Genetically Engineered Cell-Derived Nanoparticles for Targeted Breast Cancer Immunotherapy

Xiaojing Shi; Qinqin Cheng; Tianling Hou; Menglu Han; Goar Smbatyan; Julie E Lang; Alan L Epstein; Heinz-Josef Lenz; Yong Zhang

doi:10.1016/j.ymthe.2019.11.020

Genetically Engineered Cell-Derived Nanoparticles for Targeted Breast Cancer Immunotherapy

Mol Ther. 2020 Feb 5;28(2):536-547. doi: 10.1016/j.ymthe.2019.11.020. Epub 2019 Nov 27.

Authors

Xiaojing Shi¹, Qinqin Cheng¹, Tianling Hou¹, Menglu Han¹, Goar Smbatyan², Julie E Lang³, Alan L Epstein⁴, Heinz-Josef Lenz², Yong Zhang⁵

Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
² Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
³ Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁵ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; Research Center for Liver Diseases, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: yongz@usc.edu.

Abstract

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.

Keywords: antibodies; breast cancer; exosome; immunotherapy; protein engineering.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents, Immunological / administration & dosage*
Biomarkers, Tumor
Breast Neoplasms / immunology*
Breast Neoplasms / pathology
Breast Neoplasms / therapy*
Cell Line, Tumor
Cell-Derived Microparticles*
Disease Models, Animal
Female
Genetic Engineering*
Humans
Immunotherapy
Lymphocyte Activation
Mice
Models, Biological
Molecular Targeted Therapy*
Nanoparticles
Receptor, ErbB-2 / antagonists & inhibitors
T-Lymphocyte Subsets / drug effects
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Immunological
Biomarkers, Tumor
ERBB2 protein, human
Receptor, ErbB-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding