Advancing the Frontiers of Our Platform Science

May 7, 2019
 

Stephen Hoge, M.D. and Melissa Moore, Ph.D.


Today, we hosted our second annual Science Day symposium. This day is our chance to provide insights into the diverse efforts we have underway to advance our platform science and our research into how to use mRNA as a medicine. In the last four years, the platform has produced over 20 investigational mRNA medicines, 11 of which have already advanced into human clinical trials. It’s our hope that these programs represent just the first wave of a new class of medicines.

While proud of our accomplishments to date, our mission is to do more for patients. We believe we are still in an early and expansionary phase of mRNA medicines. Since our founding, our investments in basic science have resulted in major steps forward in our platform’s capabilities that have allowed us to open new therapeutic areas and new scientific directions. Our basic science research (for instance, into the molecular biology of mRNA translation) often puts us at the leading edge of scientific knowledge or requires us to build beyond state-of-the-art tools.

We and our many academic collaborators publish extensively on these scientific efforts in peer-reviewed literature in a wide range of disciplines. In the past three years, that includes more than 25 peer-reviewed papers, with 11 published in the last year alone. Our team will continue to share their learnings as we generate new findings and increase our understanding of the potential for mRNA therapeutics.

While we actively engage with the scientific community, given the long timelines and significant uncertainty inherent in basic science, we haven’t regularly talked about our research to general or investor audiences. We created Science Day as an opportunity to update the broader community on what we do, how we do it and the rationale behind it.

With more than 200 talented and relentless Moderna scientists working every day on this part of our mission, it’s impossible to be exhaustive at Science Day. So, like last year’s event, we selected a few vignettes to dig into from within our Delivery Science and mRNA Science efforts.

DELIVERY SCIENCE

Over the past seven years we’ve invested more than $500 million into platform research, with as much or more of those resources going to delivery science as mRNA science. In fact, we often feel like we are more of a delivery company than an mRNA company. Four years ago, we advanced our first mRNA in a lipid nanoparticle (LNP) into human testing in our flu vaccine programs. Since then, we’ve made key advances in tolerability and potency, some of which we highlighted at our 2018 Science Day event. To date, our investments in delivery science have culminated in three next-generation proprietary LNP systems – all chemically and structurally distinct – that we’ve already advanced into first-in-human studies. These include a second-generation vaccine LNP that is rapidly moving into Phase 2 with our personalized cancer vaccine program (mRNA-4157), a first-generation intra-tumoral immunotherapy LNP that is moving into a Phase 2 cohort in ovarian cancer (mRNA-2416) and our first-generation systemic therapeutic LNP that is currently in Phase 1 testing with the chikungunya antibody program (mRNA-1944).

We’ve published the preclinical science behind some of these improvements and have had the privilege of sharing our interim clinical data from three of these delivery systems at various scientific conferences in the past year, including a first-in-human mRNA-LNP in cancer and a first-in-human intravenous systemic mRNA-LNP. But we are just beginning.

At today’s event, we tried to highlight two ways in which we’re continuing to benefit from our basic science investments: first, inventing delivery technologies able to access new tissues (the immune system) and second, continuing to probe the fundamental science behind our current delivery systems so that we can drive the next generation of improvement in their performance.

Expanding the delivery of mRNA into the immune system

The immune system is a powerful and complex network of cells, tissues and organs that protects our body from invaders like viruses and bacteria. When it doesn’t function properly, it can cause infections, autoimmune disorders, neurological diseases or even cancer.

Today, we described our program of advancing new delivery technologies toward creating a generation of mRNA-based immune system therapeutics. This includes exciting translational work demonstrating that our novel immune nanoparticles are able to deliver mRNA to a significant proportion of T cells, Natural Killer cells, B cells and myeloid cells. We demonstrated that we can express functional proteins in vivo across multiple preclinical species, and ex vivo in human blood. We are tremendously excited by this progress, as the fraction of immune cells that we could reprogram or redirect –10-20 percent for most types and sub-types – appears to be substantial. For reference, having less than one percent of T cell clones responsive to cancer or an infectious pathogen are generally enough to control those diseases.

Dose-dependent in vivo pharmacology in a wide range of cell types is only part of the story. We also summarized our work to use the software-like features of mRNA – specifically microRNA targeting – to drive cell-type specificity in our immune therapeutics research. We showed how new proteins could be used to confer new functional phenotypes on cells, including chimeric antigen receptors on effector cells and demonstration of in vivo gene editing using the Cre-recombinase reporter system. Finally, Uli von Andrian M.D., Ph.D., one of our collaborators from Harvard Medical School and a member of the Moderna Scientific Advisory Board, summarized the importance of cell trafficking in immune responses and highlighted the potential of this new platform to impact disease states by modifying immune cell trafficking.

While these technologies remain early – and not yet ready for development in people – we see immense potential given the central role of the immune system in cancer (an immune-escape disease), neurodegenerative and autoimmune diseases. We know new treatments are urgently needed for patients in all of these areas, and our team is committed to doing the work to learn if mRNA may play a role in the future.

Quantum modelling: Big insights from modelling of small (nanoscale) things

Over the last several years we’ve tried to push the state-of-the-art of biology and chemistry of LNPs to develop improvements in potency and tolerability. But there’s only so far that today’s technologies can go. We regularly run assays that require an X-ray gun (SAXS), a nuclear reactor (SANS) and an electron microscope. But in seeking insight into the most fundamental characteristics of LNPs – those that are present in the earliest stages of their formation – none of those suffice. We’ve needed to move into the realm of theoretical physics, specifically quantum chemistry.

