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Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice

Nature Biomedical Engineering volume 3, pages 706–716 (2019)Cite this article

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Abstract

Approximately 15–40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13—the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma—a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow–liver–thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases.

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Fig. 1: Timed-release nanocapsules facilitate brain delivery of RTX in mice.
Fig. 2: Nanocapsulation enhances the anti-lymphoma activity of RTX against CNS lymphomas in the 2F7-BR44 murine xenograft model.
Fig. 3: CXCL13 conjugation mediates 2F7-BR44 cell-specific nanocapsule targeting without affecting overall biodistribution.
Fig. 4: CXCL13 conjugation improves the anti-lymphoma activity of n-RTX.
Fig. 5: CXCL13 conjugation improves the anti-lymphoma activity of n-RTX at different stages of lymphoma progression.
Fig. 6: n-RTXCXCL13 exhibits superior anti-lymphoma activity against CNS lymphomas in 2F7-BR44-Luc cell xenograft humanized mice.

Data availability

The authors declare that all data supporting the results of this study are available within the paper and its Supplementary Information files. Source data collected in this study are available from the corresponding author upon request.

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Acknowledgements

This work was supported by the UCLA AIDS Institute HIV Extinction Project funded by the McCarthy Family Foundation (to M.K.), NIH grants RO1 CA232015 and RO1 AI110200 (to M.K.), U19AI117941 (to I.S.Y.C.) and R21 AI114433 (to I.S.Y.C.), and the California HIV/AIDS Research Grants Program (ID15-LA-050 to D.Widney). Equipment located at the UCLA AIDS Institute is supported by the James B. Pendleton Charitable Trust. Cell sorting was performed in the CFAR Flow Cytometry Core Facility supported by NIH grants P30 CA016042 and 5P30 AI028697.

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  1. These authors contributed equally: Jing Wen, Di Wu.

Authors and Affiliations

  1. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Jing Wen, Meng Qin, Lan Wang, YooJin Lee, Otoniel Martinez-Maza & Irvin S. Y. Chen

  2. UCLA AIDS Institute, Los Angeles, CA, USA

    Jing Wen, Meng Qin, Lan Wang, Emiko Kranz, YooJin Lee, Otoniel Martinez-Maza, Daniel Widney, Irvin S. Y. Chen & Masakazu Kamata

  3. Department of Chemical and Biomolecular Engineering, School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA

    Di Wu, Chaoyong Liu, Duo Xu & Yunfeng Lu

  4. Department of Pathology and Laboratory Medicine (Neuropathology), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Harry V. Vinters

  5. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Harry V. Vinters

  6. State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China

    Yang Liu

  7. Division of Haematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Emiko Kranz & Masakazu Kamata

  8. Biopharmaceutical Research and Development Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China

    Xin Guan

  9. Institute of Medicinal Plant Development, Chinse Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Guibo Sun & Xiaobo Sun

  10. Department of Epidemiology, School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA

    Otoniel Martinez-Maza

  11. Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Daniel Widney

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  1. Jing Wen
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Contributions

J.W. and M.K. contributed to the study design, performed the experiments, analysed the data and wrote the paper. D.Wu, M.Q., C.L., L.W., D.X., H.V.V., Y.Liu, E.K., X.G, G.S., Y.Lee and X.S. performed the experiments. D.Widney, O.M.-M. and Y.Lu. interpreted the data. I.S.Y.C. wrote the paper and interpreted the data. All authors reviewed the manuscript.

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Correspondence to Yunfeng Lu, Irvin S. Y. Chen or Masakazu Kamata.

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I.S.Y.C. has a financial interest in CSL Behring. The remaining authors declare no competing interests.

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Wen, J., Wu, D., Qin, M. et al. Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice. Nat Biomed Eng 3, 706–716 (2019). https://doi.org/10.1038/s41551-019-0434-z

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