Journal
MOLECULAR THERAPY
Volume 28, Issue 2, Pages 536-547Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2019.11.020
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Funding
- University of Southern California School of Pharmacy Start-Up Fund for New Faculty
- University of Southern California Ming Hsieh Institute for Engineering Medicine for Cancer
- American Cancer Society [IRG-16-181-57]
- STOP CANCER Research Career Development Award
- PhRMA Foundation Research Starter Grant in Translational Medicine and Therapeutics
- [P30CA014089]
- [P30DK048522]
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Exosomes are nanosized membranous vesicles secreted by a variety of cells. Due to their unique and pharmacologically important properties, cell-derived exosome nanoparticles have drawn significant interest for drug development. By genetically modifying exosomes with two distinct types of surface-displayed monoclonal antibodies, we have developed an exosome platform termed synthetic multivalent antibodies retargeted exosome (SMART-Exo) for controlling cellular immunity. Here, we apply this approach to human epidermal growth factor receptor 2 (HER2)-expressing breast cancer by engineering exosomes through genetic display of both anti-human CD3 and anti-human HER2 antibodies, resulting in SMART-Exos dually targeting T cell CD3 and breast cancer-associated HER2 receptors. By redirecting and activating cytotoxic T cells toward attacking HER2-expressing breast cancer cells, the designed SMART-Exos exhibited highly potent and specific anti-tumor activity both in vitro and in vivo. This work demonstrates preclinical feasibility of utilizing endogenous exosomes for targeted breast cancer immunotherapy and the SMART-Exos as a broadly applicable platform technology for the development of next-generation immunonanomedicines.
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