by Natalie Losada
Everyone is anxiously awaiting the arrival of a vaccine for COVID-19 that will hopefully allow for daily life to resume. Scientists around the world are working hard to develop drugs and vaccines, analyze clinical trial outcomes, and balance effectiveness with cost of distribution of the vaccines. We all just want the punchline, the end of the book, or the answer to the riddle, but it takes time, effort, money, and many intelligent people to develop these technologies. Fortunately, companies like Regeneron are using those required resources to make the necessary medical advancements.
If you are studying in a STEM field and you attend Rutgers University, then there is a good chance you have heard of the company, Regeneron. For those who haven’t, Regeneron is a biotechnology company that focuses its efforts on research and development of novel medicines with their registered trademark technology from the VelociSuite® (includes VelociGene®, VelociMouse®, VelocImmune®, and VelociMAb®). The company was started in 1988 by co-founders Leonard S. Schleifer MD, PhD and George D. Yancopoulos MD, PhD. I encourage everyone to take a look at the full history of Regeneron, which has voice recordings from the founders of the company answering interesting questions – including the origin story of their company name.
Since 2016, Regeneron has held their annual Science to Medicine Forums and this year they successfully moved the entire event online for the first time. The goal of this all-day event is to provide scientists from around the country with an opportunity to share their latest exciting research, much like other conferences or symposiums. Regeneron uses the term “Forum” to describe their event because the research presentations are divided into four small symposiums: “Development, Molecular Genetics, and Health”, “Immunology and Infectious Diseases”, “Oncology and Immuno-Oncology”, and “Neuroscience”. Regeneron also included a keynote lecture from their Vice President of Research, Dr. Christos Kyratsous, and uniquely included an information session to discuss the history of Regeneron, recent developments, and their postdoctoral program. This article will take you through their outstanding antibody developments, the research efforts from academic scientists related to SARS-COV-2, and the opportunities at Regeneron, including Regeneron’s postdoctoral program.
Dr. Christos Kyratsous, the Vice President of Research at Regeneron, was the keynote speaker for this event and his talk was titled, “The Rapid Selection, Characterization, and Clinical Development of Fully-human Antibodies Against Emerging Infectious Diseases”. The background section of the talk was particularly interesting as Dr. Kyratsous explained the exclusive methods and techniques that Regeneron utilizes. Their innovative mouse strain called VelociMouse® is comprised of a significant number of genes replaced with the human equivalent sequence. The principally human sequence allows the mouse to produce antibodies that are almost identical to human antibodies, though they are polyclonal. The various antibodies are assayed against a virus and Regeneron’s registered trademark technique, VelocImmune®, allows them to rapidly isolate the antibody that performs the best in both binding and neutralizing assays. Another registered trademark technique, VelociMAb®, is utilized to sort B cells with flow cytometry for mass production of the desired antibody. Regeneron has used these Veloci technologies to quickly produce disease-fighting antibodies against MERS-COV, Ebola Virus (EBOV), and now against SARS-COV-2.
Dr. Kyratsous also described the company’s method of attack for EBOV and how that knowledge has been extended to SARS-COV-2. They used a cocktail of three antibodies, called REGN EB3, but this cocktail was not simply composed of the best binders and best neutralizers (i.e. antibodies that effectively block entry into susceptible cells). Dr. Kyratsous explained that a synergistic cocktail would require three effective antibodies that did not bind to similar locations on the virus spikes or else they would work competitively instead of cooperatively. In general, scientists prefer to treat with multiple antibodies at once so the virus does not acquire a sufficient number of random mutations that would lead to resistance. Regeneron has successfully found three antibodies that fit these requirements and is currently waiting on approval. Dr. Kyratsous noted that this cocktail treatment will be the first ever developed for EBOV.
To develop the SARS-COV-2 antibody, Dr. Kyratsous explained that due to the number of mutations that have already occurred in the virus, the scientists had to first check if their antibodies could neutralize not only one viral strain, but neutralize all of the variants of the virus. Through cell passaging experiments, they found two particular antibodies that neutralized the virus and promisingly, bound to separate locations. The cocktail of these two antibodies prevented resistant mutations for many more passages than using any single antibody. An audience member asked why they developed three antibodies for the EBOV and only two for the SARS-COV-2 cocktails and Dr. Kyratsous explained that the target for SARS-COV-2 was much smaller and could not fit three antibodies without some overlap in binding site.
Dr. Kyratsous combined the answers of a few questions by also explaining that in addition to all the previously stated requirements for antibody cocktails, they needed to balance three factors: which antibodies are produced by the mice in large enough quantities, which have the least negative impact on the human immune system, and which are the most potent.
Simply because an antibody shines in one experiment, does not mean that it is feasible to mass produce and administer to millions of humans. This is where the development of vaccines has to slow down and be precise. Rest assured, however, that scientists are able to work at an accelerated pace with the knowledge of previous viruses and the help of advanced biotechnology, like Regeneron’s Veloci technologies, providing hope for the production of a vaccine against the novel SARS-COV-2 virus.
The Four Small Symposiums Covered:
Development, Molecular Genetics, and Health Symposium moderated by Akshay Shekhar
In this symposium, Bahar Javdan from Princeton, discussed “Personalized mapping of drug metabolism by the human gut microbiome”. He studies novel gut microbiome interactions and performs pharmacokinetic experiments to compare how drugs perform differentially in different patients/gut microbiome environments. After, Siyu Sun from NYU presented her talk about “Integrating genetics and proteomics to understand cellular quiescence” and had some interesting results for starvation effects on both metabolism and gene expression. Finally, Burcu Vitrinel also from NYU discussed “Discovering post-transcriptional regulators of heart development” using mouse experiments and mass spec to find what regulates differentiation specification of cells.
