Genetically Engineered Cell-Derived Nanoparticles for Targeted Breast Cancer Immunotherapy

• Published in: Molecular therapy 2020-02, Vol.28 (2), p.536-547
• Main Authors: Shi, Xiaojing, Cheng, Qinqin, Hou, Tianling, Han, Menglu, Smbatyan, Goar, Lang, Julie E., Epstein, Alan L., Lenz, Heinz-Josef, Zhang, Yong
• Format: Article
• Language: English
• Subjects: Animals; antibodies; Antineoplastic Agents, Immunological - administration & dosage; Biomarkers, Tumor; breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cell Line, Tumor; Cell-Derived Microparticles; Disease Models, Animal; exosome; Female; Genetic Engineering; Humans; Immunotherapy; Lymphocyte Activation; Mice; Models, Biological; Molecular Targeted Therapy; Nanoparticles; Original; protein engineering; Receptor, ErbB-2 - antagonists & inhibitors; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.11.020

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 immuno-nanomedicines. [Display omitted] Zhang and colleagues report that reprogramming cell-derived exosomes with distinct types of monoclonal antibodies resulted in synthetic multivalent antibodies retargeted exosomes (SMART-Exos) displaying excellent potency and specificity in redirecting and activating T cells toward HER2-positive breast cancer cells for destruction, which may lead to an innovative class of exosome-based immunotherapeutics.