From Bench Research to New Medicines
A team searches for the “sweet spot” to control autoimmunity
The immune system has a difficult job: fighting disease without endangering healthy tissue. A better understanding of immunity is already producing new therapies for cancer, autoimmune diseases and other conditions.
Thomas Malek, Ph.D., professor and chair of microbiology and immunology, has spent decades trying to understand how immune cells are regulated. Those efforts have translated into a new drug for autoimmune diseases, which is in clinical trials for lupus, an autoimmune condition that can cause chronic inflammation in multiple organs.
The Malek lab has focused on regulatory T cells (Tregs), which help keep killer T cells from getting out of hand. The group has been studying how the hormone interleukin-2 (IL-2) reacts with Tregs. Not surprisingly, IL-2 has a complicated role. Larger quantities of IL-2 drive an immune response. Smaller quantities activate Tregs, which shut down immune attacks.
“If you get COVID-19, for example, IL-2 is one of the key players driving the immune response to get rid of the infection,” Dr. Malek said. “That’s high-dose IL-2. Low-dose IL-2 boosts Tregs, and there’s a big enough therapeutic window between high- and low-dose that we can target Tregs, and moderate autoimmune responses, without delivering too much that might stimulate unwanted immune responses.”
The challenge is hitting that IL-2 sweet spot. The hormone has only a brief half-life in the body, but compensating with more IL-2 could produce the wrong results — boosting the immune response rather than controlling autoimmunity. The researchers needed to develop a way to consistently deliver IL-2 at low levels. They eventually created a fusion protein called IL-2/CD25, which could treat lupus and other autoimmune conditions.
“It’s designed to slowly release IL-2,” Dr. Malek said. “The fusion protein goes in biologically inactive, and then it slowly releases the active form.”
It has been a long road, with multiple collaborations. After years of bench research and testing in many different models, IL-2/CD25 was licensed to a pharmaceutical company, which has moved it into trials.
Still, good science is about constant improvement. Even though the initial fusion protein is in trials, Dr. Malek and collaborators are working to build a better one. They are trying to fuse an additional protein to help control inflammation.
The team is also engaged in other projects, including collaborating with Robert Levy, Ph.D., professor of microbiology and immunology, ophthalmology and medicine. He has been working with a different molecule to stimulate Tregs to limit graft versus host disease after patients with cancer receive stem cell transplants. These two approaches, when combined, could provide more precise control over graft versus host disease and, perhaps, autoimmune diseases.
Following this theme, the Malek lab is also collaborating with Paolo Serafini, Ph.D., associate professor of microbiology and immunology, to develop new treatments for another autoimmune condition: Type 1 diabetes. In that case, the immune system mistargets and destroys insulin-producing islet cells.
“He has a biologic drug that boosts molecules on islet cells to inhibit islet-reactive T cells,” Dr. Malek said. “Dr. Serafini’s approach is trying to suppress this autoimmune response by exhausting autoreactive cells. We’re also testing how well this works when we combine it with the original fusion protein that targets Tregs. Early studies have shown our therapies reinvigorate islet cells, which is a great sign.”
From Bench Research to New Medicines
From left, Paolo Serafini, Ph.D., Thomas Malek, Ph.D., and Robert Levy, Ph.D.
University of Miami Medicine
FALL 2024