Immunology & Infectious Diseases Symposium moderated by Dylan Kwart, Postdoctoral Fellow
Audrey Baeyens from NYU Langone presented a talk on “Inflammatory monocyte-derived S1P in the lymph node regulates immune responses” and a molecule with a previously unknown purpose that holds an unexpected role in the immune response signaling pathway. Daniel Blanco-Melo from Mount Sinai discussed “Imbalanced host response to SARS-CoV-2 drives development of COVID-19” and that SARS-COV-2 antiviral response seems to be dependent on the initial number of viral particles. Finally, Rahul Sharma from Memorial Sloan Kettering Cancer Center discussed “Metabolic checkpoint regulates B cell mediated humoral immune responses”.
Oncology & Immuno-Oncology Symposium moderated by Disi An, Postdoctoral Fellow
Alan Chramiec from Columbia discussed “Human organ-on-a-chip models for predictive drug screening to determine anti-tumor efficacy and cardiac safety”. He noted that much of their experimental results reflected the same results from the clinical trials. Cansu Cimen Bozkus from Mount Sinai gave a talk about “Characterization of shared immunogenic poly-epitope frameshift mutations in microsatellite unstable tumors to guide the design of off-the-shelf immunotherapies” and finally, Andrej Gorbatenko also from Mount Sinai presented a talk about the “Role of ss18 in detachment mediated cell death and breast cancer”.
Neuroscience Symposium moderated by Ram Sundaramoorthy, Postdoctoral Fellow
Osasumwen Virginia Aimiuwu from Columbia Med Center presented “RNAi-based gene therapy rescues developmental and epileptic encephalopathy in a genetic mouse model” and the results of unbalanced excitation and inhibition. Anna Giarratana from iJOBS Executive Director Janet Alder’s lab at Rutgers, discussed “The Role of Genetic Polymorphisms in a Mouse Model of Traumatic Brain Injury and Personalized Treatment Approaches”. Dylan E. Iannitelli from NYU discussed “Intercellular, interspecies integrative modeling of ALS” and finally, Sanjid Shahriar from Columbia Med Center discussed “Single-cell RNA-sequencing implicates venous endothelial cells as a source of neoangiogenesis in acute and chronic EAE”.
Information Session and postdoctoral program:
Caroline Hrehovcik, part of University Relations at Regeneron, started off the information session with many interesting facts about the company to establish who they are and what they strive to be. Two MD PhDs started Regeneron with a small group of scientists, including three Nobel Prize laureates, with a goal to pursue research in neuroscience. Now their company has locations in the US and Europe and seven FDA-approved medicines. There are more scientists than business employees in the company and these scientists are continually encouraged to pursue new projects. Innovation is a big focus for Regeneron so it is their priority to allow the scientists creative flexibility. Caroline Hrehovcik also discussed Regeneron’s Genetic Center (RGC) that focuses on comparing exon sequences from the genomes of clinical study participants. Their goal is to learn about the relationship between the clinical trial results and previously understudied exons. Caroline’s introduction set a great tone for Susan Croll’s presentation about their rewarding postdoctoral program.
Susan Croll is the Senior Director of Neuroscience and the Postdoctoral Program Director Emeritus. She provided an in depth look at the postdoctoral program and how to apply. The program provides postdoctoral fellows with training, discussion groups, various mentors, and career counseling. The fellow receives a peer mentor, a research mentor that functions as a supervisor, and a career mentor that is usually from a different department. A committee at Regeneron will decide which applicants to interview and the final decisions are made after phone and in-person interviews, in that order. Regeneron accepts about five new postdocs every year for their R&D department and about two every year for the RGC. Once accepted, the program lasts no longer than four years. The postdoc is able to choose their project with the given guidelines: the project cannot be part of a time-critical path in the pipeline, the project should be feasible (i.e. allow for publication before completion of the program), and the project should have “forward looking questions”.
Overall, the scientists at Regeneron want their postdocs to have the freedom to be creative. They understand that if their work is time sensitive, there is less room for creativity. They want their postdocs to ask forward thinking questions so they are encouraged to think in non-traditional ways to solve their problems.
As much as they want to foster creativity, Regeneron also wants their postdocs to be competitive in the job market after they finish their program, which is why there is a publication requirement. There are other requirements, opportunities, and planned activities for the postdoctoral program that come together for a rewarding experience, so I suggest finding more information on their website.
The application deadline is the beginning of December and the acceptance letters are sent out at the end of January. An audience member asked a very good question about where the postdoc fellows usually end up after the program. Susan Croll actually had exact numbers for the previous year because the group is small. 21 of the 27 stayed with Regeneron, two were hired by biotech companies, two entered big pharma, and two entered academia.
Regeneron does not feel like most other companies.
The Vice President of Research and Postdoctoral Program Director, David Glass, as well as Caroline Hrehovcik, Susan Croll, and Christos Kyratsous, all made it very clear that company efforts are focused on research. They are not balancing R&D with customer service because they do not provide services directly to consumer customers. In addition, they do not simply conduct experiments—they constantly strive to innovate new technologies and lead the world into the next generation of medicines. It is really quite fitting that their slogan is “Lead with Science”.
Junior Editor: Huri Mücahit
Senior Editor: Helena Mello