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Systemically Administered Anti-uPAR Antibody Plasma and Lung ELF Pharmacokinetics Characterized by Minimal Lung PBPK Model

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  • Advances in Drug Delivery by Inhalation - Official Collection from AAPS Inhalation & Nasal Community (INC)
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Abstract

Antibody-based therapeutics have recently gained keen attention for the treatment of pulmonary indications. However, systemically administered antibody exposure in the lungs needs to be better understood and remains a topic of interest. In this study, we evaluated the exposure of two different uPAR (urokinase-type plasminogen activator receptor) targeting full-length monoclonal IgGs in plasma and lung epithelial lining fluid (ELF) of mice after IP and IV administration. Antibody AK17 exhibited linear pharmacokinetics (PK) in plasma and ELF at 3 and 30 mg/kg single IV dose. The average plasma and ELF half-lives for AK17 and AK21 ranged between ~321–411 h and ~230–345 h, respectively, indicating sustained systemic and lung exposure of antibodies. The average ELF to the plasma concentration ratio of antibodies was ~0.01 and ~0.03 with IP and IV dosing, respectively, over 2 weeks post single dose. We simultaneously characterized plasma and ELF PK of antibody in mice by developing a minimal lung PBPK model for antibody. This model reasonably captured the plasma and ELF PK data while estimating three parameters. The model accounts for the convective transport of antibody into the tissues via blood and lymph flow. FcRn-mediated transcytosis was incorporated into the model for antibody distribution across the lung epithelial barrier. This model serves as a platform to predict the pulmonary PK of systemically administered antibodies and to support optimal dose selection for desired exposure in the lungs as the site of action.

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Authors and Affiliations

  1. Biotherapeutics Discovery, Research & Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./P.O. Box 368, Ridgefield, Connecticut, 06877-0368, USA

    Sharad Sharma, Antony Leonard, Kathryn Phoenix, Hsueh Yuan Chang, Jun Wang & Steven Hansel

Authors
  1. Sharad Sharma
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  2. Antony Leonard
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  4. Hsueh Yuan Chang
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Contributions

SS and AL: In vivo PK study design and experimental work. KP: anti-uPAR antibody generation and characterization. SS, HYC, and JW: antibody minimal lung PBPK model development. SS: writing original manuscript. HYC, JW, and SH: review and editing.

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Correspondence to Sharad Sharma.

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Philip Kwok, Francesca Buttini, Jenny Lam and Vivek Gupta

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Sharma, S., Leonard, A., Phoenix, K. et al. Systemically Administered Anti-uPAR Antibody Plasma and Lung ELF Pharmacokinetics Characterized by Minimal Lung PBPK Model. AAPS PharmSciTech 24, 236 (2023). https://doi.org/10.1208/s12249-023-02689-3

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