Engineering clearing agents to eliminate specific antibodies

Engineering clearing agents to eliminate specific antibodies

When these molecules start doing more harm than good, we need a way to degrade them
June 20, 2017

Through their ability to specifically bind to targets, or antigens, antibodies are usually in the body to help fight off invading pathogens that cause infection. They can also be delivered into the body for medical purposes, such as for targeting cancer, infectious disease and autoimmune disorders. Another application area is their use, in labeled form, in diagnostic imaging to detect tumors.

However, sometimes antibodies go awry and need to be cleared out of the body. That’s why E. Sally Ward, PhD, a professor in both the Department of Molecular and Cellular Medicine and the Department of Microbial Pathogenesis and Immunology at the Texas A&M College of Medicine, and her team developed a new class of agents that cause the selective clearance of antibodies that bind to particular antigens. They’ve named these agents Seldegs, for ‘selective degradation of antigen-specific antibodies,’ because these agents do not affect antibodies that recognize other antigens. Their findings were published recently in the journal Nature Communications.

“What excites me is that Seldegs are able to clear their targeted antibodies rapidly from the body,” said Siva Charan Devanaboyina, PhD, a postdoctoral fellow in Ward’s lab and the first author of the paper. For example, Seldegs may be useful in autoimmune diseases to clear antigen-specific antibodies, particularly in cases where the disease-causing antibodies recognize a relatively small number of antigens.

Seldegs also have the potential to clear out radioactive antibodies that are not bound to the tumor during diagnostic imaging, which will improve the image quality using positron emission tomography (PET) scans and help with tumor detection. Ward received $887,134 last year from the Cancer Prevention and Research Institute of Texas (CPRIT) to support work related to this application. Essentially, what happens with PET scans is that a patient is dosed with radioactive antibodies to help highlight the tumor locations, but once the antibodies have bound to the tumor, the residual antibodies in the blood and tissues need to be removed so that they don’t cause background “noise” that can hide the tumors.

Seldegs are antibody-based agents that work by binding very tightly to a particular receptor called FcRn. They also contain antigen molecules so that they bind to antigen-specific antibodies. Their tight binding to FcRn allows them to transport the antigen-specific antibodies into a part of the cell called the lysosome, which breaks them down. “Seldegs essentially reroute the bound antibodies inside the cells, in an antigen-specific way,” Ward said. “They add another option to existing therapeutics, and their different dynamic behavior broadens the palate of choices.”

Seldegs can be used in relatively low doses because they need to capture only the unwanted, antigen-specific antibodies. They are also designed so that they do not form large immune complexes, reducing the risk of inflammation.

“They’re quite efficacious,” Devanaboyina said. “They perform their function within two hours to clear most of the background, which can be a big benefit for the patient.” For example, instead of having to wait for up to a week between the administration of the antibodies and the diagnostic imaging test, the use of Seldegs is expected to greatly reduce this time window.

“If you can reduce the time between delivery of radiolabeled antibody and imaging, that’s much more attractive from the patient care perspective,” Ward said. “It’s much more convenient.”

The researchers’ next steps are to demonstrate Seldegs’ usefulness in animal models with the longer-term goal of testing them in clinical trials. “This epitomizes the sort of work that we do, which is highly interdisciplinary, involving biologists, engineers and other physical scientists,” Ward said. “To molecularly engineer something, understand the cell biology using advanced microscopy techniques and then test it in whole-body animal models—this is a process that can lead up to being able to test a therapeutic in patients.”

Other contributors to the study include Raimund Ober, PhD, a professor in the Department of Biomedical Engineering and Department of Molecular and Cellular Medicine and with whom Ward runs a joint laboratory, and Priyanka Khare, PhD, and Dilip Challa, PhD, both postdoctoral fellows in the Ward-Ober laboratory in the Department of Molecular and Cellular Medicine.

— Christina Sumners

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