The human immune system is an incredible defense mechanism that has the ability to interrogate and respond to any harmful entity (or ‘antigen’) that it is exposed to. When we are exposed to viruses, our dendritic cells sample the particles, process them, and then mobilize the immune system into action, resulting in the production of antibodies against the virus. The same mechanism has been exploited for vaccination, of course.

But the immune system also has a darker side – antibodies can form in response to anything deemed as ‘foreign,’ including biological medicines that are intended to improve – or to save – the patient’s life. A well-known example is coagulation factor VIII – a clotting protein required by patients with hemophilia A. In a surprisingly large percentage of patients (over 30 percent), the immune system treats factor VIII as if it were a harmful entity and starts to make anti-drug antibodies (ADAs). This often results in a loss of efficacy and may also cause severe hypersensitivity reactions, including anaphylaxis.

Arrested development and allergic responses

When I started my career, most therapeutics were small chemical molecules, but today the focus has shifted to biologics. The immune system does not react to small molecules, but it can often react to biologic drugs, such as proteins, monoclonal antibodies and enzymes. A surprisingly large number of biologics already on the market induce the production of ADAs in many patients. Not only can ADAs reduce drug efficacy and modify pharmacokinetics and pharmacodynamics, they can also cause allergic responses. Over 100 approved biologics already list immune responses on their labels. As one example, a majority of patients taking Humira make ADAs (1). It often takes several months to a year for antibodies to build up and become a problem, but it is a key reason why patients on anti- TNF alpha inhibitors are often forced to switch medications.

The real problem arises when there is no alternative treatment. For instance, for patients with Pompe disease, there is only one approved enzyme: alglucosidase alfa. If patients develop ADAs to alglucosidase alfa – and the vast majority of patients do – the loss of alglucosidase alfa efficacy can prove to be fatal. ADAs also prevent a number of drugs from even reaching the market.

Antibody action

We need an approach to deal with ADAs that goes beyond ‘wait and see.’ At present, some physicians are avoiding certain approved medications because of the drug’s immunogenic profile or are unaware that a patient has developed ADAs because they are not routinely monitored. Other physicians are experimenting with immunosuppressive cocktails to overwhelm the immune system to keep the ADAs at bay and allow the medication to work. However, the need to broadly immunosuppress patients comes with clear drawbacks and risks.

At Selecta, we are aiming to improve the efficacy and safety of biologic medications by resolving the ADA issue. One of our cofounders, Ulrich von Andrian (the Mallinckrodt Professor of Immunopathology at Harvard Medical School) is one of the world’s leading immunologists, and much of his work has been focused on the role of dendritic immune cells. The dendritic cell acts as the teacher and sentinel of the immune system. They sample viruses and nanoparticles in general and, if they sense danger, they activate the immune system to respond by inducing the activation of virus-specific T cells and B cells, which leads to the production of specific antibodies to fight the danger. Von Adrian demonstrated that you can also achieve the opposite result by taking dendritic cells out of an animal and teach them to induce immune tolerance to an antigen. He then reinjected those dendritic cells into another animal, which prevented the animal from making antibodies against the specific antigen.

We believe that it is also possible to combat ADAs in vivo by using synthetic vaccine particles (SVPs). We have designed these nanoparticles with the goal of permitting them to “talk” to the immune system – telling it when to fight and, just as importantly, when not to fight. We hope to use SVPs to program the immune system to elicit tolerance to a specific antigen, without impacting the rest of the immune system. Rather than taking the dendritic cells out of the patient and dosing it with a biologic and an immunomodulator in a petri dish to prevent ADAs, we enable the critical process – specifically SVP-Rapamycin dosed in combination with a biologic – to take place within the patient to induce longer term immune tolerance.

The design of SVP-Rapamycin took a significant time as we were looking to overcome serious scientific challenges and had to meet many important criteria. For instance, we wanted them to work when dosed both subcutaneously or intravenously. We wanted to ensure that these nanoparticles resembled viruses so that they would be taken up selectively by the dendritic cells. We designed the nanoparticles to remain intact once they were injected and to only release their payload once they were taken up by the dendritic cells. In addition, of course, we had to develop a means to produce the particles in a way that made business sense and could facilitate our scale-up. We have already translated our SVPs from in vitro, to mice and to non-human primates – and this research has been published (2). But, of course, we needed to make the most important translational step of all – demonstrating that our approach would work in humans.

