Origins of new autoimmune treatments found in Balthasar lab

How could giving patients with autoimmune diseases more antibodies be beneficial? That was a question Joseph Balthasar found himself asking while attending a seminar as a UB doctoral student in 1993.

Perplexed by the lack of information about this phenomenon, Balthasar dedicated the early years of his career to finding an answer. Little did he know, the investigative journey would lead to the establishment of a new field through a groundbreaking discovery: that high doses of immunoglobulin G antibodies increase the elimination of disease-causing antibodies by inhibiting an antibody transporter, the neonatal Fc receptor (FcRn).

Now a UB pharmacy professor, Balthasar and his team were the first researchers to demonstrate that administration of high doses of immunoglobulin G, an antibody, increases the elimination of pathogenic antibodies that cause autoimmune disease by overtaxing FcRn. He also received the first grant from the National Institutes of Health (NIH) to develop FcRn inhibitors, published the first demonstration that specific anti-FcRn inhibitors increase antibody elimination, and received the nation’s first patent for specific anti-FcRn drugs to treat autoimmune diseases.

In December 2021 — nearly two decades after Balthasar’s initial findings — the U.S. Food and Drug Administration approved Vyvgart, marking the first time an FcRn inhibitor was authorized for medical use. The medication, which is prescribed to treat myasthenia gravis, an autoimmune disease that causes muscle weakness, was approved for use in the European Union in August.

And the promising drug at the heart of Johnson & Johnson’s $6.5 billion acquisition of Momenta Pharmaceuticals is nipocalimab, an FcRn inhibitor that may be used to treat a range of autoimmune diseases, from rheumatoid arthritis to lupus. Nipocalimab is expected to be approved by the FDA within the next few years, says Balthasar, noting that Momenta Pharmaceuticals licensed his patent from UB to support their work.

“It may be argued that our basic science research, performed here at UB, has led directly to the development of a new class of treatments for autoimmunity,” says Balthasar, David and Jane Chu Endowed Chair in Drug Discovery and Development in the School of Pharmacy and Pharmaceutical Sciences. “These advancements are a great example of the downstream benefit of basic science research that is pursued within a university.”

More than 70 years ago, scientist F.W. Rogers Brambell made a counterintuitive discovery: the higher the concentration of antibodies in the body, the faster they are eliminated. Although Brambell was unsure of the underlying mechanisms, he hypothesized that the body had a system for protecting antibodies from elimination, Balthasar says.

Brambell’s hypothesis was further solidified in the 1980s after a chance finding by clinician Paul Imbach, who noticed that high doses of intravenous immunoglobulin (IVIG) improved the condition of patients with autoimmune disease. The treatment soon became standard practice despite immunologists having little understanding of how it worked.

The unknown mechanisms behind how IVIG worked is what most intrigued Balthasar when he learned about this therapy at a seminar. A doctoral student in the UB Department of Pharmaceutical Sciences interested in antibody therapies, he made uncovering the mechanisms of IVIG action the subject of an assignment for which he was required to prepare a research proposal in the form of an NIH grant. Although Balthasar never submitted the proposal as a student, he revisited the subject as a UB faculty member.

“Shortly after I started my own lab as an assistant professor, the National Institutes of Health issued a request for proposals (RFP) to investigate mechanisms of IVIG action. The RFP was entirely consistent with the research proposal that I developed as a student at UB,” says Balthasar. “I was able to dust off and update my proposal, and with the help of Dr. Victor Yang from the University of Michigan, who agreed to serve as a co-investigator on the project, I was able to receive an NIH grant to test IVIG mechanisms systematically using pharmacokinetic and pharmacodynamic analyses.”

His lab was the first to demonstrate in animals that FcRn saturation was the secret to the effects of IVIG in increasing the elimination of pathogenic antibodies. FcRn binds to immunoglobulin G to transport and protect the antibody from elimination. Since there is only a limited amount of FcRn available in the body, the protein can only guard a finite number of antibodies. When the body is flooded with IVIG, FcRn binds to what it can while the rest of the antibodies are eliminated. In patients with autoimmune disease, high doses of IVIG are beneficial because pathogenic antibodies are often eliminated as well.

The articles detailing the findings, published in Blood and in Thrombosis and Haemostasis, were among the journals’ most highly downloaded and cited papers during the months following their publication, Balthasar notes.

The groundwork laid during his assignment as a student would later help him receive a second NIH grant to investigate development of FcRn inhibitors — the first NIH award issued to develop specific anti-FcRn antibodies to treat autoimmune disease. The inhibitors block FcRn from binding with pathogenic antibodies, achieving the same effect as IVIG therapy in much smaller quantities, Balthasar explains. IVIG is extracted from blood plasma given by donors. Since massive amounts of IVIG are required to treat autoimmune disease, treatments are dependent on both the number and health of donors, he says, making specific FcRn inhibitors a more efficient therapy. The inhibitors may be effective at treating any autoimmune disease associated with immunoglobulin G, he says.

Key investigators who collaborated on the development of FcRn inhibitors include UB alumni Ryan Hansen, executive director at Eli Lilly and Company, and Feng Jin, founder and chief executive officer of Polaris Consulting. Along with Balthasar, both are co-inventors on the first U.S. patent for the development and use of specific FcRn inhibitors as a treatment for autoimmune disease. Other researchers include UB research technician Maureen Adolf and UB alumni Rong Deng and Tommy Li.

Since filing the patent, Balthasar has shifted his focus to investigating novel methods of using antibodies to fight cancer, allowing companies to continue to research and develop FcRn inhibitors for the market.

“For faculty members, when you create a patent, you have two options: start a company or license the patent to others,” says Balthasar. “At the time of our FcRn work, I was a young faculty member and I felt that it was important to devote all of my time and efforts to become established as a teacher, mentor and researcher. I did not feel that I was ready to take on the challenges of being an entrepreneur.”

Now, after 20 years of researching antibody therapies and growth as a scientist and educator, Balthasar believes that, at this point in his career, he has the bandwidth necessary to take a more active role in commercializing technologies developed in his lab.

Balthasar and his group are currently developing a new adjuvant technology that enables improved distribution of anti-cancer antibodies within solid tumors, increasing their efficacy. Balthasar is licensing the technology to the Empire Discovery Institute (EDI), a nonprofit drug discovery and development accelerator that is a joint venture between UB, Roswell Park Comprehensive Cancer Center and the University of Rochester. With support from EDI, Balthasar and his group are building this new technology with the goal of bringing their new strategy to cancer patients.

Balthasar has also formed the startup Abceutics Inc. to pursue development of payload-binding selectivity enhancers (PBSEs), a class of drugs created in his lab that may prevent the entry of anti-cancer drug molecules into non-cancer cells. The PBSEs mop up excess anti-cancer molecules, helping to prevent highly toxic cancer treatments from harming healthy cells. By decreasing undesired toxicity, PBSEs allow increased dosing of the anti-cancer therapy and improve anti-cancer efficacy.