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The Airways, a Novel Route for Delivering Monoclonal Antibodies to Treat Lung Tumors

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ABSTRACT

Purpose

Lung cancer is the leading cause of cancer-related death worldwide. The efficacy of current systemic treatments is limited, with major side effects and only modest survival improvements. Aerosols routinely used to deliver drugs into the lung for treating infectious and inflammatory lung diseases have never been used to deliver monoclonal antibodies to treat lung cancer. We have shown that cetuximab, a chimeric anticancer anti-EGFR mAb, is suitable for airway delivery as it resists the physical constraints of aerosolization, and have evaluated the aerosol delivery of cetuximab in vivo.

Methods

We developed an animal model of lung tumor sensitive to cetuximab by injecting Balb/c Nude mice intratracheally with A431 cells plus 10 mM EDTA and analyzed the distribution, pharmacokinetics and antitumor efficacy of cetuximab aerosolized into the respiratory tract.

Results

Aerosolized IgG accumulated durably in the lungs and the tumor, but passed poorly and slowly into the systemic circulation. Aerosolized cetuximab also limited the growth of the mouse tumor. Thus, administering anticancer mAbs via the airways is effective and may limit systemic side effects.

Conclusion

Delivery of aerosolized-mAbs via the airways deserves further evaluation for treating lung cancers.

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ACKNOWLEDGMENTS

This work was supported by grants from the Ligue Contre le Cancer, the Cancéropôle Grand-Ouest, Région Centre and the IFR “Imagerie fonctionelle”. A. Maillet was financed by SPLF, Pneumologie Développement and ARAIR. Laurent Guilleminault holds a fellowship from the Fondation pour la Recherche Médicale. We thank Hervé Leroux, Maryline Le Mée, Stéphanie Rétif, Georges Roseau and Julien Sobilo for their help with the animal studies and imaging. We are grateful to Dr. A. Courtois for providing the FITC-cetuximab. Many thanks to Pr. Francis Gauthier for his comments on the manuscript and to J.F. Tournamille from CHU Bretonneau, Tours. The English text was edited by Dr. Owen Parkes.

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Authors and Affiliations

  1. INSERM U618, Université François Rabelais de Tours, Tours, France

    Agnès Maillet, Laurent Guilleminault, Etienne Lemarié, Pascale Reverdiau, Christelle Parent, Yves Courty, Michèle De Monte, Patrice Diot, Alain Le Pape & Nathalie Heuzé-Vourc’h

  2. CHRU de Tours, Tours, France

    Etienne Lemarié & Patrice Diot

  3. TAAM–CIPA UPS44, Orléans, France

    Stéphanie Lerondel & Alain Le Pape

  4. UMR6239 GICC, CHRU de Tours, Tours, France

    Nicolas Azzopardi, Nicolas Congy-Jolivet, Gilles Paintaud & Hervé Watier

  5. PPF « Animaleries », Faculté de Médecine, Tours, France

    Jérôme Montharu

  6. Laboratoires Novaxia, Saint Laurent Nouan, France

    Brigitte Legrain & Dominique-Henri Douvin

  7. CHU d’Angers Service de Pneumologie, Angers, France

    José Hureaux

  8. Faculty of Medicine, INSERM U618, 10 Blvd Tonnellé, 37032, Tours, France

    Nathalie Heuzé-Vourc’h

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  1. Agnès Maillet
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  2. Laurent Guilleminault
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Corresponding author

Correspondence to Nathalie Heuzé-Vourc’h.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure S1

A431 implantation in lungs with and without EDTAto establish an animal model of ectopic lung tumor sensitive to cetuximab.A431 cells (2.5 × 106) in medium with or without 10 mM EDTA were gently infused into the main bronchus of the mice via a catheter. (PDF 11 kb)

Supplementary Figure S2

Evaluation of sprayed cetuximab affinity to EGFR. A431 cells were incubated with native cetuximab or microsprayer sprayed cetuximab. Cells were then incubated with FITC-cetuximab and analyzed by flow cytometry. Results of cells treated with native cetuximab are indicated as a black line and with microsprayer sprayed cetuximab as a gray line. (docx 110 kb)

Supplementary Figure S3

Absence of toxicity attributed to airways delivery of cetuximab in BALB/c mouse. BALB/c mice were treated with cetuximab via i.p or airways, or PBS in the presence of Tc99m during 5 weeks. A : Weight variation and leukocyte formulation of mouse. Results are expressed as median for each group. Stripped bars: lymphocytes, black bars: monocytes and white bars: granulocytes. B: Histological analysis conducted post-mortem on liver (i), ileum (ii), oesophagus (iii), skin (iv), lungs (v), spleen (vi), kidney (vii) and trachea (viii) in a mouse that received sprayed cetuximab. Images are representative of one animal out of 10. (docx 750 kb)

Supplementary Figure S4

Evaluation of Xenofluor750™-cetuximab affinity to EGFR. A431 cells were incubated with unlabelledcetuximab or Xenofluor750™- cetuximab. Cells were then incubated with FITC-cetuximab and analyzed by flow cytometry. Results of cells treated with unlabelledcetuximab are indicated as dashed line and with Xenofluor750™-cetuximab as solid line. (doc 54 kb)

Supplementary Figure S5

Administration of free Xenofluor750™ by airways (A) or i.v.(B). (PDF 812 kb)

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Maillet, A., Guilleminault, L., Lemarié, E. et al. The Airways, a Novel Route for Delivering Monoclonal Antibodies to Treat Lung Tumors. Pharm Res 28, 2147–2156 (2011). https://doi.org/10.1007/s11095-011-0442-5

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  • DOI: https://doi.org/10.1007/s11095-011-0442-5

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