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Inhibición del loop de amplificación de la vía alternativa con anticuerpos monoclonales frente a C3 y FB. Potenciales aplicaciones en la terapia de patologías del complemento.

AutorSubías, Marta
DirectorRodríguez de Córdoba, Santiago
Palabras claveSistema del complemento
Anticuerpos monoclonales
Terapia y patologías del complemento
Fecha de publicación4-jul-2017
EditorCSIC - Centro de Investigaciones Biológicas (CIB)
Universidad Autónoma de Madrid
ResumenThe complement system plays a crucial role in a long list of rare and common diseases. The activity of the complement system depends, regardless of the trigger, on the alternative pathway (AP). Therefore, inhibition of the AP C3-convertase is predicted to be a very efficient target to block complement activation for the treatment of complement dysregulation disorders. We describe the generation and characterization of mouse monoclonal antibodies (mAbs) against FB and C3, the two components of the AP C3-convertase; one mAb targeting FB and three targeting C3. These mAbs effectively block the formation of the AP C3-convertasa or the interaction between the AP C3-convertase and the C3 substrate, inhibiting completely complement activation. Different in vitro and in vivo models of complement related diseases such as atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH) or myasthenia gravis (MG) help us to demonstrate the usefulness of these mAbs as therapeutic tools. We also describe another mAb that specifically binds to a neoepitope in the proteolytic C3 fragments iC3b/C3dg. These mAbs are very rare and offer interesting diagnostic opportunities. Eculizumab is currently the only drug approved to inhibit complement in the clinic. Nowadays, PNH and aHUS patients are successfully treated with this humanized mAb, however, eculizumab treatment have been reported to be heterogeneous among PNH patients. We have studied a cohort of PNH patients under eculizumab treatment for signs of hemolysis, and assessed complement biomarkers trying to explain the differences in response to eculizumab. We shown that despite complete C5 blockage, most of the patients studied presented low level hemolysis, probably as a consequence of the extracellular removal of the C3 opsonized PNH-erythrocytes (PNH-E) generated during the eculizumab treatment. We also show that levels of the complement regulator complement receptor 1 correlated with C3 deposition in PNH-E, and that continuous AP activation in these patients could result in an acquired partial C3 deficiency that may increase their susceptibility to infections. As a result of this study, we have developed a procedure for the evaluation of eculizumab levels and complement inhibition in the treated patients, which is currently being used to personalize the eculizumab administration.
Descripción123 p.-28 fig.-6 tab.-anexo.
Aparece en las colecciones: (CIB) Tesis
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