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Rybakova, Yulia and Kowalski, Piotr S and Huang, Yuxuan and Gonzalez, John T and Heartlein, Michael W and DeRosa, Frank and Delcassian, Derfogail and Anderson, Daniel G
2019
January
Molecular Therapy
MRNA Delivery For Therapeutic Anti-Her2 Antibody Expression In Vivo
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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. Utilization of in vitro-transcribed messenger RNA (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 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 (LNP) 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 458.6 g/ml for 14 days post LNP injection. Further studies demonstrated 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 volume of HER2-positive tumors and improved animal survival. Taken together, our study demonstrates that utilizing 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.
10.1016/j.ymthe.2019.05.012
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