title: An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice.
abstract: Activation of complement is a key determinant of neuropathology and disability after traumatic brain injury (TBI), and inhibition is neuroprotective. However, systemic complement is essential to fight infections, a critical complication of TBI. We describe a targeted complement inhibitor, comprising complement receptor of the Ig superfamily (CRIg) fused with complement regulator CD59a, designed to inhibit membrane attack complex (MAC) assembly at sites of C3b/iC3b deposition. CRIg and CD59a were linked via the IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited MAC formation and prevented complement-mediated lysis in vitro. CD59-2a-CRIg dimer bound C3b-coated surfaces with submicromolar affinity (KD). In experimental TBI, CD59-2a-CRIg administered posttrauma homed to sites of injury and significantly reduced MAC deposition, microglial accumulation, mitochondrial stress, and axonal damage and enhanced neurologic recovery compared with placebo controls. CD59-2a-CRIg inhibited MAC-induced inflammasome activation and IL-1β production in microglia. Given the important anti-infection roles of complement opsonization, site-targeted inhibition of MAC should be considered to promote recovery postneurotrauma.
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;
authors.forename: Marieta M
authors.initials: MM
authors.lastname: Ruseva
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ramaglia
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; harriscl@cardiff.ac.uk.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018957:CD59 Antigens / Q000235:genetics / Q000494:pharmacology*; D003179:Complement C3b / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D011951:Receptors, Complement; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology
chemical_list: D018957:CD59 Antigens; C539311:CD59a protein, mouse; D015938:Complement Membrane Attack Complex; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D011951:Receptors, Complement; D011994:Recombinant Proteins; C509992:VSIG4 protein, mouse; D003179:Complement C3b
keywords: CD59; CRIg; complement; therapy; traumatic brain injury