A novel class of anti-IL-12p40 antibodies Potent neutralization via inhibition of IL-12-IL-12Rβ2 and IL-23-IL-23R

• Published in: mAbs Vol. 2; no. 5; pp. 539 - 549
• Main Authors: Clarke, Adam W., Poulton, Lynn, Wai, Hoi Yi, Walker, Stuart A., Victor, Shanti David, Domagala, Teresa, Mraovic, Dragana, Butt, Danyal, Shewmaker, Nina, Jennings, Phil A., Doyle, Anthony G.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.09.2010; Landes Bioscience
• Subjects: Animals; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - immunology; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Line; Cells, Cultured; Cycle; Enzyme-Linked Immunosorbent Assay; HEK293 Cells; Humans; Hybridomas; Interferon-gamma - blood; Interferon-gamma - metabolism; Interleukin-12 - immunology; Interleukin-12 - metabolism; Interleukin-12 Subunit p40 - immunology; Interleukin-12 Subunit p40 - metabolism; Interleukin-23 - immunology; Interleukin-23 - metabolism; Jurkat Cells; Landes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mutation; Organogenesis; Protein Binding - immunology; Proteins; Receptors, Interleukin - immunology; Receptors, Interleukin - metabolism; Receptors, Interleukin-12 - immunology; Receptors, Interleukin-12 - metabolism; Recombinant Proteins - immunology; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Signal Transduction - immunology; Skin - drug effects; Skin - immunology; Skin - pathology
• ISSN: 1942-0862; 1942-0870
• DOI: 10.4161/mabs.2.5.13081

While current therapeutic antibodies bind to IL-12 and IL-23 and inhibit their binding to IL-12Rβ1, we describe a novel antibody, termed 6F6, that binds to IL-12 and IL-23 and inhibits the interaction of IL-12 and IL-23 with their cognate signalling receptors IL-12Rβ2 and IL23R. This antibody does not affect the natural inhibition of the IL-12/23 pathway by the antagonists monomeric IL-12p40 and IL-12p80, which suggests that a dual antagonist system is possible. We have mapped the epitope of 6F6 to domain 3 of the p40 chain common to IL-12 and IL-23 and demonstrate that an antibody bound to this epitope is sufficient to inhibit engagement of the signalling receptors. Antibodies with this unique mechanism of inhibition are potent inhibitors of IL-12 induced IFN-γ production and IL-23 induced IL-17 production in vitro, and in an in vivo model of psoriasis, treatment with a humanized variant of this antibody, h6F6, reduced the inflammatory response, resulting in decreased epidermal hyperplasia. We believe that this new class of IL-12/23 neutralising antibodies has the potential to provide improved potency and efficacy as anti-inflammatory agents, particularly in diseases characterized by an overproduction of IL-12.