Inhibition of complement alternative pathway function with anti-properdin monoclonal antibodies.
Complement activation products appear to contribute to the pathology of several acute and chronic inflammatory conditions. The relative contributions of the classical and alternative complement pathways to these pathologies have, in large part, been undefined. Considerable progress has been made recently in identifying inhibitors of complement activation and demonstrating that such molecules can attenuate inflammation in various models of disease. However, most of these complement inhibitors affect aspects of both the classical and alternative pathways. In an effort to better define the role of the alternative complement pathway in complement-mediated inflammatory conditions, we have developed monoclonal antibodies that specifically inhibit alternative pathway function. These blocking antibodies bind human properdin with high avidity and prevent its interaction with the alternative pathway C3 convertase. This results in a cessation of alternative pathway function in several in vitro assay systems. When tested in a model of cardiopulmonary bypass, in which human blood passes through tubing, a selected antiproperdin antibody caused nearly complete inhibition of the C3a and C5b-9 formation that was seen in untreated blood. Moreover, the anti-properdin agent resulted in a dramatic reduction of neutrophil and platelet activation in the bypass model. Surprisingly, the monoclonal antibody also caused a significant inhibition of C5b-9 generation when classical pathway activators, such as heparin-protamine or immune complexes, were added to human blood. These latter data suggest that the alternative pathway contributes significantly to the formation of complement activation products in blood when the classical pathway is initially triggered.
Gupta-Bansal
R
R
Exploratory Research, Gliatech Inc., Cleveland, OH 44122, USA.
Parent
J B
JB
Brunden
K R
KR
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002315:Cardiopulmonary Bypass; D015926:Complement C3a / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D003171:Complement Pathway, Classical / Q000187:drug effects; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D011414:Properdin / Q000276:immunology* / Q000378:metabolism*; D016897:Respiratory Burst
D000911:Antibodies, Monoclonal; D015938:Complement Membrane Attack Complex; D011414:Properdin; D015926:Complement C3a; D019272:Leukocyte Elastase