April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Anti-Factor D Fab Specifically Inhibits the Alternative Complement Pathway: In vitro Characterization and in vivo Effects Following Administration to Cynomolgus Monkeys
Author Affiliations & Notes
  • K. M. Loyet
    Research,
    Genentech, South San Francisco, California
  • J. Good
    Development Sciences,
    Genentech, South San Francisco, California
  • L. Sturgeon
    Research,
    Genentech, South San Francisco, California
  • T. Davancaze
    Development Sciences,
    Genentech, South San Francisco, California
  • M. Wong
    Development Sciences,
    Genentech, South San Francisco, California
  • A. Morimoto
    Development Sciences,
    Genentech, South San Francisco, California
  • M. van Lookeren Campagne
    Research,
    Genentech, South San Francisco, California
  • L. DeForge
    Research,
    Genentech, South San Francisco, California
  • P. Haughney
    Development Sciences,
    Genentech, South San Francisco, California
  • L. A. Damico
    Development Sciences,
    Genentech, South San Francisco, California
  • Footnotes
    Commercial Relationships  K.M. Loyet, Genentech, Inc., E; J. Good, Genentech, Inc., E; L. Sturgeon, Genentech, Inc., E; T. Davancaze, Genentech, Inc., E; M. Wong, Genentech, Inc., E; A. Morimoto, Genentech, Inc., E; M. van Lookeren Campagne, Genentech, Inc., E; L. DeForge, Genentech, Inc., E; P. Haughney, Genentech, Inc., E; L.A. Damico, Genentech, Inc., E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 2980. doi:
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      K. M. Loyet, J. Good, L. Sturgeon, T. Davancaze, M. Wong, A. Morimoto, M. van Lookeren Campagne, L. DeForge, P. Haughney, L. A. Damico; Anti-Factor D Fab Specifically Inhibits the Alternative Complement Pathway: In vitro Characterization and in vivo Effects Following Administration to Cynomolgus Monkeys. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2980.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : FCFD4514S is a recombinant, humanized monoclonal antibody Fab fragment directed against factor D, a rate-limiting serine protease in the alternative complement pathway (AP). Anti-factor D Fab (Anti-fD) is being evaluated as a potential therapeutic for intravitreal (IVT) administration to geographic atrophy patients. Herein we characterize Anti-fD inhibition with in vitro hemolytic activity assays and assess in vivo effects in serum following intravenous (IV) or IVT administration to cynomolgus monkeys.

Methods: : The ability of Anti-fD to inhibit AP and classical complement pathway (CP) activity was tested in AP- and CP-specific hemolysis activity assays using human or monkey serum as a source of complement. In addition, Anti-fD was administered IV to monkeys at 0.2, 2, or 20 mg per animal; and bilateral IVT at 1 or 10 mg per eye. Serum Anti-fD concentrations and complement activity were determined by ELISA and AP activity assays, respectively.

Results: : Anti-fD dose-dependently inhibited AP but not CP activity using human or monkey serum. In IV dosed monkeys, higher doses resulted in longer inhibition of systemic AP activity, but only at serum concentrations ≥ 2 µg/mL. Systemic Anti-fD levels following IVT injection were low (maximum concentration (Cmax) < 1.8 or 18 µg/mL for the 1 or 10 mg/eye dose), resulting in partial or transient AP inhibition only for the 10 mg/eye dose. The effect of IVT dosing on AP inhibition was not directly related to serum concentration at any time point, suggesting that recovery of AP activity was likely attributable to the rapid factor D de novo synthesis (60% turnover/hour), possibly neutralizing the activity of free serum Anti-fD.

Conclusions: : Anti-fD specifically inhibits AP activity. A systemic effect was seen only when the serum Anti-fD levels were ≥ 2 µg/mL, a concentration ~ 200-2400-fold greater than the estimated Cmax of the predicted active IVT dose for Anti-fD. Thus, significant systemic Anti-fD effect on AP inhibition is not expected with IVT administration.

Keywords: age-related macular degeneration • retina 
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