By “earliest stages” of LNPs, we mean less than 0.000001 seconds after a nanoparticle starts to form. It is effectively impossible to conduct experiments at this time scale. The earliest time points we can regularly observe experimentally are ~10 seconds after LNP formation. But our data suggest that critical features of LNP performance are determined on nanosecond time scales. While quantum chemistry traditionally has been useful to explore such states, even today’s cloud computing capabilities can’t handle the calculations necessary to model an all-atom version of something at the scale of an LNP. Such a simulation could take years of computer time.

At Science Day we shared some of our efforts to advance a new form of modelling – called Coarse Grained Molecular Dynamics – for the study of LNPs. These molecular simulations have provided unique insights into the earliest stages of LNP self-assembly that we are increasingly able to match with our empirical observations. These insights have already begun to change our thinking about the process for manufacturing LNPs.

mRNA SCIENCE

Much of our investment in mRNA science is directed toward increasing the therapeutic potency or expanding the safety margins of our mRNA-based medicines. Though we’ve had recent successful Phase 1 clinical readouts, our team continues to push forward with new approaches. Today, we described a few opportunities where we’re already driving two-fold or greater improvements in the potency of our mRNA medicines.

The latest science behind evading the innate immune system

One important feature of our mRNAs is the modification of all uridine bases to evade the immune sensors that have evolved in cells to sense exogenous viral RNA. At Science Day, we shared the latest in vivo characterization of the nature of that innate immune response and our ability to greatly reduce it as a potential safety risk in our medicines. This includes demonstrating the independent roles of mRNA process and uridine chemistry in evading specialized proteins including Toll-like Receptors (TLRs) and RIG-I like receptors. These improvements have proven essential for enabling our mRNA medicines to slip past the immune system.

Big gains from untranslated regions

Optimizing the amount of protein produced from each mRNA molecule is largely a function of how well the ribosome initiates and translates the sequence along with how long the mRNA persists. Nearly all eukaryotic mRNAs share a common anatomy that includes what are called the 5’ cap, 5’ untranslated region (5’ UTR), the coding sequence, 3’ untranslated region (3’ UTR) and poly (A) tail. The coding sequence contains the information that is translated into the protein. But the non-coding parts of the mRNA molecule can be just as important to driving expression.

For example, the scientific community knows that the sequence of the 5’ UTR strongly influences translation initiation and hence overall translational efficiency, but the exact mechanisms behind this have not been entirely explored. Currently the field has no way to accurately predict protein expression from a eukaryotic 5’ UTR sequence. Today, we showed the first results of our efforts to use neural networks (a type of machine learning) to analyze massive experimental data generated from libraries of hundreds of thousands of variant sequence mRNA to create a model capable of predicting protein expression based on 5’ UTR sequences. These data are already helping us design 5’ UTR sequences that optimize protein expression for our medicines, often driving several-fold improvements in the amount of protein without changing the coding sequence. Finally, we shared how these findings are offering new insights into the biology of translational regulation.

mRNA structure and ribosome traffic jams

We also discussed the role of mRNA structure in improving the efficiency of translation. mRNA is often depicted in textbook diagrams as a single strand that is spooled through and read by the ribosome, much like how film is passed through a projector. It is conventionally believed that, like film, folds, knots or other structural elements in the mRNA would hinder the movement of the ribosome and make translation less efficient. We’re convinced that is not the whole story.

Our research shows that the folded structure of mRNA, known as secondary structure, is very important for translation efficiency. Far from decreasing translational efficiency, we believe that strong secondary structure tends to increase total protein output. Why might this be? When ribosomes are unhindered by secondary structure, they may be able to move more quickly, but as a result will tend to collide with one another, creating ribosome traffic jams. This not only slows the ribosomes involved in the jam but is a known trigger of mRNA decay. Secondary structure may work as a “buffer” to space out fast-translating ribosomes, allowing for the maximum efficiency of ribosome traffic along the mRNA molecule.

Our responsibility to contribute to the state-of-the-art in basic science

The work we shared today represents only a small piece of our team’s intense focus and thirst for deeper, broader knowledge. We do this work – both within Moderna and with many external collaborators – because we believe it may one day translate into life-changing therapeutics and vaccines for people with serious diseases. We are privileged to be a part of a broad ecosystem of researchers from academia and industry who are expanding the understanding of mRNA. We are always excited to find both new partners and colleagues with new and different expertise who may bring novel ideas to help accelerate our learning.

We look forward to sharing our learnings now and in the future as we continue investing in the basic science that allows us to embrace the unknown and gets us closer to our goal of helping patients.

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Forward-Looking Statements

This blog contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. In some cases, forward-looking statements can be identified by terminology such as “will,” “may,” “should,” “expects,” “intends,” “plans,” “aims,” “anticipates,” “beliefs,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this blog are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties and other factors, many of which are beyond Moderna’s control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties and other factors include those described in Moderna’s most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) and in subsequent filings made by Moderna with the SEC, which are available on the SEC's website at www.sec.gov. Except as required by law, Moderna disclaims any intention or responsibility for updating or revising any forward-looking statements in this blog in the event of new information, future developments or otherwise. These forward-looking statements are based on Moderna’s current expectations and speak only as of the date hereof.