Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients

Immunobiology
Christoph Q SchmidtKevin J Marchbank

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated cell lysis due to deficiency of GPI-anchored complement regulators. Blockage of the lytic pathway by eculizumab is the only available therapy for PNH patients and shows remarkable benefits, but regularly yields PNH erythrocytes opsonized with fragments of complement protein C3, rendering such erythrocytes prone to extravascular hemolysis. This effect is associated with insufficient responsiveness seen in a subgroup of PNH patients. Novel C3-opsonin targeted complement inhibitors act earlier in the cascade, at the level of activated C3 and are engineered from parts of the natural complement regulator Factor H (FH) or complement receptor 2 (CR2). This inhibitor class comprises three variants of "miniFH" and the clinically developed "FH-CR2" fusion-protein (TT30). We show that the approach of FH-CR2 to target C3-opsonins was more efficient in preventing complement activation induced by foreign surfaces, whereas the miniFH variants were substantially more active in controlling complement on PNH erythrocytes. Subtle differences were noted in the ability of each version of miniFH to protect human PNH cells. Importantly, miniFH and FH-CR2 interfered only...Continue Reading

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Citations

Jun 21, 2016·Seminars in Immunology·Daniel Ricklin, John D Lambris
Jun 28, 2016·Seminars in Immunology·Antonio M Risitano, Serena Marotta
Oct 27, 2016·Immunological Reviews·Christoph Q SchmidtDaniel Ricklin
Oct 27, 2016·Immunological Reviews·Daniel RicklinJohn D Lambris
Oct 8, 2017·Seminars in Immunopathology·Claire L Harris
Mar 29, 2018·Journal of the American Society of Nephrology : JASN·Yi YangKevin J Marchbank
Sep 19, 2018·EMBO Molecular Medicine·Isha Akhtar-SchäferThomas Langmann
Sep 17, 2019·Therapeutic Advances in Hematology·Sigbjørn BerentsenMarc Michel
Jun 30, 2016·Immunobiology·Dimitrios C MastellosJohn D Lambris
Jul 24, 2018·Seminars in Hematology·Dimitrios C MastellosJohn D Lambris

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