Tapping Preclinical Understanding For Smarter Trials

Regeneron recently announced the treatment of the first patients in a clinical trial with a novel investigational cancer medicine – a CD28 costimulatory bispecific antibody. Getting to this milestone required close collaboration between diverse functions. Here, preclinical research lead Dimitris and clinical research lead Beth share how their partnership led to the design of a “smarter” clinical trial.

Dimitris: When we first considered the idea of studying CD28 costimulatory bispecific antibodies and their role in cancer biology, we saw unique potential. The big idea was to evaluate whether we could enhance immune system T-cells to kill cancer cells by stimulating their CD28 receptors. However, we knew we had to approach our research in a new way given the past history with CD28-targeted therapies.

Beth: A little more than 10 years ago, there was a lot of hope around an experimental medicine called CD28 superagonist antibodies. These were designed to supercharge T-cells and induce localized killing of cancer cells. However, in a first-in-human clinical trial in healthy volunteers, the CD28 superagonists unexpectedly caused widespread T-cell activation throughout the body within hours of being administered. This led to a life-threatening side effect called cytokine release syndrome (CRS), and the healthy volunteers ended up hospitalized in intensive care for days.

The CRS caught the researchers completely by surprise and had not been observed in their preclinical safety work. There were several consequences for future clinical research. One was that widespread changes were made to better focus on safety in first-in-human studies in general. Another was that the field largely abandoned testing new CD28-targeted therapies.

Dimitris: As a student of immunology, my scientific curiosity was piqued when it came to the CD28 target. Rather than just seeing the tricky history of the class, I and many of my Regeneron colleagues saw the potential of CD28-based treatments. And after doing a series of experiments, we were convinced that the CD28 pathway has the potential to boost the ability of T-cells to kill cancer cells.

However, we knew we’d have to take a dramatically different approach to better address patient safety, and it had to start in the lab. Thankfully, at Regeneron, we have deep support to invest the time and necessary resources in our preclinical research.

Our first step was to create an investigational medicine that works on the CD28 pathway of T-cells in the presence of cancer cells. With costimulatory bispecific antibodies, we found an innovative way to do this by designing one arm to bind to the cancer cell and the second arm to the CD28 receptor on T-cells. In this way, we were able to focus CD28 activation of the T-cell at the cancer site.

We then performed numerous experiments in cell cultures and animal models to see how these CD28 costimulatory bispecifics would perform. Some were conducted to better understand how they affected T-cell behavior and their ability to kill cancer cells. But many experiments were focused on early patient safety and testing that our CD28 costimulatory bispecific antibodies were ready for in-human clinical trials. We especially wanted to hopefully avoid the CRS seen with CD28 superagonists, and in several cell culture and sophisticated animal model experiments, we were able to demonstrate that this wasn’t happening in animals with our CD28 costimulatory bispecifics.

Read what Dimitris and his team discovered in Science Translational Medicine

Beth: This preclinical research was invaluable in helping our team make smarter decisions when designing the clinical trial for our first investigational CD28 costimulatory bispecific.

For instance, the results of our preclinical research supported the investigation of CD28 costimulatory bispecifics in combination with other treatments. As a result, we setup our initial clinical trial to first evaluate patient safety by giving our CD28 costimulatory bispecific alone for a short period of time, before cautiously adding a second therapy to see if this combination could kill cancer cells. Advancing to combination therapy usually takes longer in this first phase of clinical research, but the strength of the preclinical data allowed us to move forward with this approach.

Ultimately, we hope this strategy will help us more rapidly understand the anti-cancer potential of this first CD28 costimulatory bispecific.

Dimitris: We’re excited to see if our preclinical results will translate in human clinical trials. If so, this novel class of medicines offers a lot of potential to study tailored, therapeutic combination approaches against diverse cancers.

Beth: This is cutting edge and exciting research, and it has been made so much more enjoyable because of the ongoing close collaboration between our preclinical and clinical research teams. At Regeneron, everyone is connected by a deep passion for science, and this culture is our key to making important medicines for patients.