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

doi:10.1016/j.ymthe.2019.05.012

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.

Authors

Yulia Rybakova¹, Piotr S Kowalski¹, Yuxuan Huang², John T Gonzalez², Michael W Heartlein³, Frank DeRosa³, Derfogail Delcassian¹, Daniel G Anderson⁴

Affiliations

¹ 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 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
³ Translate Bio, Lexington, MA 02421, USA.
⁴ 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.

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.

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

Substances

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

Grants and funding

P30 CA014051/CA/NCI NIH HHS/United States