A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice

Studies in gene-targeted mice have demonstrated that factor B of the alternative complement pathway plays an important role in several disease models, but an exogenous inhibitor of factor B has not previously been available. We have developed an inhibitory monoclonal antibody directed against a crit...

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Bibliographic Details
Published in:Molecular immunology 2005, Vol.42 (1), p.87-97
Main Authors: Thurman, Joshua M., Kraus, Damian M., Girardi, Guillermina, Hourcade, Dennis, Kang, Hee J., Royer, Pamela A., Mitchell, Lynne M., Giclas, Patricia C., Salmon, Jane, Gilkeson, Gary, Holers, V. Michael
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies, Antiphospholipid - adverse effects
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal - therapeutic use
Antigens/peptides/epitopes
Autoantibodies
Complement
Complement Activation - drug effects
Complement Factor B - antagonists & inhibitors
Complement Factor B - immunology
Disease Models, Animal
Epitope Mapping
Female
Fetal Death - immunology
Fetal Death - prevention & control
Humans
Mice
Mice, Knockout
Pregnancy
Pregnancy Complications, Hematologic - drug therapy
Rodent
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Summary:Studies in gene-targeted mice have demonstrated that factor B of the alternative complement pathway plays an important role in several disease models, but an exogenous inhibitor of factor B has not previously been available. We have developed an inhibitory monoclonal antibody directed against a critical epitope on mouse factor B and have tested it in a model of antiphospholipid (aPL) antibody (Ab)-induced fetal loss. Gene-targeted factor B-deficient mice (fB −/−) were injected with a fusion protein comprised of the second and third short consensus repeat (SCR) domains of mouse factor B linked to a mouse IgG 1 Fc domain. Hybridomas were made from splenocytes of the immunized mouse. One mAb, designated 1379, produced an IgG 1 antibody that inhibited alternative pathway activation in vitro and in vivo by preventing formation of the C3bBb complex. Strikingly, this mAb inhibited alternative pathway activation in serum from mice, rats, humans, monkeys, pigs and horses. Fab fragments made from this mAb also inhibited alternative pathway activation. Epitope mapping demonstrated that this antibody binds to factor B within the third SCR domain. When mAb 1379 was administered to mice that also received human IgG containing antiphospholipid antibodies, it provided significant protection from antiphospholipid antibody-induced complement activation and fetal loss. Thus, this mAb to factor B has broad species reactivity and effectively inhibits alternative pathway activation. The mAb protects mice in an in vivo model of antiphospholipid antibody syndrome, demonstrating the therapeutic potential for the inhibition of factor B in this disease.
ISSN:0161-5890
1872-9142
DOI:10.1016/j.molimm.2004.07.043