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.

Innate immune responses to trauma

“…However, microglia are also critical for an extensive and often sustainable (up to years) generation of cytokines (for example, IL-1β and IL-6) and ROS, which in turn recruit neutrophils and blood monocytes-macrophages to the injured area 103,105,108 . Furthermore, complement 109 or lysophosphatidylcholine activates inflammasomes in microglia or astrocytes soon after TBI and during neuro-inflammation 110 . After exposure to IL-1β, astrocytes rapidly generate immune signals in the form of extracellular vesicles dispatched to the periphery, which results in the further recruitment of neutrophils and systemic release of cytokines 111 .…”

“…By the standards of randomized clinical trials, however, most of the proposed approaches have failed to significantly improve mortality 1 . Pioneering immunomodulation has employed damage targeting; for example, by the detection of C3b-iC3b (deposited in injured tissue) using the complement modulator CD59-2a-CRIg (a dimer in which each monomer consists of CD59 (an inhibitor of the complement complex MAC) fused to CRIg (a complement receptor of the immunoglobulin superfamily) via IgG2a hinge region) 109 or by the sensing of proteoglycan complexes in injured brain areas with the small peptide CAQK 183 . Promising innate immunomodulatory therapies have been applied early after trauma or in a delayed fashion 27,104,109,113,160,162,183–196 (Table 1).…”

“…Pioneering immunomodulation has employed damage targeting; for example, by the detection of C3b-iC3b (deposited in injured tissue) using the complement modulator CD59-2a-CRIg (a dimer in which each monomer consists of CD59 (an inhibitor of the complement complex MAC) fused to CRIg (a complement receptor of the immunoglobulin superfamily) via IgG2a hinge region) 109 or by the sensing of proteoglycan complexes in injured brain areas with the small peptide CAQK 183 . Promising innate immunomodulatory therapies have been applied early after trauma or in a delayed fashion 27,104,109,113,160,162,183–196 (Table 1). Other innovative strategies could include glycocalyx compounds to seal broken barriers, exosomes to alter different functions (for example, coagulation), as well as bioelectronical devices to modulate the inflammatory ‘immune reflexes’ 121 , or they might derive from in silico modeling of the complex trauma response.…”

New milestones ahead in complement-targeted therapy

“…TT30 has been clinically developed for treatment of PNH and found safe in phase 1 trials [70], but no further development steps have been announced. Meanwhile, the targeted regulation strategy has been adapted to different regulatory units and/or targeting entities (e.g., TT32/CR1-CR2 [71], CD59-CRIg [72]) or dual-pathway activity (e.g., FH-MAP1 [73]). Finally, a targeting moiety can also be attached to the surface as a protective coating in order to recruit regulators from circulation; for example, the FH-binding peptide 5C6 has been shown to adsorb FH on biomaterial and cell surfaces and protect them from AP activation [74, 75].…”

Viral-derived complement inhibitors: current status and potential role in immunomodulation

“…[56][57][58][59][60][61][62][63][64][65] Such inflammatory diseases involve dysregulated control of the complement pathways which results in inappropriate secretion of reactive oxygen species, eicosanoids, cytokines and chemokines, inducing the influx of inflammatory cells. A few examples are discussed below.…”