A novel class of anti-IL-12p40 antibodies: potent neutralization via inhibition of IL-12-IL-12Rβ2 and IL-23-IL-23R.
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.
Clarke
Adam W
AW
Cephalon Australia Pty. Ltd., North Ryde, NSW, Australia. aclarke@cephalon.com
Poulton
Lynn
L
Wai
Hoi Yi
HY
Walker
Stuart A
SA
Victor
Shanti David
SD
Domagala
Teresa
T
Mraovic
Dragana
D
Butt
Danyal
D
Shewmaker
Nina
N
Jennings
Philip
P
Doyle
Anthony G
AG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D006825:Hybridomas; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000276:immunology* / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D011485:Protein Binding / Q000276:immunology; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma