In May, the Food and Drug Administration granted fast-track designation for sabatolimab (MBG453) for the treatment of adult patients with myelodysplastic syndromes (MDS) — a group of conditions in which the blood-forming cells of the bone marrow begin to act abnormally. Patients with MDS can receive chemotherapy, but most are not responsive to currently available treatments, and approximately 1 in 3 patients with this condition will advance to acute myeloid leukemia. For these patients, sabatolimab is a beacon of hope.
For researchers in the Kuchroo lab, sabatolimab — which gets its name from laboratory alumna Catherine Sabatos, PhD — is a drug two decades in the making, and an example of the power of perseverance in science. For many years, sabatolimab’s drug target — a protein known as TIM-3 — remained underappreciated and the path to clinical impact unclear.
“We never lost hope,” said principal investigator Vijay Kuchroo, PhD, reflecting on the winding road that led to the protein’s discovery, drug development and, eventually, clinical trials. Now, as the scientific and medical community awaits news on sabatolimab, Kuchroo’s team continues to pursue the many secrets of TIM-3, and its potential to illuminate and lead to treatments for other kinds of cancer.
Journey to Discovery
The journey to sabatolimab began with a basic research question in the Kuchroo lab 20 years ago. The lab was working to identify molecules that could distinguish between different kinds of T helper cells — critical players in the immune system. The lab screened more than 20,000 antibodies, looking for those that had different patterns of binding activity in two kinds of Th cells. This led to the discovery of an antibody that bound Th1 cells but not Th2 cells — and that antibody recognized TIM-3.
TIM-3 stands for T cell immunoglobulin and mucin domain-containing molecule 3 — a mouthful of a name for a protein whose biological role in immunity and inflammation is still being pinned down by researchers today. TIM-3 expression has been shown to mark the most severely “exhausted” or dysfunctional T cells that arise in chronic viral infections, such as HIV and HCV, as well as in cancer. Most recently, Kuchroo lab researchers have found that loss of TIM-3 on another type of cell — dendritic cells — can reduce tumor burden in mice engrafted with colon, lung, or melanoma cells. (Read more on that here.)
But when Sabatos, who was a graduate student in the lab at the time, first cloned the gene for TIM-3, the protein didn’t even have a name. The molecule — in fact, its entire family of molecules — was completely unknown. But that was about to change.
Starting with a Lock
While the lab was intrigued by a molecule that could distinguish Th1 and Th2 cells, at first, it was unclear what TIM-3 did.
“It was like we had found the lock, and then we had to find the key,” said Kuchroo.
Ana Anderson, PhD, a graduate student and then a postdoc in the Kuchroo lab, also worked on TIM-3.
“Our work began with a very basic science question about T cells and their behavior,” said Anderson. “And, amazingly, it led to a new paradigm in our understanding of what these cells are doing.”
The team found that TIM-3 was among the molecules tasked with turning off T cells after they had completed their work of clearing an infection. These “checkpoint molecules” play a key role not only in immunity but also in cancer — mutations can lead to T cells being turned off inappropriately, allowing cancer to evade the immune system. Around the time that the Kuchroo lab was working on TIM-3, other labs had identified additional checkpoint molecules known as PD-1 and CTLA-4.
Soon, a clearer picture of the interplay between the immune system and cancer began to emerge and PD-1 and CTLA-4 rose to prominence as drug targets. Drugs that block function of immune checkpoint molecules can prevent the molecules from turning T cells off, allowing T cells to get back to the business of killing cancer cells. In preclinical studies that Anderson worked on, the Kuchroo lab found that blocking PD-1 and TIM-3 together had a powerful effect against tumors. Anderson also found that TIM-3 was expressed not only in T cells, but also on myeloid cells — a key discovery that would lead to sabatolimab as a potential treatment for MDS.
But even as the research evidence and the biological understanding of the role of TIM-3 deepened, the development of a drug to target the molecule began to stall.
‘Beyond What I Could Have Imagined’
Over the next several years, multiple drug companies picked up a collection of patents that included one for work related to the Kuchroo lab’s discovery of TIM-3, but then returned the portfolio without having pursued the drug target.
In 2011, after the portfolio was once again returned to Mass General Brigham, Kuchroo, together with Arlene Sharpe, MD, PhD, of the Department of Pathology, and Gordon Freeman, PhD, an immunologist at Dana-Farber Cancer Institute, co-founded CoStim Pharmaceuticals. Sabatos, who had recently completed a research fellowship overseas, came back to serve as the company’s director of immunology. Anderson served on CoStim’s scientific advisory board and had a front row seat to what happened next.
For two years, CoStim developed a pipeline of antibody agents for the treatment of cancer and chronic viral diseases. In 2014, the company was acquired by Novartis. Within a year, clinical trials for sabatolimab had begun.
“It’s one of the most exciting things that can happen for a researcher, to see a discovery made in a Brigham research lab lead to the founding of a company that the Brigham invested in, which was sold to a pharmaceutical company, and now to see a drug taken into clinical trials — it’s beyond what I could have imagined,” said Anderson. “You always want to work on a project that will have an impact on patients’ lives. Usually, you only get to see that toward the end of your career. To be a part of this work from such an early time in my career, it’s just beyond words.”
Pursuing Questions, Big and Small
Today, there are more than a dozen clinical trials being conducted by industry to explore targeting TIM-3 in solid tumors, including melanomas and small-cell lung carcinomas, as well as treating patients who have become resistant to other forms of cancer immunotherapy.
In the Kuchroo lab, researchers are continuing to pursue basic research questions — some of which could lead to the next big discovery.
Karen Dixon, PhD, joined the lab in 2016 as a Marie Curie Global Fellow after encountering patients suffering from a variety of immunological conditions, ranging from allergies and primary immunodeficiencies to autoimmune diseases and cancer. She hopes to improve the understanding of the mechanisms driving these debilitating immune-mediated diseases.
Dixon is currently working to understand TIM-3’s role in dendritic cells and the molecules’ influence over the activity of inflammasomes — a group of immune sensors that have been implicated in a host of inflammatory disorders. She describes herself as coming in for the last part of the relay race and by building on the lab’s long history of working on TIM-3 has been able to uncover mechanistic insight on the function of TIM-3 in myeloid cells.
“From a basic science point of view, everyone is trying to chase the big discoveries but a lot of the smaller studies from a number of fellows in the lab over the years have chipped away at how we understand the role of TIM-3 in inflammation and immunity,” said Dixon. “The little pieces all together are so important later when you make observations in patients. You start to make connections — in isolation, it’s not clear what’s happening but as you put the pieces together, the picture starts to reveal itself.”
Beyond potential FDA approval, TIM-3 research has led to successes on many fronts. Dixon recently published a paper on her findings in Nature. Anderson has gone on to launch her own laboratory at the Brigham and now holds an endowed position supported by a President’s Scholar Award. Sabatos has likewise had a remarkable career, joining Novartis after her time with CoStim, becoming a lead in the development of Sabatolimab and now a CSO at a biotech company.
“We have had the right people at the right time fighting to make sure that we realized the full potential of TIM-3,” said Kuchroo. “And it’s been remarkable to see where it’s led. The results have been spectacular.”