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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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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.
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.
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.
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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