mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo

Mol Ther. 2019 Aug 7;27(8):1415-1423. doi: 10.1016/j.ymthe.2019.05.012. Epub 2019 May 18.


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.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / genetics*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Disease Models, Animal
  • Drug Delivery Systems
  • Gene Expression*
  • Gene Transfer Techniques*
  • Genetic Therapy
  • Humans
  • Lipids
  • Mice
  • Molecular Targeted Therapy
  • Nanoparticles
  • RNA, Messenger / administration & dosage
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Trastuzumab / administration & dosage
  • Trastuzumab / genetics
  • Trastuzumab / pharmacokinetics
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Lipids
  • RNA, Messenger
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab