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Antitumour activity and tolerability of an EphA2-targeted nanotherapeutic in multiple mouse models

Nature Biomedical Engineering volume 3, pages 264–280 (2019)Cite this article

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Abstract

Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2—a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue. We also show that administration of the nanotherapeutic in rats and dogs resulted in minimal haematological toxicity, as well as the absence of neutropenia and improved overall tolerability in multiple rodent models. Targeting of the nanotherapeutic to EphA2 improved tumour penetration and resulted in markedly enhanced antitumour activity (compared with administration of free docetaxel and non-targeted nanotherapeutic controls) in multiple tumour-xenografted mice. This nanomedicine could become a potent and safe therapeutic alternative for cancer patients undergoing chemotherapy.

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Fig. 1: Chemical structure and formulation of EphA2-ILs-DTXp.
Fig. 2: Plasma and tumour pharmacokinetics of EphA2-ILs-DTXp.
Fig. 3: Animal toxicity of EphA2-ILs-DTXp.
Fig. 4: The in vivo activity of EPhA2-ILs-DTXp is superior to free DTX at equitoxic dosing in six xenograft models of cancer.
Fig. 5: In vivo activity of EphA2-ILs-DTXp versus NT-Ls-DTXp in four xenograft mouse models.
Fig. 6: In vivo mechanisms of EphA2 targeting.
Fig. 7: Ratiometric imaging of EphA2-targeted liposomes in normal and tumour tissues.

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Data availability

The datasets generated and/or analysed during the study, and source data for the figures, are available in Figshare at https://doi.org/10.6084/m9.figshare.7786205.

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Acknowledgements

This work was supported in part by a grant from the Department of Defense (grant number OC150083 to C.P.R.). This work was also partially supported by National Cancer Institute grant P30CA016056, involving the use of Roswell Park’s Bioanalytics, Metabolomics and Pharmacokinetics Shared Resource (J.H.W. and S.A.S.). We also acknowledge L. Zalutskaya for support with both preparation and submission of the manuscript.

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  1. Charles O. Noble & Mark E. Hayes

    Present address: ZoneOne Pharma, San Francisco, CA, USA

  2. These authors contributed equally: Walid S. Kamoun, Dmitri B. Kirpotin, Zhaohua Richard Huang, Suresh K. Tipparaju.

Authors and Affiliations

  1. Merrimack Pharmaceuticals, Cambridge, MA, USA

    Walid S. Kamoun, Dmitri B. Kirpotin, Zhaohua Richard Huang, Suresh K. Tipparaju, Charles O. Noble, Mark E. Hayes, Lia Luus, Alexander Koshkaryev, Jaeyeon Kim, Ken Olivier, Tad Kornaga, Shinji Oyama, Vasileios Askoxylakis, Christine Pien, Geoffrey Kuesters, Nancy Dumont, Alexey A. Lugovskoy, Melissa L. Geddie, James Suchy, Stephanie Grabow, Neeraj Kohli, Andrew J. Sawyer & Daryl C. Drummond

  2. Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Sarah A. Schihl & John H. Wilton

  3. Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    C. Patrick Reynolds & Rachel Blaydes

  4. University of California at San Francisco, San Francisco, CA, USA

    Yu Zhou & James D. Marks

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Contributions

W.S.K., D.B.K., Z.R.H., S.K.T., L.L., K.O., G.K., A.A.L., C.P.R., V.A. and D.C.D. designed the studies. D.B.K., Z.R.H., S.K.T., C.O.N., M.E.H., M.L.G., J.D.M. and D.C.D. designed the molecule. W.S.K., D.B.K., Z.R.H., S.K.T., C.O.N., M.E.H., L.L., A.K., T.K., S.O., C.P., N.D., S.A.S., J.H.W., M.L.G., J.S., S.G., N.K., R.B., Y.Z. and A.J.S. collected the data. W.S.K., D.B.K., Z.R.H., S.K.T., C.O.N., M.E.H., L.L., A.K., J.K., K.O., T.K., S.O., G.K., S.A.S., J.H.W., C.P.R., R.B., Y.Z., A.J.S. and D.C.D. analysed the data. W.S.K., V.A. and D.C.D. wrote the manuscript.

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Correspondence to Daryl C. Drummond.

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All of the authors affiliated with Merrimack Pharmaceuticals were employees of Merrimack Pharmaceuticals at the time of the study, with D.C.D., A.K., J.D.M., Z.R.H., A.J.S., L.L. and G.K. currently owning stock or stock options in Merrimack Pharmaceuticals.

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Kamoun, W.S., Kirpotin, D.B., Huang, Z.R. et al. Antitumour activity and tolerability of an EphA2-targeted nanotherapeutic in multiple mouse models. Nat Biomed Eng 3, 264–280 (2019). https://doi.org/10.1038/s41551-019-0385-4

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