data analysis using SimBiology and MATLAB","volume":"27","author":"Park","year":"2019","journal-title":"Transl. Clin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s40259-014-0103-4","article-title":"Comparative nonclinical assessments of the proposed biosimilar PF-05280014 and trastuzumab (Herceptin\u00ae)","volume":"28","author":"Hurst","year":"2014","journal-title":"BioDrugs"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"533","DOI":"10.4103\/0019-5049.165849","article-title":"Anatomy and physiology of respiratory system relevant to anaesthesia","volume":"59","author":"Patwa","year":"2015","journal-title":"Indian J. Anaesth."},{"key":"ref_29","unstructured":"Cotes, J.E., Chinn, D.J., and Miller, M.R. (2009). Lung Function: Physiology, Measurement and Application in Medicine, John Wiley & Sons."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/scientificamerican0266-56","article-title":"The lung","volume":"214","author":"Comroe","year":"1966","journal-title":"Sci. Am."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1164\/rccm.201206-1063PP","article-title":"Respiratory infection and the impact of pulmonary immunity on lung health and disease","volume":"186","author":"Mizgerd","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0025-6196(12)64949-0","article-title":"Immunoglobulin G and its function in the human respiratory tract","volume":"63","author":"Reynolds","year":"1988","journal-title":"Mayo Clin. Proc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.ejps.2006.02.002","article-title":"Assessment of transport rates of proteins and peptides across primary human alveolar epithelial cell monolayers","volume":"28","author":"Bur","year":"2006","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"L616","DOI":"10.1152\/ajplung.00121.2004","article-title":"Net absorption of IgG via FcRn-mediated transcytosis across rat alveolar epithelial cell monolayers","volume":"287","author":"Kim","year":"2004","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_35","first-page":"72","article-title":"Protein metabolism in lung: Use of isolated perfused lung to study protein degradation","volume":"47","author":"Chiang","year":"1979","journal-title":"J. Appl. Physiol. Respir. Environ. Exerc. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kilany, L.A.A., Gaber, A.A.S., Aboulwafa, M.M., and Zedan, H.H. (2021). Trastuzumab immunogenicity development in patients\u2019 sera and in laboratory animals. BMC Immunol., 22.","DOI":"10.1186\/s12865-021-00405-z"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1089\/jamp.2020.29029.cd","article-title":"Deposition mechanisms","volume":"33","author":"Darquenne","year":"2020","journal-title":"J. Aerosol. Med. Pulm. Drug Deliv."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1183\/09059180.05.00009501","article-title":"Lung defences: An overview","volume":"14","author":"Nicod","year":"2005","journal-title":"Eur. Respir. Rev."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/10\/1259\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:05:14Z","timestamp":1760112314000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/10\/1259"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,27]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["pharmaceutics16101259"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16101259","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,27]]}}}