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Innovative Research Revolutionizes Antibody Generation for Complex Proteins
The Food and Drug Administration has sanctioned over 100 monoclonal antibodies aimed at treating a variety of medical conditions. Additionally, some antibodies serve diagnostic purposes for physicians or facilitate advancements in scientific research.
Despite the significant growth in the global market for antibodies utilized in both clinical and research settings, experts acknowledge that there remains a substantial opportunity to discover new antibodies. Biological functions are often carried out by protein complexes, which consist of multiple proteins that work together. However, the traditional approach for antibody generation, which typically involves immunizing animals, has encountered challenges when it comes to these protein complexes.
This conventional method often falls short due to the inherent instability of protein complexes during the immunization process, which disrupts the ability of immune cells to generate the requisite antibodies.
A recent study conducted by scientists from Sanford Burnham Prebys and Eli Lilly and Company, published on March 5, 2025, in the Journal of Immunology, presents a promising advancement in addressing this issue. The researchers found that by fusing protein complexes together, they could enhance stability during immunization, thereby facilitating the generation of effective antibodies.
The investigation centered on two proteins, B and T lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM), known to appear on immune cell surfaces. These proteins interact to form a complex that modulates the intensity of immune responses. The study highlights that the relative amounts of these individual proteins versus their combined complex may influence diseases like lupus, although measuring these mixtures has proven difficult.
To overcome this challenge, the researchers developed a fusion protein derived from the BTLA-HVEM complex. This increased stability allowed the team to generate monoclonal antibodies successfully. They identified the specific antibody that effectively binds to the fusion protein and used it to measure the levels of both the individual proteins and their combined complex across various immune cells.
“Our study marks the first instance of such direct measurement on live cells using a complex-specific monoclonal antibody,” remarked Carl Ware, PhD, a professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. “These results could advance the diagnosis and monitoring of conditions like lupus and certain cancers such as lymphoma, which are frequently associated with mutations in HVEM.”
“Moreover, this innovative method of generating monoclonal antibodies through fusion proteins may pave the way for exploring other protein complexes related to various diseases, potentially opening avenues for new therapeutic options,” he added.
Shane Atwell, PhD, senior director of biologics research at Neurocrine Biosciences and a participant in this study, emphasizes the collaborative effort that the research required. He shares the lead authorship with Tim Cheung, PhD, a research associate professor in Ware’s lab at Sanford Burnham Prebys.
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