Art Courtesy of CC Chong.
Our bodies are constantly under siege by dangerous pathogens. Thankfully, our biological systems have developed immune defenses to fight off these pathogens and stave off illness. White blood cells, which are produced by bone marrow, lie at the center of our immune system. Without them, we cannot fight off disease. For patients with bone marrow damage, however, this shield is compromised.
Currently, there are a few ways to fight off disease in spite of injured bone marrow, such as antibiotics, immunoglobulin therapy, and drug treatments to stimulate white blood cell production. In many cases, though, these treatments fall short. Thanks to recent work by Nikolai Jaschke, a postdoctoral researcher in the Wang lab at Yale, that might change. Jaschke discovered new therapeutic potential in a synthetic molecule called A485, which was originally developed by a pharmaceutical company named AbbVie in 2017. He theorized that A485, which previously demonstrated potential anti-tumor effects, may have more effects than what its original characterization suggested—among them, a mechanism to combat infection in people with injured bone marrow.
Putting A485 to the Test
Produced by bone marrow, white blood cells enter the bloodstream and tissues, where they can rally against pathogens to protect from infection. If bone marrow is injured or experiences failure, it is unable to produce sufficient numbers of white blood cells. A severely low white blood cell count leads to an increased risk of infection and complication.
Currently, patients who exhibit bone marrow failure are treated with granulocyte colony-stimulating factor (G-CSF). G-CSF is naturally produced by the body to stimulate the production of neutrophil granulocytes, the white blood cells that form the front line of defense against infection. G-CSF has also been developed into a drug administered to counteract a drop in white blood cells, known as neutropenia. However, some patients treated with G-CSF following bone marrow injury may still develop neutropenia and subsequent infection. This complication is known as acute neutropenic fever and is currently hard to tackle therapeutically.
Enter Jaschke and his research on A485. Previously published research on A485 by AbbVie had shown that A485 could inhibit a histone acetyltransferase domain. Mutations in this domain are often associated with leukemia, a cancer characterized by the uncontrolled release of blood cells. Thus, Jaschke posited that A485, by temporarily inhibiting this leukemia-inducing region, may be able to trigger the release of white blood cells.
Now, this hypothesis had to be tested. First, Jaschke demonstrated that A485 increases neutrophil mobilization into the bloodstream. Specifically, he found that mice treated with both G-CSF and A485 had significantly greater neutrophil mobilization than mice treated with just G-CSF or A485 alone. However, while the effects of G-CSF are more prolonged (white blood cell counts remain at higher levels for a long time), only twelve hours after the injection of A485, the white blood cell count dropped back to pre-administration levels. This rapid return to baseline levels reduces the likelihood of side effects and enables greater precision in treatment administration. “What we showed was that this increase in white blood cells is sufficient to clear a substantial amount of bacteria from the blood. And of course, if you clear a lot of the pathogen that is trying to destroy your tissues and compromise your health, you will ultimately end up in a better place than another mouse or a patient that didn’t receive this therapy,” Jaschke said.
The researchers then took their work a step further. Bone marrow injury can often affect cancer patients undergoing chemotherapy. Chemotherapy targets are rapidly proliferating cell types, including those in the bone marrow. Thus, bone marrow injury often emerges as a side effect of the primary purpose of killing cancerous cells when administering chemotherapy.
To simulate the bone marrow injury of chemotherapy-treated cancer patients, Jaschke used a mouse model of chemotherapy-induced bone injury. They infected the mice with a bacterium called Listeria monocytogenes, causing a systemic infection of the bacteria in the mice. Following infection, the mice were treated either with A485 or an empty control after the point of infection. They found that a significantly higher percentage of A485-treated mice survived the infection compared to the control group, despite both having initially low white blood cell counts.
The “Stress” Axis
Though the researchers’ results revealed the powerful effects of A485, the mechanism behind its activity remained a mystery. After many different experiments, Jaschke found that A485 treatment greatly increased levels of corticosterone, the mouse corollary to human cortisol. Thus, he reasoned, A485 must work through the hypothalamic-pituitary-adrenal axis, or “stress” axis. The hypothalamic-pituitary-adrenalaxis is a set of endocrine pathways associated with the production and circulation of various stress hormones, including cortisol. But Jaschke found something unexpected—A485 activity did not rely upon corticosterone at all. Instead, intermediary molecules like adrenocorticotropic hormone (ACTH) helped facilitate the effects of A485. Based on these findings, Jaschke and his team proposed that ACTH must be more than simply an intermediate, opening new doors of research into additional functions of ACTH.
Jaschke had begun his work on A485 in Germany, performing the bulk of the research there. Upon joining the Wang lab at Yale, Jaschke was able to complete his infection models and fully address his hypothesis. “There were a lot of things that could not be done in Germany; a lot of the conceptual framework was substantially rejiggered. It became a very different story in [Jaschke’s] time here,” said Andrew Wang, the principal investigator of the lab and an associate professor of internal medicine at the Yale School of Medicine.
The Wang lab focuses on how a patient’s state of mind affects how they manifest disease and respond to treatments. A big mystery for Wang and his lab is why white blood cells are released upon feelings of stress—there is no tissue damage or infection, so what are the white cells being mobilized for? While this big question remains largely unanswered, Jaschke’s work revealed a direct correlation between white blood cells and the stress pathways of our body. He showed that white blood cells rely upon an aspect of the stress axis to be released and mobilized against the disease.
A New Immune Drug?
Jaschke considered his findings curious but also warned the public against jumping to any conclusions. “This is an interesting observation, but it doesn’t mean that this has any therapeutic relevance for humans,” Jaschke said. He emphasized the need for extensive further testing before any clinical treatments could be made with A485, especially given the limitations of his research. For instance, the study exclusively used L. monocytogenes for infection models; the results of this one infection model cannot automatically be generalized to the whole range of harmful human infections. Also, the researchers knew the precise disease type and its time of onset in the mice, which is rarely the case in real-world clinical practice.
Ambitions of A485 entering the clinical scene as a drug to recruit white blood cells to fight disease remain. But Jaschke knows that the next steps are largely out of his hands. “For me personally, I’ve done the work I wanted to do. […] If there is an interest from a larger scale to really screen it in the clinics, it would be great,” Jaschke said. The next crucial step for A485 is to become an approved drug in clinical trials, beginning with more mouse models and eventually evaluations for safety in humans. If successful, patients battling infection with an injured bone marrow could look to A485 for hope.