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Identification of a complement receptor 1 peptide for inhibition of immune hemolysis.

ABSTRACT: Complement sensitization of red blood cells (RBCs) can cause life-threatening hemolytic anemias. We have previously shown that complement receptor 1 (CR1) derivatives specifically the N-terminal region with decay accelerating activity (DAA) for inactivation of a key enzyme in the complement cascade can reduce complement-mediated RBC destruction in vitro and in an in vivo mouse model of hemolytic transfusion reaction. In the present study, we have modeled the N-terminal CR1 molecule based on the X-ray crystal structure of decay accelerating factor and the NMR structure of a homologous CR1 domain. Based on the homology model, we identified a 34-mer peptide encompassing the putative DAA which in vitro reduced hemolysis, C3a release and surface C3 deposition. More importantly, this peptide at 0.6 mM was effective in prolonging survival of transfused incompatible RBCs in vivo. Our results indicate that CR1-based structure-function studies may provide insights for developing structure-derived transfusion therapeutics in the future.

SUBMITTER: Yu J

PROVIDER: S-EPMC4804343 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Identification of a complement receptor 1 peptide for inhibition of immune hemolysis.

Yu Jin J Heck Susanne S Debnath Asim A Yazdanbakhsh Karina K

Biochemical and biophysical research communications 20061211 2

Complement sensitization of red blood cells (RBCs) can cause life-threatening hemolytic anemias. We have previously shown that complement receptor 1 (CR1) derivatives specifically the N-terminal region with decay accelerating activity (DAA) for inactivation of a key enzyme in the complement cascade can reduce complement-mediated RBC destruction in vitro and in an in vivo mouse model of hemolytic transfusion reaction. In the present study, we have modeled the N-terminal CR1 molecule based on the ...[more]

PMID: 17178110

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Project description:Previous studies have demonstrated that staphylococcal superantigen-like protein 7 (SSL7), a protein produced by Staphylococcus aureus, potently inhibits the formation of the complement membrane attack complex by binding to complement component 5 (C5). However, because of the predicted immunogenicity of SSL7 as a foreign protein in humans, its potential as a new complement inhibitor for treating complement-mediated diseases is uncertain. In this study, we found that administration of SSL7 significantly prevented complement-mediated hemolysis and reduced hemoglobinuria in a mouse model of complement-mediated intravascular hemolysis. Interestingly, although repetitive administrations of SSL7 elicited anti-SSL7 antibody production, administration of SSL7 at a dose of 2 ?g/mouse was still able to significantly attenuate complement-mediated intravascular hemolysis in vivo in the presence of the antibodies. In addition, even though anti-SSL7 antibodies were detectable in normal human donors, these antibodies did not significantly reduce the complement inhibitory activity of SSL7 in in vitro assays. Finally, inoculation of SSL7 in the anterior chamber of the eye suppressed the production of SSL7-reactive antibodies after repetitive SSL7 administration. These results suggest that SSL7 could be developed as an economical alternative to the existing C5-targeted drug, eculizumab, especially for controlling acute complement activation in catastrophic conditions such as drug-induced immune hemolytic anemia and ABO-incompatible erythrocyte transfusions. These data also suggest that approaches such as anterior chamber-associated immune deviation could be employed to establish an antigen-specific immune tolerance for long-term SSL7 administration. KEY MESSAGES:• SSL7 functions in the presence of anti-SSL7 antibodies both in vitro and in vivo. • SSL7 has the potential to be developed as a new and economical complement inhibitor for treating complement-mediated hemolysis.

Project description:Key Points • Complement inhibitor–naive patients with PNH had greater hemoglobin stabilization and LDH reduction with pegcetacoplan vs control.• Pegcetacoplan’s comprehensive control of hemolysis and favorable safety profile in these patients may help expand the treatment population. Visual Abstract Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response or intolerance to a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for ≥3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan vs control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor–naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomly assigned and stratified based on their number of transfusions (<4 or ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary end points were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n = 35) or control (n = 18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1%; 95% confidence interval [CI], 57.2-89.0; P < .0001) and change from baseline in LDH (least square mean change: pegcetacoplan, −1870.5 U/L; control, −400.1 U/L; difference, −1470.4 U/L; 95% CI, −2113.4 to −827.3; P < .0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals were observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor–naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04085601.

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Identification of a complement receptor 1 peptide for inhibition of immune hemolysis.

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Identification of a complement receptor 1 peptide for inhibition of immune hemolysis.

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