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

Jing Wen; Di Wu; Meng Qin; Chaoyong Liu; Lan Wang; Duo Xu; Harry V Vinters; Yang Liu; Emiko Kranz; Xin Guan; Guibo Sun; Xiaobo Sun; YooJin Lee; Otoniel Martinez-Maza; Daniel Widney; Yunfeng Lu; Irvin S Y Chen; Masakazu Kamata

doi:10.1038/s41551-019-0434-z

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

Nat Biomed Eng. 2019 Sep;3(9):706-716. doi: 10.1038/s41551-019-0434-z. Epub 2019 Aug 5.

Authors

Jing Wen^#^{1

2}, Di Wu^#³, Meng Qin^{1

2}, Chaoyong Liu³, Lan Wang^{1

2}, Duo Xu³, Harry V Vinters^{4

5}, Yang Liu⁶, Emiko Kranz^{2

7}, Xin Guan⁸, Guibo Sun⁹, Xiaobo Sun⁹, YooJin Lee^{1

2}, Otoniel Martinez-Maza^{1

2

10}, Daniel Widney^{2

11}, Yunfeng Lu¹², Irvin S Y Chen^{13

14}, Masakazu Kamata^{15

16}

Affiliations

¹ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² UCLA AIDS Institute, Los Angeles, CA, USA.
³ Department of Chemical and Biomolecular Engineering, School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Pathology and Laboratory Medicine (Neuropathology), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China.
⁷ Division of Haematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Biopharmaceutical Research and Development Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China.
⁹ Institute of Medicinal Plant Development, Chinse Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹⁰ Department of Epidemiology, School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹² Department of Chemical and Biomolecular Engineering, School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA. luucla@ucla.edu.
¹³ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. syuchen@mednet.ucla.edu.
¹⁴ UCLA AIDS Institute, Los Angeles, CA, USA. syuchen@mednet.ucla.edu.
¹⁵ UCLA AIDS Institute, Los Angeles, CA, USA. masa3k@ucla.edu.
¹⁶ Division of Haematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. masa3k@ucla.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / therapeutic use*
Brain
Central Nervous System*
Chemokine CXCL13 / drug effects
Chemokine CXCL13 / metabolism
Disease Models, Animal
Drug Delivery Systems / methods*
Lymphatic Metastasis / drug therapy
Lymphoma, B-Cell / drug therapy*
Lymphoma, Non-Hodgkin / drug therapy
Mice
Molecular Targeted Therapy / methods*
Nanocapsules
Receptors, CXCR5 / drug effects
Receptors, CXCR5 / metabolism
Rituximab / pharmacology*
Xenograft Model Antitumor Assays

Substances

Antibodies, Monoclonal
CXCR5 protein, mouse
Chemokine CXCL13
Cxcl13 protein, mouse
Nanocapsules
Receptors, CXCR5
Rituximab

Abstract

Publication types

MeSH terms

Substances

Grants and funding