A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice
| Autor: | Pamela A. Royer, Lynne M. Mitchell, Jane E. Salmon, Dennis E. Hourcade, Patricia C. Giclas, V. Michael Holers, Gary S. Gilkeson, Joshua M. Thurman, Guillermina Girardi, Damian M. Kraus, Hee J. Kang |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
medicine.drug_class
Immunology Biology Monoclonal antibody Complement factor B Epitope Mice Pregnancy medicine Animals Humans Complement Activation Fetal Death Molecular Biology Mice Knockout Pregnancy Complications Hematologic Autoantibody Antibodies Monoclonal Molecular biology Complement system Disease Models Animal Epitope mapping Antibodies Antiphospholipid Alternative complement pathway biology.protein Female Antibody Epitope Mapping Complement Factor B |
| Zdroj: | Molecular Immunology. 42:87-97 |
| ISSN: | 0161-5890 |
| Popis: | 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 IgG1 Fc domain. Hybridomas were made from splenocytes of the immunized mouse. One mAb, designated 1379, produced an IgG1 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. |
| Databáze: | OpenAIRE |
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