2. Academic Validation
  3. In vivo biodistribution and pharmacokinetics of sotrovimab, a SARS-CoV-2 monoclonal antibody, in healthy cynomolgus monkeys

In vivo biodistribution and pharmacokinetics of sotrovimab, a SARS-CoV-2 monoclonal antibody, in healthy cynomolgus monkeys

  • Eur J Nucl Med Mol Imaging. 2022 Oct 28;1-12. doi: 10.1007/s00259-022-06012-3.
Tolulope A Aweda 1,  Shih-Hsun Cheng 1,  Stephen C Lenhard 1,  Armin Sepp 2,  Tinamarie Skedzielewski 1,  Chih-Yang Hsu 1,  Shelly Marshall 3,  Heather Haag 3,  Jonathan Kehler 4,  Prabhas Jagdale 5,  Alessia Peter 6,  Michael A Schmid 6,  Andrew Gehman 7,  Minh Doan 1,  Andrew P Mayer 4,  Peter Gorycki 5,  Marie Fanget 8,  Christophe Colas 9,  Brenda Smith 10,  Curtis C Maier 11,  Hasan Alsaid 12
Affiliations

Affiliations

  • 1 Bioimaging, GSK, 1250 S. Collegeville Rd, Collegeville, PA, 19426, USA.
  • 2 Certara UK Ltd, Sheffield, UK.
  • 3 Integrated Biological Platform Sciences, GSK, Collegeville, PA, USA.
  • 4 Bioanalysis, Immunogenicity & Biomarkers, GSK, Collegeville, PA, USA.
  • 5 DMPK, GSK, Collegeville, PA, USA.
  • 6 mAb Engineering & Bioanalytics, Humabs BioMed SA, Vir Biotechnology, Inc, Bellinzona, Switzerland.
  • 7 Non-Clinical and Translational Statistics, GSK, Collegeville, PA, USA.
  • 8 Bioanalytical Department, Vir Biotechnology, Inc, San Francisco, CA, USA.
  • 9 DMPK, Vir Biotechnology, Inc, San Francisco, CA, USA.
  • 10 Toxicology, Vir Biotechnology, Inc, San Francisco, CA, USA.
  • 11 Non-Clinical Safety, GSK, Collegeville, PA, USA.
  • 12 Bioimaging, GSK, 1250 S. Collegeville Rd, Collegeville, PA, 19426, USA. [email protected].
PMID: 36305907 DOI: 10.1007/s00259-022-06012-3
Abstract

Purpose: Sotrovimab (VIR-7831), a human IgG1κ monoclonal antibody (mAb), binds to a conserved epitope on the SARS-CoV-2 spike protein receptor binding domain (RBD). The Fc region of VIR-7831 contains an LS modification to promote neonatal Fc receptor (FcRn)-mediated recycling and extend its serum half-life. Here, we aimed to evaluate the impact of the LS modification on tissue biodistribution, by comparing VIR-7831 to its non-LS-modified equivalent, VIR-7831-WT, in cynomolgus monkeys.

Methods: 89Zr-based PET/CT imaging of VIR-7831 and VIR-7831-WT was performed up to 14 days post injection. All major organs were analyzed for absolute concentration as well as tissue:blood ratios, with the focus on the respiratory tract, and a physiologically based pharmacokinetics (PBPK) model was used to evaluate the tissue biodistribution kinetics. Radiomics features were also extracted from the PET images and SUV values.

Results: SUVmean uptake in the pulmonary bronchi for 89Zr-VIR-7831 was statistically higher than for 89Zr-VIR-7831-WT at days 6 (3.43 ± 0.55 and 2.59 ± 0.38, respectively) and 10 (2.66 ± 0.32 and 2.15 ± 0.18, respectively), while the reverse was observed in the liver at days 6 (5.14 ± 0.80 and 8.63 ± 0.89, respectively), 10 (4.52 ± 0.59 and 7.73 ± 0.66, respectively), and 14 (4.95 ± 0.65 and 7.94 ± 0.54, respectively). Though the calculated terminal half-life was 21.3 ± 3.0 days for VIR-7831 and 16.5 ± 1.1 days for VIR-7831-WT, no consistent differences were observed in the tissue:blood ratios between the Antibodies except in the liver. While the lung:blood SUVmean uptake ratio for both mAbs was 0.25 on day 3, the PBPK model predicted the total lung tissue and the interstitial space to serum ratio to be 0.31 and 0.55, respectively. Radiomics analysis showed VIR-7831 had mean-centralized PET SUV distribution in the lung and liver, indicating more uniform uptake than VIR-7831-WT.

Conclusion: The half-life extended VIR-7831 remained in circulation longer than VIR-7831-WT, consistent with enhanced FcRn binding, while the tissue:blood concentration ratios in most tissues for both drugs remained statistically indistinguishable throughout the course of the experiment. In the bronchiolar region, a higher concentration of 89Zr-VIR-7831 was detected. The data also allow unparalleled insight into tissue distribution and elimination kinetics of mAbs that can guide future biologic drug discovery efforts, while the residualizing nature of the 89Zr label sheds LIGHT on the sites of antibody catabolism.

Keywords

89Zr-PET; Biodistribution; Monoclonal antibody; Physiologically based pharmacokinetics (PBPK); Radiomics; Respiratory tract; SARS-CoV-2; Sotrovimab.

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