RNA molecule illustration (Nicolle Rager Fuller, National Science Foundation)
3 March 2017. Academic and industry researchers demonstrated production of therapeutic antibodies inside cells of lab mice, offering a simpler and lower-cost alternative to monoclonal antibodies. The team led by University of Pennsylvania immunologist Drew Weissman describes its technology in the 2 March issue of the journal Nature Communications.
Monoclonal antibodies, synthetic proteins designed to treat disease by neutralizing proteins responsible for the condition, are a fast-growing segment of the pharmaceutical industry for treating diseases including cancer and autoimmune disorders. These synthetic antibodies, however, are costly to develop and often expensive for patients. An emerging option to synthetic antibodies is gene therapy that uses adeno-associated viruses to deliver antibody-producing genes to counter disease-causing proteins. While adeno-associated viruses are considered benign, they still present safety risks for some patients, including unwanted immune responses.
In their paper, Weissman and colleagues demonstrated another alternative, engineered messenger ribonucleic acid or mRNA, a nucleic acid related to DNA with the instructions used by cells to produce the amino acids in proteins for carrying out functions in the body. The researchers — with team members from UPenn’s medical school and biotechnology companies BioNTech AG in Mainz, Gemany and Acuitas Therapeutics in Vancouver, British Columbia — evaluated harnessing mRNA to deliver the instructions for producing therapeutic antibodies inside cells, rather than delivering antibodies created outside the body.
In its natural state, however, mRNA would present the same problems some patients encounter with adeno-associated viruses, namely immune reactions such as inflammation. To overcome this obstacle, the researchers encased mRNA in nanoscale lipid capsules, a technique devised by post-doctoral researcher Norbert Pardi and doctoral candidate Michael Hogan, co-authors of this paper and tested earlier with an mRNA vaccine candidate for the Zika virus. Acuitas Therapeutics is commercializing this technology and prepared the lipid nanoparticles for this project.
In the study, the team demonstrated delivery of mRNA to produce an antibody protecting against the HIV virus that causes AIDS. The antibody, known as VRC01, addresses a common target found across multiple strains of HIV, and is being tested both as a treatment and protective vaccine for HIV. Cost to patients is a key issue with HIV medications, and a synthetic VRC01 antibody would likely be too expensive for many patients and public health agencies.
The researchers tested mRNA encoding VRC01 antibodies in lab mice induced with compromised immune systems and thus highly susceptible to HIV infections. Within 24 hours following a single injection of the lipid nanoparticles with mRNA, the mice showed higher concentrations VRC01 antibodies in their blood. And with weekly injections, the mice could maintain a basic threshold level of VRC01.
The team also tested the ability of the mRNA in lipid nanoparticles encoding VRC01 to protect against HIV viruses. The researchers found small vaccine-style quantities of these nanoparticles could protect against two different HIV strains. For comparison, doses 40 times larger were needed to provide the same protection against HIV infections, when directly injecting VRC01 antibodies.
Weissman believes encoding mRNA to produce antibodies in cells may be safer for patients than some biotechnology manufacturing practices. “Biotech manufacturing,” says Weissman in a university statement, “requires a cell line and extensive purification that can aggregate or misfold the protein, resulting in an unwanted immune response against the protein or other adverse events.”
Nonetheless, biotech companies are exploring this technology. Katalin Kariko, an adjunct professor at UPenn and co-author of the paper, is vice-president of BioNTech, a company developing therapies from synthetic forms of mRNA. As reported in Science & Enterprise, the Genentech division of the Roche Group, is licensing BioNTech’s mRNA technology for cancer treatments.
More from Science & Enterprise:
- RNA Drug Delivery Technique Shown Safe in Monkeys
- Funds Provided for Developing RNA-Based Zika Vaccine
- RNA Technology Licensed for Cystic Fibrosis Therapy
- RNA Technology Allows for Fast Vaccine Development
- Patent Granted for RNA Transcription Technology
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