XOMA 052, a potent, high-affinity monoclonal antibody for the treatment of IL-1β-mediated diseases

• Published in: mAbs Vol. 3; no. 1; pp. 49 - 60
• Main Authors: Owyang, Alexander M., Issafras, Hassan, Corbin, John, Ahluwalia, Kiran, Larsen, Paul, Pongo, Elizabeth, Handa, Masahisa, Horwitz, Arnold H., Roell, Marina K., Haak-Frendscho, Mary, Masat, Linda
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2011; Landes Bioscience
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antibody Affinity - immunology; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Line; Cross Reactions - immunology; Cycle; Dose-Response Relationship, Drug; Epitopes - chemistry; Epitopes - immunology; Epitopes - metabolism; Fibroblasts - drug effects; Fibroblasts - immunology; Fibroblasts - metabolism; Humans; Inflammation - blood; Inflammation - immunology; Inflammation - prevention & control; Interleukin-1beta - immunology; Interleukin-1beta - pharmacology; Interleukin-6 - immunology; Interleukin-6 - metabolism; Kinetics; Landes; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Sequence Data; Organogenesis; Protein Binding - immunology; Protein Structure, Tertiary; Proteins; Rats; Sequence Homology, Amino Acid
• ISSN: 1942-0862; 1942-0870
• DOI: 10.4161/mabs.3.1.13989

Interleukin-1β (IL-1β) is a potent mediator of inflammatory responses and plays a role in the differentiation of a number of lymphoid cells. In several inflammatory and autoimmune diseases, serum levels of IL-1β are elevated and correlate with disease development and severity. The central role of the IL-1 pathway in several diseases has been validated by inhibitors currently in clinical development or approved by the FDA. However, the need to effectively modulate IL-1β-mediated local inflammation with the systemic delivery of an efficacious, safe and convenient drug still exists. To meet these challenges, we developed XOMA 052 (gevokizumab), a potent anti-IL-1β neutralizing antibody that was designed in silico and humanized using Human Engineering™ technology. XOMA 052 has a 300 femtomolar binding affinity for human IL-1β and an in vitro potency in the low picomolar range. XOMA 052 binds to a unique IL-1β epitope where residues critical for binding have been identified. We have previously reported that XOMA 052 is efficacious in vivo in a diet-induced obesity mouse model thought to be driven by low levels of chronic inflammation. We report here that XOMA 052 also reduces acute inflammation in vivo, neutralizing the effect of exogenously administered human IL-1β and blocking peritonitis in a mouse model of acute gout. Based on its high potency, novel mechanism of action, long half-life, and high affinity, XOMA 052 provides a new strategy for the treatment of a number of inflammatory, autoimmune and metabolic diseases in which the role of IL-1β is central to pathogenesis.