mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo.
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.
['Rybakova|Yulia|Y|', 'Kowalski|Piotr S|PS|', 'Huang|Yuxuan|Y|', 'Gonzalez|John T|JT|', 'Heartlein|Michael W|MW|', 'DeRosa|Frank|F|', 'Delcassian|Derfogail|D|', 'Anderson|Daniel G|DG|']
D000818:Animals D000911:Antibodies, Monoclonal D001943:Breast Neoplasms D004195:Disease Models, Animal D016503:Drug Delivery Systems D015870:Gene Expression D018014:Gene Transfer Techniques D015316:Genetic Therapy D006801:Humans D008055:Lipids D051379:Mice D058990:Molecular Targeted Therapy D053758:Nanoparticles D012333:RNA, Messenger D018719:Receptor, ErbB-2 D000068878:Trastuzumab D023041:Xenograft Model Antitumor Assays
mRNA delivery antibody-based drugs trastuzumab Herceptin breast cancer lipid nanoparticles mRNA design mRNA therapeutics