EASD: XOMA Presents Novel Mechanism of Action for XOMA 052 in Regulating IL-1 Beta Levels

XOMA, a leader in the discovery and development of therapeutic antibodies, announced new data demonstrating the unique regulatory mechanism of action of XOMA 052, a potent antibody drug candidate that inhibits the inflammatory cytokine interleukin-1 beta (IL-1 beta). XOMA 052 is currently under study for the treatment of patients with Type 2 diabetes, cardiovascular and other diseases.

“XOMA 052 is the first example of using an antibody to regulate, or fine-tune, a physiological pathway by altering a cytokine’s affinity for its receptor, rather than by completely blocking signaling,” noted Stephen Doberstein, Ph.D., Vice President of Research for XOMA. “Using XOMA’s state-of-the-art antibody discovery and engineering technologies, we are able to create sophisticated antibodies to regulate the activities of a wide range of therapeutic targets. This is a major advance in the field of antibody discovery and development.”

Unlike traditional antibodies that completely block all contact between target and receptor, XOMA 052 regulates IL-1 beta signaling, allowing the maintenance of beneficial low levels of signaling while reducing pathologically high levels that cause disease. XOMA 052 acts by reducing the affinity of IL-1 beta for its signaling receptor, while having no effect on the decoy receptors that clear excess IL-1 beta from the body. This regulatory mechanism of action for XOMA 052 may confer advantages for the drug in the treatment of IL-1 beta implicated diseases, such as Type 2 diabetes and cardiovascular disease, compared to antibodies that completely block the IL-1 beta pathway.

While excess IL-1 beta secretion is known to cause inflammation and disease, IL-1 beta also has beneficial effects. Low levels of IL-1 beta act as a stimulatory, growth and survival factor for the pancreatic beta cells that are responsible for insulin secretion. High levels of IL-1 beta secretion lead to insulin resistance and a loss of healthy beta cell function and mass, which contributes to the pathology of Type 2 diabetes. An optimal therapy would reduce high levels of IL-1 beta activity to lower, beneficial levels. In addition, IL-1 beta has an important role in infection resistance, and clinical results to date with XOMA 052 suggest that this role may be unaffected by XOMA 052 treatment.

XOMA 052 is a potent monoclonal antibody with the potential to improve the treatment of patients with a wide variety of inflammatory diseases. XOMA 052 binds strongly to IL-1 beta, a pro-inflammatory cytokine involved in the development of Type 2 diabetes, cardiovascular disease, rheumatoid arthritis, gout and other diseases. By binding to IL-1 beta, XOMA 052 inhibits the activation of the IL-1 receptor, thereby preventing the cellular signaling events that produce inflammation. XOMA 052 has a half-life of 22 days. Based on its binding properties, specificity to IL-1 beta and half-life, XOMA 052 may provide convenient dosing of once per month or less frequently. Phase 1 clinical trials with XOMA 052 are complete. XOMA 052 was well tolerated in these trials and demonstrated evidence of biological activities in diabetic and cardiovascular outcomes.

The results were reported at the European Association for the Study of Diabetes medical conference in Vienna, Oct. 1, 2009. A more detailed summary of the research presented at EASD has been submitted for publication in a peer-reviewed journal.