mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo
Open accessAbstract
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.
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Lipid nanoparticle-mRNA formulations have been investigated for ex vivo engineering of CAR T cells and for the production of antibodies, such as anti-CD20, anti-human epidermal growth factor receptor 2 and anti-CD3/claudin 6.
“Lipid nanoparticle–mRNA formulations have also been investigated for ex vivo engineering of CAR T cells217 and for the production of antibodies, such as anti-CD20 (ref.146), anti-human epidermal growth factor receptor 2 (HER2)95 and anti-CD3/claudin 6 (ref.147).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [95]
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References 61 · Cited by 218
Research works printed but not linked: 2
- [36]36. [Valleriani, A., Zhang, G., Nagar, A., Ignatova, Z., and Lipowsky, R. (2011). Lengthdependent translation of messenger RNA by ribosomes. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 83 , 042903.](http://refhub.elsevier.com/S1525-0016(19)30226-6/sref36)
- [52]52. [Stadler, C.R., Bähr-Mahmud, H., Celik, L., Hebich, B., Roth, A.S., Roth, R.P., Karikó, K., Türeci, Ö., and Sahin, U. (2017). Elimination of large tumors in mice by mRNAencoded bispeci fi c antibodies. Nat. Med. 23 , 815 -817.](http://refhub.elsevier.com/S1525-0016(19)30226-6/sref52)
- Authors
- Rybakova, Y., Kowalski, P. S., Huang, Y., Gonzalez, J. T., Heartlein, M. W., DeRosa, F., Delcassian, D., & Anderson, D. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Translate Bio (United States) (US)
- Harvard University (US)
- Corresponding author
- Anderson, Daniel G.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 27
- Issue
- 8
- Pages
- 1415-1423
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC6698250
- OpenAlex
- W2945697388
- Cited by
- 218
- References
- 61
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 43 · 2023: 43 · 2022: 39 · 2021: 17 · 2020: 11 · 2019: 1
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Juvenile Diabetes Research Foundation International (3-PDF-2017-383-A-N)
- Center for Outcomes Research and Evaluation, Yale School of Medicine (P30-CA14051)
- Defense Advanced Research Projects Agency (W32P4Q-13-1-001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- mRNA delivery, in vitro transcribed mRNA, trastuzumab, anti-HER2 antibody, HER2-positive breast cancer, lipid nanoparticles, pharmacokinetics, anticancer activity
- MeSH terms
- Trastuzumab, Animals, Antibodies, Monoclonal, Breast Neoplasms, Disease Models, Animal, Humans, Lipids, RNA, Messenger, Genetic Therapy, Gene Expression, Drug Delivery Systems, Gene Transfer Techniques, Erb-b2 Receptor Tyrosine Kinases, Xenograft Model Antitumor Assays, Mice, Nanoparticles, Molecular Targeted Therapy
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