Different Levels of Incomplete Terminal Pathway Inhibition by Eculizumab and the Clinical Response of PNH Patients

Frontiers in Immunology
Markus J HarderChristoph Q Schmidt

Abstract

Background: Eculizumab blocks the lytic complement pathway by inhibiting C5 and has become the standard of care for certain complement-mediated diseases. Previously, we have shown that strong complement activation in vitro overrides the C5 inhibition by Eculizumab, which accounts for residual terminal pathway activity. Results: Here we show that the levels of residual hemolysis in ex vivo assays differ markedly (up to 3.4-fold) across sera collected from different paroxysmal nocturnal hemoglobinuria (PNH) patients on Eculizumab treatment. This large variability of residual activity was also found in sera of healthy donors, thus cross-validating the findings in patients. While PNH patients with residual lytic activities of 11-30% exhibited hemolysis levels around the upper limit of normal (i.e., plasma LDH of ~250 u/L), as expected for PNH patients on Eculizumab therapy, we found sustained and markedly increased LDH levels of around 400 u/L for the patient with the highest residual activity of 37%. Furthermore, the clinical history of nine out of 14 PNH patients showed intravascular breakthrough hemolysis at the time of documented infections despite ample amounts of administered Eculizumab and/or experimentally determined excess...Continue Reading

References

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Citations

Jan 10, 2020·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Bruno Fattizzo, Austin G Kulasekararaj
Mar 7, 2020·Immunology and Cell Biology·Benjamin S Goldberg, Margaret E Ackerman
Jan 12, 2021·Frontiers in Immunology·Wioleta M Zelek, B Paul Morgan
Dec 29, 2020·Frontiers in Immunology·Marion OrtPriska Kaufmann

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Methods Mentioned

BETA
serum collection
ELISA

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