Kinetic Approach to Pathway Attenuation Using XOMA 052, a Regulatory Therapeutic Antibody That Modulates Interleukin-1β 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-1β (IL-1β) antibody XOMA 052 is a potent inhibitor of IL-1β activity that reduces the affinity of IL-1β 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-1β bound by XOMA 052 is 20–100-fold lower than that of IL-1β in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1β while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1β 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. 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-1β (IL-1β) antibody XOMA 052 is a potent inhibitor of IL-1β activity that reduces the affinity of IL-1β 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-1β bound by XOMA 052 is 20–100-fold lower than that of IL-1β in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1β while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1β 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.