Drew Murphy, PhD, Executive Vice President of Research at Regeneron: An antibody is a natural substance in your body that usually your body makes in order to fight off infections like viruses and bacteria.

Drew: An antibody medicine is a natural molecule that we make in the laboratory, which looks exactly like the antibodies in your body but which does something to prevent diseases beyond what antibodies normally do which is to block bacteria and viruses. The beautiful thing about antibodies is that they combine to almost anything. The only thing they're really limited to are things on the surface of your cells or are floating around in your blood in general, which means there's lots and lots and lots of potential things that you could use antibodies to bind to. The trick is finding the right things. There are actually many different kinds of antibodies. The kinds of antibodies that people usually use as medicines are a kind of antibody which has two different arms.

Drew: Pretend I'm an antibody with my two arms, and my specificity is I like to bind oranges. If I see apples, I won't grab them, but if I see oranges, I will grab them with my hands. Now, if I have enough antibodies, I can coat all the oranges, pretend an orange is a virus. I can coat all the viruses in your body and prevent those viruses from entering a new cell and hurting you. So the great thing about working on antibodies, it's like the kid in a candy store. As a kid in a candy store, you get excited for the next candy that you happen to see.

Drew: When I speak to patients that have benefited from drugs that I've helped to invent, it's unbelievably heartwarming. So you have this experience of, "Oh, I was having fun doing science, but I helped this person that was in need. And not only that, but I probably helped hundreds and thousands or millions of other people in need as well."

[Man] At Regeneron, we provide so much to people who are sick. Innovation, it's the name of the game. It drives everything we do. It's really cool because we go from the really big thought, the really big idea, all the way to seeing the impact on a person. We have a healthy dose of optimism and just enough naivete to think anything's possible. When you think about the ethos of this company, what you'll hear over and over again is science, science, science, science leads, science dictates. But I think what keeps us all grounded is the fact that these are people that wanna help people.

Once a promising target has been identified, its function and impact on a disease needs to be further investigated, this is known as target validation. A common approach for target validation is the use of genetically modified mice to learn more about the function of a promising target in the context of a living mammalian organism. For example, the mutation identified in humans through RGC data can be replicated in a mouse to get a deeper understanding of how the target is related to the disease.

However, traditional technologies for producing genetically modified mice were slow, labor intensive, and not amenable to high throughput. With a strong belief in and extensive knowledge of the power of mouse genetics, the scientists at Regeneron were not willing to accept these limitations, which led to development of one of our fundamental platform technologies, VELOCIGENE^®. A proprietary technology and key driver of our clinical pipeline VELOCIGENE enables rapid, automated and high scale manipulation of the mouse DNA with almost no limitations on the size and sophistication of modifications.

A core element of VELOCIGENE technology at Regeneron are bacterial artificial chromosomes or BACs, which are used to manipulate the mouse DNA. The unique properties of BACs enable the deletion or insertion of very large pieces of DNA, resulting in so-called BACVecs. These permit the complete humanization of the variable regions of antibody genes that empower the use of the drug discovery platform VELOCIMMUNE^®.

The engineered BACVec is delivered into mouse embryonic stem cells. These ES cells are progenitor cells that ultimately produce every other cell in the mouse. Once introduced into the ES cells, the BACVec replaces the target gene with unmatched precision through a process called homologous recombination. However, homologous recombination is still a rare event. Previously, it required laborious screening processes to find the desired modifications. A key component of VELOCIGENE, our novel loss of alleles screening assay addresses this problem.

The assay uses thoroughly automated and scalable processes to rapidly identify embryonic stem cells with the desired genetic modification among the vast majority of non-targeted cells. VELOCIGENE offers the fastest path to modifying very large portions of the mouse genome with unmatched precision and is the foundation for many critical steps in the drug discovery process at Regeneron, such as the creation of the VELOCIMMUNE mice, which are used to produce fully human antibodies.

VELOCIGENE^® modified embryonic stem cells can also be used to produce mice with the exact same desire genetic modification using another Regeneron invention, VELOCIMOUSE^®.

In contrast to conventional methods, which produce animals with a mixture of cells from the host embryo and injected stem cell. With VELOCIMOUSE the modified stem cells are injected into the mouse embryo at a very early stage to ensure that the resulting mice are completely derived from the modified embryonic stem cells. After the genetically modified embryo is implanted into a surrogate mother, the first generation of mice born now directly contain the desired genetic modifications, accelerating the discovery timeline.

Conventional techniques typically need multiple mice generations and several months to get to this point. With VELOCIMOUSE technology, Regeneron has dramatically shortened the time needed to engineer genetically modified mice, while at the same time reducing costs and improving precision.

We have also shared the important VELOCIGENE suite of technologies with others through multiple publications, collaborations, and the production of a large public resource of genetically modified embryonic stem cells.

Taken together, VELOCIGENE and VELOCIMOUSE offer the fastest path to validate the function of possible targets for drug discovery.

Furthermore, using these technologies to produce preclinical disease models in order to study a disease in more detail or to determine the efficacy of a new drug means we have higher confidence in a potential therapeutic solution for humans at an earlier stage in the process.

The ultimate goal for allergic diseases would be to find a cure. And I think it's possible given the technological advances that are happening every day right before our eyes. I have three young children who all suffer from food allergies and asthma, and I see every day the effects that these disorders have on their lives. It's unknown why people develop allergies in the first place. But what is known is that some people have an aberrant response to different pollens, or different foods, or other things in the environment.

