mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo

Rybakova, Yulia; Kowalski, Piotr S.; Huang, Yuxuan; Gonzalez, John; Heartlein, Michael W.; DeRosa, Frank; Delcassian, Derfogail; Anderson, Daniel G.

doi:10.1016/j.ymthe.2019.05.012

Cited by 132 publications

(99 citation statements)

References 56 publications

(69 reference statements)

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“…Thus, we expected the liver will serve as a factory for protein production upon hsACE2 mRNA transfection as shown in other studies for secretory proteins 27,28 . To demonstrate this in vitro, the human liver cell line, Hep G2, was transfected with LNPs.…”

Section: Mainmentioning

confidence: 84%

Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2

Kim

Mukherjee

Nelson

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters through the airways and infects the lungs, causing lethal pulmonary damage in vulnerable patients. This virus contains spike proteins on its envelope that binds to human angiotensin-converting enzyme 2 (hACE2) expressed on the surface of airway cells, enabling entry of the virus for causing infection1,2. In severe cases, the virus enters the circulatory system, contributing to multiorgan failure. Soluble form of hACE2 binds to SARS-CoV-2 spike protein and prevents viral entry into target cells3. Moreover, soluble recombinant ACE2 ameliorates lung injury4 but its short half-life limits its therapeutic utility5. Here, we engineered synthetic mRNA to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. Novel lipid nanoparticles (LNPs) were used to package mRNA and transfect mammalian cells for enhanced production of secreted proteins. Intravenously administered LNP led to hepatic delivery of the mRNA. This elicited secretion of hsACE2 into the blood circulation within 2 h, and levels of circulating hsACE2 peaked at 6 h and gradually decreased over several days. Since the primary site of entry and pathogenesis for SARS-CoV-2 is the lungs, we instilled LNPs into the lungs and were able to detect hsACE2 in the bronchoalveolar lavage fluid within 24 h and lasted for 48 h. Through co-immunoprecipitation, we found that mRNA-generated hsACE2 was able to bind with the receptor binding domain of the SARS-CoV-2 spike protein. Furthermore, hsACE2 was able to strongly inhibit (over 90%) SARS-CoV-2 pseudovirus infection. Our proof of principle study shows that mRNA-based nanotherapeutics can be potentially deployed for pulmonary and extrapulmonary neutralization of SARS-CoV-2 and open new treatment opportunities for COVID-19.

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Section: Mainmentioning

confidence: 84%

Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2

Kim

Mukherjee

Nelson

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Sanofi Pasteur and Translate Bio (Lexington, MA, USA) are collaborating to develop a novel mRNA vaccine based on Translate Bio's proprietary mRNA therapeutic platform (MRT TM ). This platform includes the design of the desired mRNA sequences and then packaging them into delivery systems ( 171 ), and it has been shown to induce therapeutic antibodies against human epidermal growth factor receptor 2-positive tumors in humanized mice ( 172 ). Centro Nacional de Biotecnología (Madrid, Spain) is developing an mRNA COVID-19 vaccine candidate based on the highly attenuated poxvirus vector MVA expressing the S protein, which has previously been tested as a vector for vaccine candidates against Zika and Ebola viruses ( 173 , 174 ).…”

Section: Vaccine Platform Technologiesmentioning

confidence: 99%

The Long Road Toward COVID-19 Herd Immunity: Vaccine Platform Technologies and Mass Immunization Strategies

et al. 2020

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There is an urgent need for effective countermeasures against the current emergence and accelerating expansion of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Induction of herd immunity by mass vaccination has been a very successful strategy for preventing the spread of many infectious diseases, hence protecting the most vulnerable population groups unable to develop immunity, for example individuals with immunodeficiencies or a weakened immune system due to underlying medical or debilitating conditions. Therefore, vaccination represents one of the most promising counter-pandemic measures to COVID-19. However, to date, no licensed vaccine exists, neither for SARS-CoV-2 nor for the closely related SARS-CoV or Middle East respiratory syndrome-CoV. In addition, a few vaccine candidates have only recently entered human clinical trials, which hampers the progress in tackling COVID-19 infection. Here, we discuss potential prophylactic interventions for SARS-CoV-2 with a focus on the challenges existing for vaccine development, and we review pre-clinical progress and ongoing human clinical trials of COVID-19 vaccine candidates. Although COVID-19 vaccine development is currently accelerated via so-called fast-track programs, vaccines may not be timely available to have an impact on the first wave of the ongoing COVID-19 pandemic. Nevertheless, COVID-19 vaccines will be essential in the future for reducing morbidity and mortality and inducing herd immunity, if SARS-CoV-2 becomes established in the population like for example influenza virus.

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“…Ultimately, nano drug delivery of paclitaxel targets markers prevalent in carcinomas and an inflamed TME, such as TAMs (67). In 2019, Rybakova et al (68) used an in vitro -transcribed mRNA (IVT-mRNA) system for the in vivo delivery of a humanized anti-HER2 (also known as ERBB2) antibody, trastuzumab, and packaged IVT-mRNA into LNPs. This approach not only ensures anticancer activity and efficient in vivo delivery but also delays degradation of the mRNA (68).…”

Section: Introductionmentioning

confidence: 99%

Nanoparticles Targeting Macrophages as Potential Clinical Therapeutic Agents Against Cancer and Inflammation

Guo

et al. 2019

Front. Immunol.

161

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With the development of nanotechnology, significant progress has been made in the design, and manufacture of nanoparticles (NPs) for use in clinical treatments. Recent increases in our understanding of the central role of macrophages in the context of inflammation and cancer have reinvigorated interest in macrophages as drug targets. Macrophages play an integral role in maintaining the steady state of the immune system and are involved in cancer and inflammation processes. Thus, NPs tailored to accurately target macrophages have the potential to transform disease treatment. Herein, we first present a brief background information of NPs as drug carriers, including but not limited to the types of nanomaterials, their biological properties and their advantages in clinical application. Then, macrophage effector mechanisms and recent NPs-based strategies aimed at targeting macrophages by eliminating or re-educating macrophages in inflammation and cancer are summarized. Additionally, the development of nanocarriers targeting macrophages for disease diagnosis is also discussed. Finally, the significance of macrophage-targeting nanomedicine is highlighted, with the goal of facilitating future clinical translation.

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mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo

Cited by 132 publications

References 56 publications

Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2

Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2

The Long Road Toward COVID-19 Herd Immunity: Vaccine Platform Technologies and Mass Immunization Strategies

Nanoparticles Targeting Macrophages as Potential Clinical Therapeutic Agents Against Cancer and Inflammation

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