Lipids: Protecting mRNA so it can protect our body

In December 2020, less than a year after the full viral genome sequence of the novel coronavirus SARS-CoV-2 was published, the first Covid-19 vaccines received authorization in multiple countries, paving the way for mass vaccination programs around the world.[1,2]

Traditional vaccines work by giving people either viral proteins or an inactivated or weakened form of a virus, triggering the body to make an immune response. But the crucial ingredient in two of the first Covid-19 vaccines – BNT162b2 ("Comirnaty" from BioNTech/Pfizer) and mRNA-1273 ("Spikevax" from Moderna) – was instead messenger ribonucleic acid (mRNA), the short-lived intermediate genetic molecule between DNA and proteins. Both of these vaccines employ synthetic mRNA molecules containing the instructions to make a specific viral protein - the spike protein that helps SARS-CoV-2 to enter our cells.[3]

“With mRNA vaccines, the viral protein is produced inside cells in the body,” explains Guido Krupp, Senior Research Fellow and founder of AmpTec GmbH, a leading mRNA CDMO that was acquired by our company in January 2021. “This then acts as an antigen, the foreign molecule that stimulates an immune response.”

mRNA was first discovered in 1961.[4] Over the following decades, researchers have been exploring the potential of mRNA vaccines for the prevention or treatment of various diseases. But while the concept itself is straightforward, the safe and effective delivery of these fragile nucleic acids into cells where their message can be translated into proteins has proved a huge challenge.

“These molecules are inherently unstable, and they are rapidly broken down by enzymes in the body,” says Gang Yao, who heads up our R&D team for lipid nanoparticles. “It’s also hard to transfer them across the protective outer layer of cells.”

For the new Covid-19 mRNA vaccines, the solution to this problem came through the development of lipid nanoparticles (LNPs). These particles, typically composed of four different lipids (ionizable lipids whose positive charges bind to the negatively charged backbone of mRNA, pegylated lipids that help stabilize the particle, and phospholipids and cholesterol molecules that contribute to the particle’s structure), provide a protective wrapper for the delicate mRNA molecules, enabling its safe and efficient delivery into cells.

“Each of these lipids plays an important role,” explains Yao. “They work together to encapsulate the mRNA, protect it from degradation and get it into cells.”

The potential of LNPs as a sophisticated drug delivery system was first highlighted by their successful application in another cutting-edge form of RNA-based therapy that uses short interfering RNAs (siRNAs).

In 2006, Andrew Fire and Craig Mello were awarded the Nobel Prize in Physiology or Medicine for their discovery of a mechanism that can break down mRNA from a specific gene.[5] The mechanism, called RNA interference, opened up exciting new possibilities for the therapeutic use of RNA molecules designed to switch off – or silence – the activity of specific genes in cells.

In 2018, the world’s first siRNA-based drug was approved by the US Food and Drug Administration (FDA) – a new treatment for a rare, life-threatening disease called hereditary transthyretin-mediated amyloidosis.[6] This medicine contains a very short piece of RNA that was designed to silence the disease-causing gene in the patient’s liver. The efficient delivery of the siRNA into these cells is critically dependent on LNP technology.[7]

Two years later, the approval of two Covid-19 mRNA vaccines within mere days marked the next major milestone in the LNP field.

After the extraordinary speed at which Covid-19 vaccines were developed and approved created, another huge challenge emerged: the manufacture and distribution of enough life-saving doses at the quality, speed, and scale required to combat the pandemic.

Very few companies in the world could manufacture the lipids in sufficient quantities and especially at the required standards of quality for Covid-19 mRNA vaccine formulations. As a global leader in lipids, we have more than two decades of experience in providing custom lipids and other critical components such as synthetic cholesterol for lipid nanoparticles, following appropriate Good Manufacturing Practices (GMP) for these types of products to ensure the highest safety standards.

“We worked hard to expand our already very high lipid production capacity to help meet the unprecedented demand,” says Tobias Haag, Head of our Process and Analytical Development team.

In February 2021, we extended our strategic partnership with BioNTech to significantly accelerate the supply of urgently needed lipids to support the production of the Pfizer-BioNTech Covid-19 mRNA vaccine Comirnaty. Three months later, we launched a new, high-purity synthetic cholesterol product, nine months ahead of schedule.

“We developed a safe, reliable manufacturing process and created the regulatory documents for filing with the global authorities, all in record time,” reflects Haag. “It was a very intense time for everyone, but the purpose and intent of helping to fight the pandemic provided us with a source of energy to give it our best efforts.”

This new SAFC^® synthetic cholesterol product increased our manufacturing capacity by 50 times, helping to support global efforts to manufacture life-saving Covid-19 mRNA vaccines that have now reached billions of people worldwide. In 2022, it is projected that about 40% of all manufactured Covid-19 vaccine doses will be based on mRNA.[8]

Recent advances in mRNA technology, accelerated by the Covid-19 pandemic, herald a new era of genetic medicine.

Flexible mRNA-based vaccine platforms can cut development time dramatically compared to conventional approaches using proteins or inactivated pathogens — enabling much more rapid responses to future emerging infectious diseases. A variety of other mRNA vaccines are currently in development to combat existing pathogens that threaten lives today — including the human immunodeficiency virus (HIV), the flu virus, and the parasite that causes malaria.[9]

But the potential applications extend far beyond preventative vaccines. RNA-based therapeutics – including mRNA – offer the promise of new treatments for a variety of infectious diseases, genetic conditions, cancer, and other illnesses.

“Since mRNA has the ability to code for any protein that you want, you could use it to replace faulty or deficient proteins, or to prime a patient’s immune system to fight infections or kill cancer cells,” says Krupp.

The enthusiasm around mRNA therapeutics is evident from the number of companies backing the technology. There are currently more than 420 active mRNA programs in (pre-)clinical development testing mRNA for over 120 different diseases — including more than 110 programs for a variety of cancers as well as approximately 100 programs for rare and other diseases.[10]

The Covid-19 pandemic has helped to accelerate incredible scientific advances, leading to the approval of the first-ever mRNA vaccines.

But this is only the beginning of the story. Next-generation RNA-based therapeutics, delivered into cells in LNP formulations, are now poised to transform the future of medicine – offering the promise of new treatments for many different diseases

With more than 20 years of experience providing critical components for mRNA therapies, we have recently further expanded our mRNA manufacturing capabilities. In February 2022, we acquired Exelead, a full service CDMO covering all phases from pre-clinical development to commercial manufacturing for LNP formulations, including fill/finish. By combining Exelead’s capabilities with AmpTec’s expertise in the development and manufacture of custom mRNAs and our extensive experience and strengthened capabilities in lipids manufacturing, we can now provide a fully comprehensive portfolio of products and services essential for RNA-based therapeutics development.

“We want to be part of this growth story from the very beginning,” says Timon Lentz, Global Marketing Lead for our drug delivery portfolio. “I find it super exciting to be involved in something where the future is still being shaped.”

_{[1] https://www.nature.com/articles/s41586-020-2008-3
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844189/
[3] https://www.nature.com/articles/s41541-021-00369-6
[4] https://www.sciencedirect.com/science/article/pii/S0960982215006065
[5] https://www.nobelprize.org/prizes/medicine/2006/summary/
[6] https://pubmed.ncbi.nlm.nih.gov/30251172/
[7] https://pubmed.ncbi.nlm.nih.gov/31397996/
[8] https://launchandscalefaster.org/Covid-19/vaccinemanufacturing
[9] https://www.cbinsights.com/research/what-are-mrna-therapies/
[10] PharmaCircle analysis - June 2022}