So developing interventions that could potentially help them at some point in their lives is really meaningful. The nature of monoclonal antibody therapy would be to very specifically target what is causing the disease. So there are a couple of different approaches where we could use antibodies for allergic and respiratory disorders. The first would be to target the offending allergen. We've developed strategies to potentially bind to that and preventing it from engaging the immune system and having this aberrant response.

The second involves targeting allergic pathways. So inflammatory mediators and cytokines that would drive and perpetuate this allergic response. The third way that we can target allergic diseases involves identifying the cells that make pathogenic IgE and removing them. IgE is an antibody that the body makes, and it's the primary antibody that causes allergic disorders.

At Regeneron, we're really striving to follow the science and continue to push the limits of our understanding and knowledge of allergic disorders. It's almost mind blowing to see that all play out, and it really is very exciting to watch and know that people's lives are changing because of some of the work that we're doing here.

Our job here is to really approach cancer as a disease that can be managed and to deconstruct it and basically find ways to change the course of cancer. So it is something that we can say, you know what? We're going to get through this, and we're going to manage it.

From day one, Regeneron was built around revolutionizing technology platforms that enable us to not only generate high quality antibodies but also address the questions that, too simply, many others couldn't address.

So the new types of antibodies that we use that have been at the vanguard of this whole revolution and immunotherapy are antibodies that are not specifically directed against the tumor but are directed to the immune system. So antibodies have this Y-shaped structure and have two parts of them that both recognize the same thing. That's what natural antibodies are. What we've done here at Regeneron is figure out a way to make novel types of antibodies that are bispecific. Meaning one part of the Y recognizes one thing. The other part of the Y recognizes something else.

For instance, the most common form of bispecific antibody that we have today binds a killer white blood cell to a tumor cell and causes that cell to get eaten.

Our goal was to generate a next generation of bispecifics that we call costimulary bispecifics, to take this to a different level.

One different kind of bispecific not only binds to a killer white blood cell and a tumor cell. And instead of telling that white blood cell directly to kill it. So the antibodies required all the time, it educates the white blood cell. It tells the white blood cell, if you see a cell that looks like this, you want to eat it. Now that white blood cell can expand and go around to different parts in your body, and keep doing that, and keep killing tumor cells.

Therefore, we can educate the army, the soldiers of our immune system to be able to more efficiently fight against cancer cells.

So these costimulary antibodies, the costim bispecifics is what we're calling them, we think have a tremendous capacity. And we're just beginning these clinical trials now and are very excited to see what they will bring.

Promising monoclonal antibody drug candidates need to be analyzed extensively for efficacy and safety before they can enter clinical testing. Our VelociMab technologies allow us to move with unprecedented speed from identification of a therapeutic antibody into clinical studies. Velocimmune mice produce numerous antibodies that bind specifically to a validated human target. However, their immune system also still produces huge numbers of other antibodies. From the hundreds of millions of antibody-producing cells, the few whose antibodies have therapeutically-desirable properties now need to be selected. For this purpose, all VelociMab technologies use flow cytometry, or facts. With this high throughput automated method, cells are labeled with a fluorescent dye and sorted at up to 70,000 cells per second according to specific characteristics. From these hundreds of millions of cells, VelociMab is able to quickly identify and isolate the thousands of cells producing antibodies with the therapeutically-desirable properties.

The selected cells then arrive at the next step. The genetic blueprint for each of these antibodies is transferred from mice into cells using the easier technology specifically developed at Regeneron and antibody-producing cells are identified using our Fastr and Nice technologies. In the same step, the mouse constant region is replaced by a human constant region. The cell lines are now antibody factories, able to produce antibodies in sufficient quantities to allow preclinical testing for the antibody with the best safety and efficacy characteristics.

VelociMab technology has another critical advantage. Once the most promising target-specific antibody producing cell is selected, a seamless jump to clinical testing is possible because these cell lines used for testing are already capable of producing thousands of liters of antibodies in specialized bioreactors.

With the powerful combination of Velocimmune and VelociMab, Regeneron has dramatically shortened the timeline and increased the efficiency of fully human antibody development for clinical use.

With a promising drug target identified and validated, the stage is set for the next step. Discovery of appropriate drug candidates. At Regeneron, we focus on therapeutic antibodies. Antibodies are naturally occurring proteins that identify and fight pathogens like bacteria or viruses. They consist of constant regions and variable regions which recognize and bind the matching target. Monoclonal antibodies have two arms that bind to the same target tightly and with high specificity, potentially reducing side effects. Importantly, antibodies are not rejected by the patient's immune system. For these reasons, we engineer therapeutic antibodies that specifically recognize drug targets.

Production of therapeutic antibodies in mice is a common method, taking advantage of a natural process. Mice, just like humans produce and select antibodies to defend themselves against pathogens. Our proprietary VelocImmune technology takes advantage of this natural and unimpaired process, creating a multitude of optimized drug candidates efficiently and directly from immunized mice. By injecting the previously identified target protein into mice, an infection is simulated, and the immune system is triggered to produce a multitude of target-specific antibodies. Conventional methods, however, require the subsequent humanization of these antibodies in order to minimize rejection by the patient's immune system.

VelocImmune overcomes the limitations of traditional platforms by rapidly creating fully human antibodies. In VelocImmune mice, the genes coding for the variable regions of antibodies are precisely replaced by their human counterparts using our velocigen and velocimouse technologies. By purposely keeping the constant region of the antibody gene of mouse origin to avoid compromising the immune system, VelocImmune triggers a strong immune response and takes advantage of the natural process that produces a broad diversity of high quality antibodies. VelocImmune mouse is one of the largest genetic engineering projects ever undertaken in mammals. These mice are living workshops that greatly increased speed and efficiency in the production of fully human therapeutic antibodies.