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

作者：Ruseva Marieta M; Ramaglia Valeria; Morgan B Paul; Harris Claire L^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(46): 14319-14324.

DOI：10.1073/pnas.1513698112

• traumatic brain injury
• complement
• therapy
• CD59
• CRIg

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 (K-D). In experimental TBI, CD59-2a-CRIg administered post-trauma 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-1 beta production in microglia. Given the important anti-infection roles of complement opsonization, site-targeted inhibition of MAC should be considered to promote recovery postneurotrauma.

• 出版日期2015-11-17