Grant Recipient Asking the “Whys” of Factor VIII Antibody Development

Patricia Zerra, MD, acknowledges that for many of the milestones in her career, timing has played a role. That is especially true of the AABB Foundation Early-Career Scientific Research Grant that she received in 2023 for her project titled, “Mechanisms Underlying factor VIII-specific CD4 T Cell Activation in Mice with Hemophilia A."

“When I received this grant, it really allowed me to focus in on new and exciting studies,” explained Zerra, assistant professor, pathology/laboratory medicine and pediatrics, at Emory University School of Medicine. “I knew I had some great data and wanted to write a R01, but this grant allowed me to have an extra year to really crank out the data needed to support that application.”

Zerra specializes in two separate but overlapping fields: pediatric hematology/oncology and transfusion medicine. She currently splits her time about 80/20 between lab research and clinical care.

In her clinical work, Zerra became intrigued by the fact that between 20% and 30% percent of patients with hemophilia A develop antibodies against factor VIII replacement products.

“This is similar to red blood cell alloimmunization, where about 30% of patients who are chronically transfused develop antibodies against red blood cell antigens,” Zerra said. “The idea came from caring for these patients. Parents asked, ‘Why did this happen to our child?’ and we don’t really know what makes one child develop antibodies and spares another child from this complication. Understanding this process can help us predict and then prevent antibody development.”

Timing struck again when one of Zerra’s mentors moved institutions during the COVID-19 pandemic. This left Zerra “trying to just survive and make the science work.” She soon received a National Heart, Lung, and Blood Institute (NHLBI) Mentored Clinical Scientist Research Career Development Award (K08) that allowed her to gain protected research time, but it did not provide the type of financial support to run her own lab and move her research interests forward.

“The AABB Foundation grant came at the perfect time: right when I was a few years into my K08 award, and I was starting to prepare for the R01,” Zerra said.

With the Foundation grant, Zerra began the work of using mouse models to define the basic immunology that occurs after someone is exposed to factor VIII replacement products.

“A few years back, we had described a special population of B cells, called marginal zone B cells, that were responsible for initiating the antibody response to factor VIII,” Zerra said. “Our goal was to figure out how those B cells were being activated and really examine all of the immune events happening right when patients are first exposed to factor VIII.”

As with all science, the research has had its ups and downs, Zerra said, but her team has made “a lot of good progress.”

“Factor VIII inhibitors are IgG antibodies, but before you get IgG antibodies you first develop IgM,” Zerra explained. “We have been focused on how IgM is leading to IgG formation and described that IgM is activating CD4 T cells.” Once that happens, she said, you’re well on your way to inhibitor development.

In theory, she said, preventing initial IgM formation could prevent progression of the immune response to IgG. Zerra and her colleagues have been able to isolate very early IgM in mice with hemophilia and are using different knockout mouse models to figure out how these antibodies are activating immune pathways. The ultimate goal is to develop approaches to prophylactically predict and prevent inhibitor development.

Because of the Foundation grant, Zerra now runs a fully independent lab with a seven-person team.

“This grant helped me go from being a junior researcher in my mentor’s lab to running my own lab,” Zerra said. “That wasn’t even my initial career plan; I thought I would always focus only on taking care of patients. But being a physician-scientist allows me not only to take care of kids, but to work toward improving the way that we take care of them.”

In addition, Zerra admits that prior to receiving the grant, she was not very familiar or involved with AABB.

“After receiving this grant, I attended my first AABB Annual Meeting and was able to meet a whole group of new mentors and collaborators I wouldn’t have otherwise met,” Zerra said. “AABB was a new home that I discovered because of this grant.”

Based on the work produced from the Foundation grant, Zerra filed an R01 application seeking to research the different sugar structures—or glycans—that decorate factor VIII products, and how those glycans may affect the activation of B cells and production of IgM. However, the current pause in much of the National Institutes of Health funding means that timing is again having an impact on Zerra’s work. The status of this application is currently still pending.

---

*To support the mission of the AABB Foundation and learn more about the Early-Career Scientific Research Grants program, visit aabb.org/foundation/early-career-scientific-research-grants-program.

 

 

Registration Opens for AABB Foundation's
World Blood Donor Day Virtual Run and Walk

Members and supporters of the blood and biotherapies community can register now to participate in the AABB Foundation’s virtual walk for World Blood Donor Day.

Each year, World Blood Donor Day is celebrated on June 14 to thank all those who make life-saving gifts of blood and raise awareness of the need for safe blood and blood products. The AABB Foundation invites members of the blood and biotherapies community to walk, run, roll or pedal a 1-mile or 5K distance anytime May 14 through June 14.

All proceeds will benefit the AABB Foundation’s efforts to fund scientific research that advances treatments and care for patients and donors around the world. Registration is available for both individuals and teams.

The AABB Foundation also encourages participants to share photos of their involvement in the virtual race on AABB’s Facebook, X (Twitter), LinkedIn, and Instagram. Photos can also be emailed directly to the AABB Foundation.

---

Thank You to Our Sponsors