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Research ArticleCellular and Molecular

Detailed Mechanistic Analysis of Gevokizumab, an Allosteric Anti–IL-1β Antibody with Differential Receptor-Modulating Properties

Hassan Issafras, John A. Corbin, Ira D. Goldfine and Marina K. Roell
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 202-215; DOI: https://doi.org/10.1124/jpet.113.205443
Hassan Issafras
XOMA Corporation, Preclinical Department, Berkeley, California
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John A. Corbin
XOMA Corporation, Preclinical Department, Berkeley, California
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Ira D. Goldfine
XOMA Corporation, Preclinical Department, Berkeley, California
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Marina K. Roell
XOMA Corporation, Preclinical Department, Berkeley, California
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Abstract

Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti–IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β–associated autoinflammatory diseases.

Footnotes

    • Received April 17, 2013.
    • Accepted November 4, 2013.
  • dx.doi.org/10.1124/jpet.113.205443.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleCellular and Molecular

Gevokizumab, an Allosteric Anti–IL-1β-Modulating Antibody

Hassan Issafras, John A. Corbin, Ira D. Goldfine and Marina K. Roell
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 202-215; DOI: https://doi.org/10.1124/jpet.113.205443

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Research ArticleCellular and Molecular

Gevokizumab, an Allosteric Anti–IL-1β-Modulating Antibody

Hassan Issafras, John A. Corbin, Ira D. Goldfine and Marina K. Roell
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 202-215; DOI: https://doi.org/10.1124/jpet.113.205443
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