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AB0091 Mathematical modeling of interleukin-6 signaling inhibition: Comparative efficiency of different intervention strategies
  1. D. Young1,
  2. P. Maisonpierre2,
  3. S. Shaw3,
  4. J. Chan2,
  5. K. Kretsos3
  1. 1Theranos Inc., Palo Alto
  2. 2Entelos Holding Corp., Foster City, United States
  3. 3UCB Pharma, Slough, United Kingdom

Abstract

Background A cascade of binding events between IL-6, IL-6R, and gp130 leads to formation of IL-6 signaling complexes in inflammatory conditions.1 Tocilizumab (TCZ), an anti-IL-6R antibody (Ab), inhibits IL-6 signaling by preventing IL-6+IL-6R dimerization (axis 1 intervention).2 Axis 1 intervention can also be achieved with anti-IL-6 Abs. Subsequent assembly steps present alternative strategies for IL-6 signal inhibition, including IL-6-targeted agents that prevent trimer formation (IL-6+IL-6R+gp130; axis 2 intervention) or the formation of the (IL-6+IL-6R+gp130)2 signaling hexamer (axis 3 intervention).

Objectives To investigate the potential impact of a number of prototypical therapeutic strategies for inhibiting formation of the IL-6 signaling complex, using a mathematical modeling system.

Methods We developed a dynamic, mathematical model of IL-6 signaling within a target compartment, with initial steady state IL-6, soluble (s) IL-6R, and sgp130 concentrations. The model encompassed IL-6 interaction with membrane-bound IL-6R (cis) or with both membrane-bound and sIL-6R (cis and trans signaling), including the impact of inhibiting membrane-bound and sgp130 by different targeted strategies. The validity of the model was confirmed by comparison to published PK/PD data for TCZ.3 Four prototypical intervention strategies were modeled: anti-IL-6R, axis 1; anti-IL-6, axis 1; anti-IL-6, axis 2; and anti-IL-6, axis 3. Simulations compared the sensitivity of drug responses to parameter variations at multiple clinically relevant IL-6, sIL-6R, and sgp130 concentration scenarios. All simulated parameters for interactions and responses were based on a one-compartment linear PK model.

Results Anti-IL-6 axis 3 intervention was predicted to be the most efficient inhibitor of combined cis+ trans IL-6 signaling. This advantage held true both when IL-6 concentration was limiting, and under conditions of equimolar IL-6 and IL-6R.4 The advantage of anti-IL-6 axis 3 intervention over anti-IL-6R or anti-IL-6 approaches to axis 1 intervention was robust to changes in single parameters, and was lost only in large excess of IL-6 over IL-6R or when multiple conditions coincided, such as a combination of: excess IL-6; inefficient Ab binding to membrane-bound targets; increased IL-6 turnover or slower IL-6R turnover; slow IL-6+IL-6R dimerization kinetics; and low Ab dissociation constant.

Conclusions Anti-IL-6 intervention at axis 3 may be more efficient at inhibiting IL-6 signaling than axis 1 intervention with an anti-IL-6R Ab, in either serum- or synovial-like conditions. Multiple factors simulating sensitivity of drug responses were required to challenge the advantage of axis 3 intervention.

  1. Boulanger MJ. Science 2003.

  2. Mihara M. Int Immunopharmacol 2005.

  3. Frey N. ACR 2007, Abst #259.

  4. Desgeorges A. J Rheumatol 1997.

Disclosure of Interest None Declared

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