July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Discovery and Planned Optimization of a Complement Factor C3-Inactivating Alterase, CB-2782
Author Affiliations & Notes
  • Eric Furfine
    Mosaic Biosciences, Lincoln, Massachusetts, United States
    Catalyst Biosciences, South San Francisco, California, United States
  • Martin Stanton
    Mosaic Biosciences, Lincoln, Massachusetts, United States
  • Brajesh Kumar
    Catalyst Biosciences, South San Francisco, California, United States
  • Nassim Usman
    Catalyst Biosciences, South San Francisco, California, United States
  • David Sloane
    Catalyst Biosciences, South San Francisco, California, United States
  • Mikhail Popkov
    Catalyst Biosciences, South San Francisco, California, United States
  • Edwin Madison
    Catalyst Biosciences, South San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Eric Furfine, catalyst Biosciences (I), Catalyst Biosciences (C), Mosaic Biosciences (E), Mosaic Biosciences (I); Martin Stanton, Mosaic Biosciences (E), Mosaic Biosciences (I); Brajesh Kumar, catalyst Biosciences (E); Nassim Usman, Catalyst Biosciences (E), Catalyst Biosciences (I); David Sloane, None; Mikhail Popkov, None; Edwin Madison, Catalyst Biosciences (C)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 60. doi:
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      Eric Furfine, Martin Stanton, Brajesh Kumar, Nassim Usman, David Sloane, Mikhail Popkov, Edwin Madison; Discovery and Planned Optimization of a Complement Factor C3-Inactivating Alterase, CB-2782. Invest. Ophthalmol. Vis. Sci. 2018;59(9):60.

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

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Abstract

Purpose : The subset of patients with dry age-related macular degeneration that have sight-threatening geographic atrophy (GA), is a large unmet medical need that has its etiology in intraocular complement pathway activation. While complement factor C3 (C3) blockade received clinical validation by reducing GA with APL-2, the drug required monthly intravitreal (IVT) injections for maximal efficacy. This program goal is to engineer a protease that specifically inactivates intraocular C3 and complement pathway-mediated inflammation, sub-stoichiometrically. This C3 inhibition combined with modest half-life extension could create a drug that treats GA with quarterly administration.

Methods : CB-2782, is engineered from a human serine protease (matriptase) and produced in E. coli. Specificity and sensitivity of CB-2782 were evaluated in peptide cleavage assays and inhibition of complement activation was evaluated in standard assays. Pharmacokinetics, C3 destruction, and tolerability were evaluated after one IVT administration, up to 125 µg/right eye, the left eye receiving vehicle, in three cynomolgus monkeys. Clinical observations, and standard ophthamological exams, including optical coherence tomography prior to administration and on days 2, 8, 15, and 28 post-administration, assessed the animals. Vitreal drug and C3 levels were measured by ELISA. Data were used to model dosing schedules with a one-compartment model.

Results : CB-2782 has 13 mutated amino acids, 300% increased catalytic efficiency inactivating C3 compared to the parental matriptase. The enzyme completely blocked complement activation at sub-stoichiometric concentrations. The drug was well-tolerated in monkeys out to 28 days, had a vitreal half-life of 1.7 days, and reduced C3 to undetectable levels for at least seven days. CB-2782 inactivated C3 was more efficiently than the typical one-to-one inhibitors, such as APL-2, based on kinetic modeling. Results suggested that a half-life of 8 days in humans (enhancing half-life to approx. four days in monkeys) would result in quarterly administration.

Conclusions : Catalytic inactivation of the C3 in the complement pathway has the potential to block ocular inflammation more effectively than traditional one-to-one inhibitors. Approximately doubling the half-life of CB-2782 in monkey eyes has the potential create a drug to reduce GA with quarterly administration in humans.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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