Pharmacokinetics and safety of TP10, soluble complement receptor 1, in infants undergoing cardiopulmonary bypass

Li, Jennifer S.; Sanders, Stephen P.; Perry, April; Stinnett, Sandra S.; Jaggers, James; Bokesch, Paula M.; Reynolds, Laurie; Nassar, Rashid; Anderson, Page A.W.

doi:10.1016/j.ahj.2003.07.004

Cited by 29 publications

(22 citation statements)

References 22 publications

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“…However, super-physiologic singledose treatment with sCR1 has been used in .500 patients (infants and adults) undergoing a variety of cardiac surgeries or after myocardial infarctions to arrest complement activation. [23][24][25][26] These studies showed that sCR1 was well tolerated with no adverse events clearly or consistently associated with its use. Importantly, the possible development of anti-sCR1 antibodies was monitored but never observed in .350 patients.…”

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confidence: 94%

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Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

Zhang

Nester

Holanda

et al. 2013

Journal of the American Society of Nephrology

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Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy. In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors. In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Shortterm use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN. Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are two widely recognized subtypes of C3 glomerulopathy (C3G). 1,2 These ultra-rare renal diseases are caused by fluid-phase dysregulation of the C3 convertase of the alternative pathway (AP) of complement, with variable concomitant dysregulation of the C5 convertase. Consistent with complement-mediated disease acting through the AP, C3G is strongly positive for C3 and notably negative for Igs by immunofluorescence microscopy. 2 Electron microscopy distinguishes DDD from C3GN, with the former characterized by pathognomonic electron-dense transformation of the lamina densa of the glomerular basement membrane (GBM). 3 In C3GN, the electron microscopy deposits are lighter in color, and are more often mesangial and/or subendothelial, intramembranous, and subepithelial in location. 4 In both diseases, mass spectroscopy of laser dissected glomeruli is highly enriched for proteins of the AP and terminal complement cascade. 4,5

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confidence: 94%

“…Importantly, the possible development of anti-sCR1 antibodies was monitored but never observed in .350 patients. 23,26 …”

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confidence: 99%

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

Zhang

Nester

Holanda

et al. 2013

Journal of the American Society of Nephrology

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“…Another complement-blocking approach under investigation in clinical studies is based on the use of soluble forms of the C3/C5 convertase inhibitor complement receptor 1 (CR1). Phase I and phase II clinical trials have shown that the soluble CR1 TP10, administered intravenously both before and during surgery, decreased complement activation and protected vascular function in infants who underwent cardiopulmonary bypass (169). In a randomized, multicenter, prospective study in 564 high-risk patients who underwent cardiac surgery on cardiopulmonary bypass, a bolus of TP10 given immediately before cardiopulmonary bypass significantly inhibited complement activity within 10 min, and this inhibition persisted for 3 d postoperatively (170).…”

Section: The Futurementioning

confidence: 99%

Hemolytic Uremic Syndrome

Noris¹,

Remuzzi²

2005

Journal of the American Society of Nephrology

498

428

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“…It has been reported that Crry-Ig, like other human systemic complement inhibitors, depends on a high level of systemic complement inhibition for efficacy (30,(55)(56)(57). To support the concept that the enhanced efficacy of CR2-Crry over Crry-Ig was due to its ability to target and localize at sites of complement activation, we performed a biodistribution study.…”

Section: Figurementioning

confidence: 99%

Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection

Atkinson

Song²,

Lü³

et al. 2005

Journal of Clinical Investigation

162

248

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Previous studies indicate a pivotal role for complement in mediating both local and remote injury following ischemia and reperfusion of the intestine. Here, we report on the use of a mouse model of intestinal ischemia/ reperfusion injury to investigate the strategy of targeting complement inhibition to sites of complement activation by linking an iC3b/C3dg-binding fragment of mouse complement receptor 2 (CR2) to a mouse complement-inhibitory protein, Crry. We show that the novel CR2-Crry fusion protein targets sites of local and remote (lung) complement activation following intestinal ischemia and reperfusion injury and that CR2-Crry requires a 10-fold lower dose than its systemic counterpart, Crry-Ig, to provide equivalent protection from both local and remote injury. CR2-Crry has a significantly shorter serum half-life than Crry-Ig and, unlike Crry-Ig, had no significant effect on serum complement activity at minimum effective therapeutic doses. Furthermore, the minimum effective dose of Crry-Ig significantly enhanced susceptibility to infection in a mouse model of acute septic peritonitis, whereas the effect of CR2-Crry on susceptibility to infection was indistinguishable from that of PBS control. Thus, compared with systemic inhibition, CR2-mediated targeting of a complement inhibitor of activation improved bioavailability, significantly enhanced efficacy, and maintained host resistance to infection. IntroductionIntestinal ischemia/reperfusion injury (IRI) is a major complication associated with abdominal surgery, cardiopulmonary bypass, ruptured abdominal aneurysm, and cardiac arrest (1-5). Reduction of abdominal blood flow as a result of hemorrhagic shock also causes intestinal IRI, which commonly leads to bacterial translocation and sepsis. Intestinal IRI causes gut dysfunction that is characterized by impaired gut motility, increased intestinal permeability, and mucosal wall injury, all of which are thought to be mediated at least in part by complement activation and the infiltration of neutrophils (6-8). Complement activation products and tissue injury result in the induction of a systemic inflammatory response with the release of cytokines and chemokines, the upregulation of adhesion molecules, and the activation of leukocytes. The activation of a systemic proinflammatory state results in remote organ damage to which the lung is particularly susceptible (9-12).Many studies have utilized rodent models of intestinal IRI to investigate the underlying pathophysiological mechanisms of IRI and to test potential therapeutic strategies. The pathogenesis of IRI is complex, but a series of elegant studies have shown that preexisting clonally specific IgM antibodies bind to neoantigens exposed by the ischemic insult and, following reperfusion, activate

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Pharmacokinetics and safety of TP10, soluble complement receptor 1, in infants undergoing cardiopulmonary bypass

Cited by 29 publications

References 22 publications

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

Hemolytic Uremic Syndrome

Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection

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