Originally published on Sanofi.com.
Bill Hobbs still remembers the advice his mentors gave him about choosing a medical research specialty. “Don’t go into hematology,” they warned him. “There’s no future in it.”
He ignored the advice and today he works with a team of Sanofi researchers who are building on scientific discoveries in hematology and related fields in their search for new treatments for rare, and often neglected, blood disorders like Cold Agglutinin Disease (CAD).
“It’s an area that has a clear future today,” says Hobbs, who works in Complement Biology Therapeutics at the company. “We have seen huge advances in the science of hematology and the development of new therapeutics that are allowing us to address many formerly untreatable blood disorders.”
The immune system gone awry
One of the most compelling rare diseases Bill and his colleagues are investigating is CAD, an autoimmune disease where the body attacks its own red blood cells.
People with CAD produce auto-antibodies that bind and destroy their own red blood cells preferentially at lower-than-core body temperature by activating a component of the immune system called complement.
One of the remarkable aspects of this condition is that it may be exacerbated by exposure to cold temperatures. Even walking along the frozen food section of the grocery store or drinking a cool beverage can trigger symptoms. Once activated in this way, the immune system begins a self-directed destruction of red blood cells through a process called hemolysis. Since the body cannot replace the cells fast enough, people with CAD develop a chronic anemia state.
People with CAD feel exhausted from debilitating fatigue and often suffer from pain in their hands and feet. CAD can also result in an increased risk of life-threatening thrombosis, such as blood clots that can cause stroke, heart attacks or pulmonary embolisms1.
Because CAD is very rare and tends to affect older people who are already predisposed to anemia, it can take months or years before a person is correctly diagnosed. A recently published study showed that CAD patients had an increased mortality risk observed as early as the first year after diagnosis2.
“This emphasizes the critical need for earlier recognition and diagnosis, as well as targeted treatment options for these people,” notes Hobbs.
Zeroing in on a specific protein target for treating CAD
A main part of the body’s immune response is called the complement system, which is comprised of three pathways: classical, alternative and lectin. This system is manned by a set of protective proteins that are on constant standby until they are mobilized to eliminate an infection or damaged cells. At that point, a chain reaction occurs that triggers the activation of proteins that can bind to the membrane of the infectious or damaged cells, acting as a kind of ‘tag’ that is then recognized by phagocytes, specialized immune attackers that engulf and destroy the tagged cells.
Researchers began several years ago to examine the connection between CAD symptoms and the classical complement pathway. In CAD, the classical complement pathway is abnormally activated and, in a similar fashion as it destroys foreign pathogens, it attacks and destroys the body’s own red blood cells, creating this chronic hemolytic anemia state. Scientists further homed in on an initial step in the classical complement pathway that involves a protein complex called ‘C1’ as a potentially useful point of therapeutic intervention.
The challenge the research team faced at this stage, Hobbs notes, was “teasing apart” the three proteins in the C1 complex and choosing which one to try to block in order to prevent the chain reaction from starting. Eventually, the researchers developed a monoclonal antibody, a laboratory-produced molecule, that specifically binds to one of the C1 complex proteins.
“For CAD, the idea was to block the classical complement pathway as far upstream as possible,” explains Karin Knobe, a pediatric hematologist who leads rare blood disorder therapeutics at Sanofi. Ultimately, the researchers were able to show that by inhibiting only one of the proteins involved in the classical complement pathway, they were able to maintain the protective immune functions of the other components of the complement system.
The research team working on CAD are excited about the early positive data from clinical trials—the results are promising enough to even get typically cool-headed scientists very emotional.
“Results from the first proof of concept in humans had us running in the streets,” recalls Hobbs.
Positive ripple effect of research
CAD is unique in its symptoms, but it has one thing in common with dozens of other diseases for which research has been lacking: its rarity. CAD only affects about 12,000 people in the U.S., Europe and Japan, a number that may not attract the attention of the scientific community who tend to focus on conditions that impact millions of people.
Yet, it is precisely its rarity that motivates scientists like Knobe and Hobbs, along with the fact that people with CAD have no specific treatment options available to them today.
While the research and testing on this investigational monoclonal antibody are ongoing, recruitment efforts for the clinical studies have already contributed to greater awareness among health care professionals and patients. The hope is that increased awareness about signs and symptoms of CAD among study investigators and patients alike will contribute to earlier detection and management of the disease in the future.
Another big reward of this work: the C1 complex is also implicated in other autoimmune diseases. So, while their current focus is on CAD, Sanofi scientists are examining how targeting the C1 complex might represent a common therapeutic pathway for those diseases as well. One such disease is immune thrombocytopenia (ITP), a disease where the immune system targets platelets rather than red blood cells.
“It is rewarding to know that the work we are doing in CAD could also hold future treatment promise for ITP and other diseases that share this common disease pathway,” says Knobe.
The investigational compound described in this article has not been evaluated for safety and efficacy by any regulatory authority.
1. Broome C, et al. Incidence of thromboembolic events is increased in a retrospective analysis of a large cold agglutinin disease (CAD) Cohort. Blood. 2017;130(suppl 1).
2. Bylsma LC, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv (2019) 3 (20): 2980-2985.