Teaching Old Drugs New Tricks Many promising treatments do not reach the market because of immunogenicity. As one example, Ira Pastan, a senior investigator with the US National Cancer Institute (NCI), discovered mesothelin, a protein that is overexpressed in mesothelioma, pancreatic cancer and other solid tumors. After identifying the target, Pastan started to work on recombinant immunotoxins consisting of an antibody fragment fused to a bacterial toxin payload intended to kill mesothelin-expressing tumor cells. NCI subsequently developed a product candidate, studied it in clinical trials – and found that almost all patients developed antibodies against the immunotoxin, rendering the drug useless. NCI then opened a small new Phase 1 trial in which a small number of terminal patients with a rare form of cancer known as mesothelioma were dosed with the immunotoxin and a potent cocktail of immunosuppressant drugs. The results were compelling. While the vast majority of patients still formed ADAs and were forced off therapy, one patient was able to receive four treatment cycles and another was able to receive six treatment cycles. Both of these patients saw marked tumor regression, and one of these patients remains alive today more than five years after his treatment (5). Roche licensed the technology and reengineered the immunotoxin with NCI to make it less immunogenic by removing certain epitopes, creating a product candidate known as LMB-100. Roche initiated a new clinical trial with LMB-100, but found that the compound was still highly immunogenic. Roche then returned the product and technology to NCI. In 2016, NCI and Selecta generated compelling preclinical data showing how SVP can prevent the formation of ADAs to LMB-100, which led Selecta to in-license the product candidate in 2017. Selecta and NCI are currently planning a Phase 1b clinical trial for this new combination product candidate, known as SEL-403.

The right indication

In order to pursue our first commercial path for SVP-Rapamycin, we needed a suitable biologic candidate to showcase the potential of SVPs, and we had the following criteria:

It had to be a product that we owned; we could have chosen to license out our technology, but we wanted to own the product for the first applications so that we would have full control of the development path and timeline.

At the same time, we needed this to be a real commercial opportunity to address real unmet patient needs.

We also wanted a product that would enable us to demonstrate a benefit very rapidly – both from an efficacy and from an ADA-mitigation aspect.

In some cases, immunogenicity is built up immediately; flu shots are designed so that you only need one shot to have an immune reaction, and some biologic drugs provoke an equally strong response. With many other drugs, ADAs build up more slowly over the course of many months.

We also wanted to find a medication that had clear biomarkers of efficacy as opposed to a longer-term clinical outcome.

Lastly, we wanted to work with adult patients for our first indication. With hemophilia and other genetic diseases, the focus is often on treating young patients. However, as SVP is a new technology, starting with children would have erected high hurdles from regulatory agencies, parents and ethics committees.

Our screen led us to the chronic severe gout market. Gout is a very prevalent disease – there are around eight million patients in the US alone. It is caused by metabolites from proteins; specifically uric acid, which normally circulates in the blood at healthy levels below 6 mg/dL. Gout patients have an imbalance between how much uric acid is formed and how much is excreted through the kidney. If the concentration goes above 6.8 mg/dL, uric acid is no longer soluble, leading to the formation of crystals that can cause inflammation in joints and tissues. To get rid of the imbalance, you may need an enzyme called a uricase that targets uric acid. However, as the human body doesn’t make uricase, it is viewed as foreign by the immune system, and ADAs form in the vast majority of patients (3).

We licensed one such enzyme, pegsiticase, and then combined it with our technology. By co-administering the enzyme drug with our SVP technology, we have generated data that show that we can prevent the formation of ADAs in human patients (4). I like to describe SVP-Rapamycin as a “negative vaccination.” With a vaccination, you are sending a danger signal to the immune system to induce the formation of antibodies to fight an antigen. With SVP-Rapamycin, we seek to teach the immune system that the biologic is not dangerous and that ADAs should not be formed. We have already generated clinical data in support of the idea that SVP-Rapamycin that is administered with pegsiticase mitigates the formation of ADAs to pegsiticase. We are now in the middle of a phase II study and expect to share additional information about this trial in late 2017. We have already started looking at the design of our phase III program, which we plan to begin in 2018.

Treat and retreat

Gene therapy could be a particularly promising area for SVP. Going back to hemophilia; what if we could teach a patient’s liver cells to make the missing coagulation factor? Gene therapy would involve delivering genetic information encoding the coagulation factor into the liver cells, but to do that you need a vehicle, such as a viral vector. Of course, as these vectors are “viral,” they are always immunogenic when you dose them systemically. Initially, the viral vector should induce liver cells to start making the missing protein. But, over time, expression may wane due to cell turnover in the liver. Currently, it is not possible to re-administer gene therapy because the immune system will have made ADAs after the first injection. This is a particularly challenging issue for pediatric patients, as cell turnover in the liver will be high as the children grow. As a result, systemic gene therapy dosing has been mostly limited to adult patients thus far. In preclinical studies; however, we have shown that by combining viral vectors with our SVP technology, ADAs can be prevented, making it possible to re-administer gene therapy.

As the problem of ADAs becomes more understood, I expect to see greater regulatory oversight – and perhaps agencies in the US and other developed markets will begin to require companies to not only study immunogenicity during clinical trials, but also after a drug has been approved and is in regular use on the market. We urgently need to address this issue as the next generation of biologic therapies are developed. Particularly in the case of gene therapies, retreatment will be incredibly important for a number of inborn diseases for which no treatments exist today. If we want to progress medicine to the next level, we need to tackle ADAs. And I believe that the most effective way to do this is through antigen-specific immune tolerance.

Werner Cautreels is Chairman, President and CEO of Selecta Biosciences, Inc.