Breakthrough in Autoimmune Treatment: Engineered Antibody Offers Potent Alternative to IVIG
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A new engineered antibody promises a significant upgrade to current treatment for autoimmune diseases, potentially overcoming the limitations of intravenous immunoglobulin (IVIG) therapy. Researchers at Rockefeller University have developed a molecule that delivers the effectiveness of IVIG at a fraction of the dose in mice, and crucially, can be manufactured without relying on scarce human plasma donations.
IVIG therapy, involving infusions of naturally occurring IgG antibodies, has been a mainstay for treating autoimmune conditions since the 1950s. Currently FDA-approved for four diseases, it’s frequently used “off-label” for over 80 others, often representing the only effective treatment option. However, the therapy is plagued by drawbacks: lengthy, high-volume infusions, exorbitant costs, and persistent supply shortages due to its reliance on donated human plasma.
The research, published in Science on February 7, 2025, details a novel approach to enhancing the anti-inflammatory properties of IgG antibodies. “We discovered that by enhancing the binding of a certain pair of receptors we can significantly lower the dose yet have an equal effect,” explained a research associate involved in the study.
Decades of Research Culminate in a Powerful Advance
The breakthrough builds upon 40 years of investigation into Fc receptors – proteins on immune cells that bind antibodies to coordinate immune responses – led by Jeffrey Ravetch at Rockefeller University’s Leonard Wagner Laboratory of Molecular Genetics and Immunology. The team’s earlier work had already yielded a molecule ten times more potent than IVIG, currently undergoing phase 2 clinical trials through the biotech company Nuvig, co-founded by Ravetch. This latest discovery dramatically improves upon that earlier success.
The foundation for this progress was laid 25 years ago with the discovery that a specific sugar modification, called sialylation, present in a small fraction of serum IgGs within IVIG, conferred its anti-inflammatory properties. Subsequent research identified two additional key components: an inhibitory Fc receptor, FcγRIIB, and a carbohydrate-binding protein called DC-SIGN. These insights led to the development of NVG-2089, the molecule currently in phase 2 trials.
“Those were the pieces that we had figured out,” Ravetch stated. “The question was, how do these three components come together to mediate the anti-inflammatory activity? That’s the work we undertook for the current study.”
Unlocking the Mechanism: Receptor Collaboration
To understand the interplay between these components, researchers developed mice expressing human Fc receptors – a crucial step, as previous studies used mice with native receptors. Through extensive in vitro experiments, they discovered that the type 1 FcγRIIB receptor and the type 2 DC-SIGN co-receptor physically bind to each other on the cell surface.
“This was a novel configuration we hadn’t seen before,” said a researcher. “We think that when they bind, they enhance the ability of the sialylated IgG antibody to trigger the anti-inflammatory signaling cascade.”
The team then engineered a recombinantly expressed IgG antibody to enhance its binding to these receptors. When tested in mice with induced arthritis, the new molecule proved remarkably effective.
Dramatic Dose Reduction and Broad Potential
The results were striking. The engineered antibody achieved the same reduction in joint swelling as conventional IVIG, but at 100 times lower dose. “This is a really substantial difference,” Ravetch emphasized. “For one, this new molecule is a recombinant protein that we can produce in vitro, so it does not need to come from human plasma. That’s an enormous advantage.”
The implications extend beyond simply addressing supply issues. The increased potency could allow for effective treatment of autoimmune diseases currently untreatable with IVIG due to dosage limitations. A second test, utilizing a mouse model of multiple sclerosis, demonstrated the molecule’s ability to protect against neuro-inflammation and prevent cell destruction, again at the same low dose.
Looking ahead, the researchers plan to further investigate the structure and molecular dynamics of the type 1 and type 2 receptors to better understand their function in various biological pathways. “What we have discovered opens the door to exploring how they might function in different biological pathways,” explained a researcher.
The molecule has been optioned to Nuvig for further testing and potential clinical development. “As of now, we’ve optioned the molecule to Nuvig, and they’ll test further to determine if they want to pursue it as a clinical product,” Ravetch said. “I hope they do. We want to see it get into patients.”
Source: Jones, A. T., et al. (2025). The anti-inflammatory activity of IgG is enhanced by co-engagement of type I and II Fc receptors. Science. doi: 10.1126/science.adv2927. https://www.science.org/doi/10.1126/science.adv2927
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