NDA@SZTAKI

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

Schmidt, C. Q.

Harder, M. J.

Nichols, E. M.

Hebecker, M.

Anliker, M.

Csincsi, Ádåm

Uzonyi, Barbara

JĂłzsi, MihĂĄly

Elsevier

2016

QR180 Immunology / immunolĂłgia

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 minimally with complement-mediated serum killing of bacteria when compared to untargeted inhibition of all complement pathways by eculizumab. Thus, the molecular design of each C3-opsonin targeted complement inhibitor determines its potency in respect to the nature of the activator/surface providing potential functionality in PNH.

angol

Article

PeerReviewed

info:eu-repo/semantics/article

text

http://real.mtak.hu/47560/1/Immunobiology_Real_final2.pdf

Schmidt, C. Q. and Harder, M. J. and Nichols, E. M. and Hebecker, M. and Anliker, M. and Csincsi, Ádåm and Uzonyi, Barbara and Józsi, Mihåly (2016) Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients. IMMUNOBIOLOGY, 221 (4). pp. 503-511. ISSN 0171-2985

http://real.mtak.hu/47560/

http://dx.doi.org/10.1016/j.imbio.2015.12.009

MTMT:3004770; doi:10.1016/j.imbio.2015.12.009

602699 (DIREKT)