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An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice

Ruseva, Marieta Milkova, Ramaglia, Valeria, Morgan, Bryan Paul and Harris, Claire Louise 2015. An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. Proceedings of the National Academy of Sciences 112 (46) , pp. 14319-14324. 10.1073/pnas.1513698112

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: traumatic brain injury, complement, therapy, CD59, CRIg
Publisher: National Academy of Sciences
ISSN: 0027-8424
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 29 September 2015
Last Modified: 10 Jun 2019 14:27
URI: http://orca-mwe.cf.ac.uk/id/eprint/84473

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