Stem cell transplants are risky business, and although their use to treat cancer and other blood-borne diseases has increased in recent years, they remain dangerous and in many cases a last resort. One startup using work from Harvard University wants to develop a suite of new techniques to make them safer and more widely available.
The firm, Magenta Therapeutics, aims to develop three new drugs, each to improve different parts of the transplant process. The Cambridge, MA-based startup has raised $48.5 million from Third Rock Ventures, Atlas Venture, and others.
Magenta will treat each drug as a standalone product but would also like to offer them as a suite to transplant centers. “They can be used on their own or as a toolbox during different stages of the transplant procedure,” said CEO Jason Gardner, who previously spent time at Atlas after a decade in various positions at GlaxoSmithKline (NYSE: GSK). Gardner declined to give a timeline for reaching clinical studies.
One drug would be a replacement for the chemotherapy or radiation that precedes a transplant. Blood cancers like leukemia and diseases like sickle cell start in the bone marrow, where all our blood and immune cells are produced. Before a transplant of healthy marrow cells, a patient’s disease-causing marrow has to be wiped out with a toxic blast that causes collateral damage to healthy cells. About 20,000 transplants were performed in the U.S. in 2014. A large minority of recipients die, varying greatly by disease; either from the radiation or chemo conditioning, or from a nasty immune reaction to the transplanted cells, or from infections that take over because the patient’s immune system has been wiped out.
More moderate forms of conditioning that only kill some of the patient’s bone marrow cells have been developed in recent years to give elderly and frail people a chance to receive transplants, too. But Magenta wants to replace the chemo or radiation conditioning with monoclonal antibodies tethered to toxic drug molecules—known as antibody-drug conjugates, or ADCs. Think of the antibody, engineered to recognize a protein on the stem cell’s surface, honing in and delivering the toxic “payload” of the drug into the cell. In a different context, this idea has led to two currently approved drugs to fight cancer. Despite decades of work, the idea has not spread widely because researchers have had trouble harnessing the powerful toxins and containing the side effects. One problem: it’s tough to find ADC targets that don’t also appear on healthy cells.
Gardner declined to say which targets Magenta would shoot for. Researchers at the heart of Magenta recently published a paper describing the use of ADCs that used saporin, a toxin derived from the seeds of the soapwort plant, and aimed at CD45, a target protein that is found on all white blood cells. They claimed the procedure, conducted in mice, cured the animals of sickle cell without much collateral damage. Much of the work was done in the lab of David Scadden, a top stem cell researcher at Harvard University and Massachusetts General Hospital. One of Scadden’s postdocs, Rahul Palchaudhuri, has joined Magenta.
But will the approach work safely in humans? “We’re looking at that in a careful way,” Gardner said. “It’s good for us that others have tested [ADCs] and know what not to do.” Magenta will partner with companies that have more experience with conjugated toxins, he said.
Magenta also aims to develop drugs that make for easier harvesting of stem cells from healthy donors. Currently, stem cells can be drawn from bone marrow—a painful surgery, usually with a large needle into the pelvic bone. Or they can be first coaxed into the bloodstream, a process called “mobilization,” and taken up in less traumatic fashion. But mobilization takes days. Magenta has license to an experimental method, also developed in the Scadden lab, that Gardner said can mobilize stem cells in 20 minutes.
Magenta will also develop drugs that can expand the harvested stem cell population outside the body. Magenta will treat all three drugs as individual products and try to prove their worth in separate clinical programs, said Gardner. The company eventually hopes to convince transplant clinics to buy the entire suite of drugs. When asked if Magenta, even in these preclinical days, is thinking of how to price the drugs, Gardner said they’ve been talking to healthcare payers. “There are lots of potential business models, but one is sharing the risk based on clinical benefit over a long period of time,” Gardner said.
Magenta isn’t the only group working on therapeutic upgrades for stem cell transplants. A team at Stanford University is starting a clinical trial for kids with X-linked severe combined immunodeficiency (X-SCID), also known as “bubble boy disease.” Their approach also uses antibodies to wipe out the patients’ diseased bone marrow in preparation for a transplant. The trial just got a green light from regulators. When the first patient is dosed, it will be a first in the U.S., said Judy Shizuru, the Stanford stem cell researcher and transplant doctor running the trial.
Unlike Magenta, Shizuru is using “naked” antibodies, no toxins attached. While unlikely to be as toxic as radiation or chemo, the antibodies have shown side effects in mice. Shizuru said anemia is one problem to watch for. The X-SCID clinical trial will only test one antibody, but ultimately the group wants to use two antibodies in tandem in various diseases.
The one-two punch works like this: One antibody looks for a protein called CD117 and clamps onto the diseased stem cells, the other blocks the cells from sending out a signal that protects them from cells called macrophages—the cleaning crew of the immune system. The signal, which Shizuru’s Stanford colleague Irv Weissman has dubbed “don’t eat me,” is also a tactic that cancer cells use to evade the immune system and survive. The signal emanates from a protein called CD47, and Weissman has founded a cancer company called Forty Seven to pursue drugs based on the underlying biology. (The company has just received a new California state grant to run a trial of a colon cancer drug, according to the California Stem Cell Report.)
Shizuru said the rights to exploit CD47 biology for transplant-related drugs are still in Stanford’s hands, but licensing them to Forty Seven “seems reasonable.” (She said she has no financial interest in the company.)
If efforts like those at Magenta, Stanford, and elsewhere prove successful, they might end up giving transplant doctors a more varied range of tools that can be tailored to different medical situations. Conditioning a patient by attacking CD45, for example, could provide a more complete kill of the bone marrow, perhaps necessary for cancer patients. Using naked antibodies should preserve some marrow cells and allow a patient to keep a functional immune system, said Shizuru, which could be a better approach for people with non-cancerous chronic blood diseases such as sickle cell or beta thalassemia.
New genetic medicines that use CRISPR-Cas9 and other techniques are likely to make an impact first in blood-borne disease. They will still require stem cell transplants. “The potential merging of success in this arena and what I do would be amazing,” said Matthew Porteus, also at Stanford, who recently published results of preclinical studies using CRISPR-Cas9 to fix the sickle cell mutation in hematopoeitic stem cells, adding to the growing body of academic work in the field.
Beyond cancer and other blood diseases, researchers have their eye on transplants to help people with autoimmune diseases, where the patient’s immune system goes awry and causes irreversible damage. Hundreds of multiple sclerosis patients whose disease had not responded well to other treatments have received transplants to reboot the immune system. (A review of those cases is here.) But generally, autoimmune diseases like MS aren’t considered perilous enough to risk transplants.
Whether new methods come from Magenta, Stanford, or other groups, it seems that stem cell transplants could play a much larger role in medicine in coming years. “We’ve been using the same agents for decades,” said Shizuru. “It’s time to change.”
Photo from the collection “Bone Marrow Donation” by Andrew Ratto via Creative Commons.