title: Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity.
abstract: Many therapeutic antibodies act as antagonists to competitively block cellular signaling pathways. We describe here an approach for the therapeutic use of monoclonal antibodies based on context-dependent attenuation to reduce pathologically high activity while allowing homeostatic signaling in biologically important pathways. Such attenuation is achieved by modulating the kinetics of a ligand binding to its various receptors and regulatory proteins rather than by complete blockade of signaling pathways. The anti-interleukin-1beta (IL-1beta) antibody XOMA 052 is a potent inhibitor of IL-1beta activity that reduces the affinity of IL-1beta for its signaling receptor and co-receptor but not for its decoy and soluble inhibitory receptors. This mechanism shifts the effective dose response of the cytokine so that the potency of IL-1beta bound by XOMA 052 is 20-100-fold lower than that of IL-1beta in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1beta while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1beta activity in concert with endogenous regulatory mechanisms. Furthermore, the ability to bind the decoy receptor may reduce the potential for accumulation of antibody.target complexes. Regulatory antibodies like XOMA 052, which selectively modulate signaling pathways, may represent a new mechanistic class of therapeutic antibodies.
authors.affiliation: Preclinical Research Department, XOMA (US) LLC, Berkeley, CA 94710, USA. roell@xoma.com
authors.forename: Marina K
authors.initials: MK
authors.lastname: Roell
authors.forename: Hassan
authors.initials: H
authors.lastname: Issafras
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bauer
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Michelson
authors.forename: Nerissa
authors.initials: N
authors.lastname: Mendoza
authors.forename: Sandra I
authors.initials: SI
authors.lastname: Vanegas
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Gross
authors.forename: Paul D
authors.initials: PD
authors.lastname: Larsen
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Bedinger
authors.forename: David J
authors.initials: DJ
authors.lastname: Bohmann
authors.forename: Genevieve H
authors.initials: GH
authors.lastname: Nonet
authors.forename: Naichi
authors.initials: N
authors.lastname: Liu
authors.forename: Steve R
authors.initials: SR
authors.lastname: Lee
authors.forename: Masahisa
authors.initials: M
authors.lastname: Handa
authors.forename: Seema S
authors.initials: SS
authors.lastname: Kantak
authors.forename: Arnold H
authors.initials: AH
authors.lastname: Horwitz
authors.forename: John J
authors.initials: JJ
authors.lastname: Hunter
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Owyang
authors.forename: Amer M
authors.initials: AM
authors.lastname: Mirza
authors.forename: John A
authors.initials: JA
authors.lastname: Corbin
authors.forename: Mark L
authors.initials: ML
authors.lastname: White
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D057005:Bioengineering; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006367:HeLa Cells / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D053583:Interleukin-1beta / Q000187:drug effects / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008024:Ligands; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007375:Interleukin-1; D053583:Interleukin-1beta; D008024:Ligands; D016328:NF-kappa B; D010750:Phosphoproteins; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D008156:Luciferases; C547697:gevokizumab
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