June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
NGM621 is a Potent Inhibitory Anti-Complement C3 Antibody in Development for Treatment of Geographic Atrophy
Author Affiliations & Notes
  • Alexander Loktev
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Iris Ngan
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Kalyani Mondal
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Yan Wang
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Jian Luo
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Darrin Lindhout
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Bin Fan
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Raj Haldankar
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Jie Tang
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Husam Younis
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • David Shen
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Hui Tian
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Zhonghao Liu
    NGM Biopharmaceuticals, South San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Alexander Loktev, NGM Biopharmaceuticals (E); Iris Ngan, NGM Biopharmaceuticals (E); Kalyani Mondal, NGM Biopharmaceuticals (E); Yan Wang, NGM Biopharmaceuticals (E); Jian Luo, NGM Biopharmaceuticals (E); Darrin Lindhout, NGM Biopharmaceuticals (E); Bin Fan, E (E); Raj Haldankar, NGM Biopharmaceuticals (E); Jie Tang, NGM Biopharmaceuticals (E); Husam Younis, NGM Biopharmaceuticals (E); David Shen, NGM Biopharmaceuticals (E); Hui Tian, NGM Biopharmaceuticals (E); Zhonghao Liu, NGM Biopharmaceuticals (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1798. doi:
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      Alexander Loktev, Iris Ngan, Kalyani Mondal, Yan Wang, Jian Luo, Darrin Lindhout, Bin Fan, Raj Haldankar, Jie Tang, Husam Younis, David Shen, Hui Tian, Zhonghao Liu; NGM621 is a Potent Inhibitory Anti-Complement C3 Antibody in Development for Treatment of Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1798.

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

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Abstract

Purpose : Advanced age-related macular degeneration (AMD) is a leading cause of blindness worldwide. The atrophic form of advanced AMD, also referred to as geographic atrophy (GA), represents an important unmet medical need with no approved therapies. Human genetics and animal models implicate dysregulation of the complement system in the pathophysiology of AMD. To address unmet need in GA, NGM Biopharmaceuticals is developing NGM621, a humanized IgG1 monoclonal antibody that potently binds complement C3 (C3) and inhibits complement activation.

Methods : NGM employed a state-of-the art hybridoma antibody discovery platform to identify and engineer NGM621. The biochemical interactions between NGM621 and purified C3 and other complement factors were characterized using surface plasmon resonance (SPR) methods. Functional inhibition of both the classical and alternative pathways (CP and AP, respectively) for complement activation was assessed by hemolytic assays using human and cynomolgus monkey serum. An in vivo lipopolysaccharide (LPS) model of complement activation was used to evaluate NGM621 inhibition of C3 in the eyes of cynomolgus monkeys.

Results : NGM621 binds with high affinity to intact human C3 (KD=0.34 nM), but shows significantly lower affinity (>100-fold) to C3 cleavage fragments C3a, C3b, C3c, and C3d. This unique NGM621 binding profile, characterized by high affinity and specificity for intact C3, translated into potent inhibition of complement activation by both the AP (IC50 =37 nM) and CP (IC50=74 nM) in hemolytic assays comprising human serum reconstituted with C3 (150 nM). In cynomolgus monkeys, NGM621 administered intravitreally effectively inhibited LPS-mediated complement activation, as evidenced by a marked reduction in concentrations of C3a, the proximal C3 cleavage product, in aqueous humor.

Conclusions : With its distinctive binding profile, NGM621 is a highly potent and selective inhibitor of C3 and effectively blocks both the alternative and classical complement activation pathways in vitro. Furthermore, using an ocular complement activation model in cynomolgus monkeys, NGM621 demonstrated in vivo efficacy consistent with these in vitro properties. NGM621 is currently being evaluated in a Phase 1 clinical trial for safety and tolerability in patients with GA.

This is a 2020 ARVO Annual Meeting abstract.

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