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Molecular therapy : the journal of the American Society of Gene Therapy
08 07, 2019;27 (8): 1415-1423.

mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo.

Yulia Rybakova, Piotr S Kowalski, Yuxuan Huang, John T Gonzalez, Michael W Heartlein, Frank DeRosa, Derfogail Delcassian, Daniel G Anderson
Author Information
  1. Yulia Rybakova: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  2. Piotr S Kowalski: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  3. Yuxuan Huang: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  4. John T Gonzalez: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  5. Michael W Heartlein: Translate Bio, Lexington, MA 02421, USA.
  6. Frank DeRosa: Translate Bio, Lexington, MA 02421, USA.
  7. Derfogail Delcassian: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  8. Daniel G Anderson: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: dgander@mit.edu.
PMID: 31160223 DOI: 10.1016/j.ymthe.2019.05.012

Abstract

Antibody-based drugs are a leading class of biologics used to treat a variety of diseases, including cancer. However, wide antibody implementation is hindered by manufacturing challenges and high production cost. Use of in-vitro-transcribed mRNA (IVT-mRNA) for endogenous protein expression has the potential to circumvent many of the shortcomings of antibody production and therapeutic application. Here, we describe the development of an IVT-mRNA system for in vivo delivery of a humanized anti-HER2 (also known as ERBB2) antibody, trastuzumab, and demonstrate its anticancer activity. We engineered the IVT-mRNA sequence to maximize expression, then formulated the IVT-mRNA into lipid-based nanoparticles (LNPs) to protect the mRNA from degradation and enable efficient in vivo delivery. Systemic delivery of the optimized IVT-mRNA loaded into LNPs resulted in antibody serum concentrations of 45 ± 8.6 μg/mL for 14 days after LNP injection. Further studies demonstrated an improved pharmacokinetic profile of the produced protein compared to injection of trastuzumab protein. Finally, treatment of tumor-bearing mice with trastuzumab IVT-mRNA LNPs selectively reduced the volume of HER2-positive tumors and improved animal survival. Taken together, the results of our study demonstrate that using IVT-mRNA LNPs to express full-size therapeutic antibodies in the liver can provide an effective strategy for cancer treatment and offers an alternative to protein administration.

Keywords

Herceptin antibody-based drugs breast cancer lipid nanoparticles mRNA delivery mRNA design mRNA therapeutics trastuzumab

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Grants

  1. P30 CA014051/NCI NIH HHS

MeSH Term

Animals
Antibodies, Monoclonal
Breast Neoplasms
Disease Models, Animal
Drug Delivery Systems
Gene Expression
Gene Transfer Techniques
Genetic Therapy
Humans
Lipids
Mice
Molecular Targeted Therapy
Nanoparticles
RNA, Messenger
Receptor, ErbB-2
Trastuzumab
Xenograft Model Antitumor Assays

Chemicals

Antibodies, Monoclonal
Lipids
RNA, Messenger
ERBB2 protein, human
Receptor, ErbB-2
Trastuzumab
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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