September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Generation and characterization of CLG561: a fully-human, anti-properdin Fab for the treatment of age-related macular degeneration
Author Affiliations & Notes
  • Leslie Johnson
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Igor Splawski
    Cardiovascular Metabolism, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Lisa Baker
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Ana Carrion
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Anh Nguyen
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Michael Twarog
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Yiqin Wang
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Ute Jager
    MorphoSys AG, Planegg, Germany
  • Mark Keating
    Cardiovascular Metabolism, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Thaddeus P Dryja
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Michael Roguska
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Leslie Johnson, Novartis (E); Igor Splawski, Novartis (E); Lisa Baker, Novartis (E); Ana Carrion, Novartis (E); Anh Nguyen, Novartis (E); Michael Twarog, Novartis (E); Yiqin Wang, Novartis (E); Ute Jager, MorphoSys (E); Mark Keating, Novartis (E); Thaddeus Dryja, Novartis (E); Michael Roguska, Novartis (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 1116. doi:
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      Leslie Johnson, Igor Splawski, Lisa Baker, Ana Carrion, Anh Nguyen, Michael Twarog, Yiqin Wang, Ute Jager, Mark Keating, Thaddeus P Dryja, Michael Roguska; Generation and characterization of CLG561: a fully-human, anti-properdin Fab for the treatment of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1116.

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

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Abstract

Purpose : Human genetic and functional studies have established a strong association between age-related macular degeneration (AMD) and over-activation of the complement alternative pathway (AP). Properdin, the only positive regulator of the AP, prevents the rapid decay of AP C3/C5 convertases, thereby amplifying complement activity. CLG561 potently inhibits both C3 and C5 AP cleavage. CLG561 was developed to test the hypothesis that blocking AP activity may be effective for treating AMD.

Methods : Anti-properdin antibodies were selected from the HuCAL GOLD™ phage-display library by panning with purified human and cynomolgus monkey properdin, followed by affinity maturation and removal of posttranslational modification sites. CLG561 was chosen as the final clinical candidate based on affinity for human and cynomolgus monkey properdin, in vitro inhibition of the AP in complement activation assays, and the Fab’s biophysical properties. Assays to characterize the in vitro potency of CLG561 included inhibition of C3a or C5a generation, inhibition of C3b or C5b-9 deposition on zymosan-coated microtiter plates, and inhibition of red blood cell hemolysis by 10% human serum. The CLG561 epitope on properdin was determined using recombinant properdin-derived chimeric peptides. Inhibition of binding to cell surfaces was assessed using apoptotic and necrotic T cells.

Results : CLG561 binds human and cynomolgus monkey properdin with affinities of 213 and 164 pM, respectively. It blocks red blood cell hemolysis caused by AP activation with an IC50 of 16.2 nM. In zymosan assays, CLG561 prevents the generation of C3a and C5a with IC50 values of 3.4 nM and 5.2 nM, respectively, and blocks the deposition of C3b and MAC with IC50 values of 9.3 and 2.6nM, respectively. Properdin binding to apoptotic or necrotic cells can also be inhibited by CLG561. The epitope for CLG561 lies within the fifth thrombospondin repeat of properdin, which has previously been identified as the site of C3b interaction with properdin.

Conclusions : CLG561 is a fully-human Fab that potently inhibits alternative pathway activity and is currently in a Phase 2 proof-of-concept clinical trial in geographic atrophy patients.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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