More Potent IVIG Developed to Treat Autoimmunity

Scientists from Rockefeller University’s Leonard Wagner Laboratory of Molecular Genetics and Immunology have used their discovery of previously unknown mechanisms in an anti-inflammatory pathway to develop a powerful engineered antibody that delivers the effectiveness of intravenous immune globulin (IVIG) at a fraction of the dose in mice, and can be synthesized without the need for human plasma. 

The discovery builds upon earlier research that led to the development of a molecule 10 times more potent than IVIG in suppressing autoimmune inflammation, which is currently in Phase II clinical trials. The earlier research, which began about 25 years ago, studied the anti-inflammatory properties of IVIG and discovered that a small fraction of serum IgGs present in IVIG possessed a naturally occurring modification: a sugar modification called sialylation, which conferred its anti-inflammatory properties. Subsequent studies identified two additional components that were required to trigger an anti-inflammatory response by IVIG: an inhibitory Fc receptor called FcγRIIB and a lectin (a carbohydrate-binding protein) called DC-SIGN. The earlier work had also been done studying IVIG activity in mice with their own native Fc receptors — not human ones. Since then, the researchers have developed mice that express human Fc receptors.

In the new study, the researchers sought to understand how these components come together to mediate IVIG activity by conducting many in vitro experiments testing a variety of scenarios of activation and interaction. “We discovered that the type 1 FcγRIIB receptor and the type 2 DC-SIGN co-receptor are actually binding to each other on the cell surface, and that seems to be important for the anti-inflammatory effect of IgG,” said Andrew Jones, PhD, a research associate in the lab. “This was a novel configuration we hadn’t seen before. We think that when they bind, they enhance the ability of the sialylated IgG antibody to trigger the anti-inflammatory signaling cascade.”

They next engineered a recombinantly expressed IgG to have enhanced binding to these receptors and infused them into mice with human Fc receptors into which they had induced arthritis (meaning they’d been injected with serum isolated from a mouse with naturally occurring arthritis). A similar group of arthritic mice was treated with the conventional IVIG infusion. Both groups benefited from the infusion, seeing reduced joint swelling. But the doses were dramatically different: 100 times as much IVIG was required to achieve the same effect as one dose of the new molecule.

A second test run used a mouse model stand-in for multiple sclerosis, an autoimmune disease that causes both cognitive and mobility deterioration. The molecule protected mice from neuro-inflammation by preventing cell destruction, and did so at the same small dose.

Next, the lab will look into the structure and molecular dynamics of the type 1 and type 2 receptors. They’ve identified many over the years, but how they pair up and what their functions are remain to be discovered. They’ll also pursue clinical potential. “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,” said Dr. Ravetch. “I hope they do. We want to see it get into patients.”