Anticuerpo anti-Factor B, composición farmacéutica útil para el tratamiento de enfermedades del complemento y sus aplicaciones.

Inventors: Santiago Rodríguez de Córdoba y Mercedes Domínguez Rodríguez


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  • Rabasco, C., Huerta, A., Caro, J., Gutierrez, E., and Praga, M. (2013). C3 Glomerulopathies. A new perspective on glomerular diseases. Nefrología 33(2), 164-170.
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  • Paixão-Cavalcante, D., López-Trascasa, M., Skattum, L., Giclas, P.C., Goodship, T.H., de Córdoba, S.R., Truedsson, L., Morgan, B.P., and Harris, C.L. (2012). Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation. Kidney International.
  • Zhou, H.-f., Yan, H., Stover, C.M., Fernandez, T.M., de Cordoba, S.R., Song, W.-C., Wu, X., Thompson, R.W., Schwaeble, W.J., and Atkinson, J.P. (2012). Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm. Proceedings of the National Academy of Sciences 109, E415-E422.

Title: Análisis estructural y funcional de proteínas del complemento asociadas con patología.

Author: Agustín Tortajada Alonso

Director: Santiago Rodríguez de Córdoba. CIB-CSIC



The complement system is a major component of the innate immunity, with crucial roles against infections, modulating the adaptive immune response and in apoptotic cell clearance and immune complex handling. The complement system is composed of a group of plasma proteins, arranged in cascades which are activated by specific signals on pathogens and foreign surfaces. The critical event in complement activation is the hydrolysis of component C3 to the active molecule C3b, which is catalyzed by unstable protease complexes, named C3 convertases. In order to avoid nonspecific activation and prevent self-injury, both the presence of C3b and the formation of the C3 convertases are strictly controlled by the regulatory proteins that limit complement activation. Thus, the proper functioning of the complement system depends on the balance between the components that activate the cascades and regulators that control the components.

Environmental factors, mutations, polymorphisms and autoantibodies with fuctional consequences on the complement proteins or altering their plasma concentration, may disturb the balance between complement activation and regulation. Thereby, many of these alterations are risk factors associated with pathological situations. Atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD) and age-related macular degeneration (AMD) are three of these complement associated diseases. The available data has shown that deregulation of the alternative pathway (AP) of complement is a common pathological feature for these disorders. Genetic and functional studies illustrate how the mutations in regulators of the AP, such as those found in factor H (fH), MCP and factor I, are loss of function mutations, while those present in activating components, such as factor B (fB) and C3 are gain of function mutations. Both situations lead to an uncontrolled activation of complement, which drives to the development of the pathology. However, the functional consequences of mutations or polymorphisms are not always known and additional risk factors for these conditions are not identified. The overall objectives of this thesis were on one hand to study the C3 convertase complex from a structural and functional approach, and secondly to identify additional risk factors and the functional characterization of variants associated with disease.

From purified proteins, we have generated and isolated pro-convertase and C3 convertase complexes. Using single-particle electron microscopy we have determined the 3-dimensional models of these complexes. The results show important aspects of the assembling mechanism of C3 convertase, such as the conformational change that undergoes on fB upon binding to C3b to form the pro-convertase, and which domains are involved in the formation and stability of the C3 convertase of both C3b and fB.

Also, the proposed models provide information on the regulatory mechanisms of these complexes. They also constitute a structural framework for the study of relevant residues involved in pathologies associated with deregulation of the AP of complement.

On the other hand, we have designed antibodies that specificaly recognize the two variants of a common polymorphism located in fH (Tyr402His), which is strongly associated with AMD. These specific antibodies have allowed us to genotype this polymorphism and to identify risk carriers for this pathology. Also, using these antibodies, we have performed allele-specific quantification of fH in different populations, which has helped us to identify low expression alleles carriers within aHUS patients, which represent an additional and measurable risk factor that can be crucial in the development of the disease. Further, our antibodies have been a useful tool in the purification of mutants fH from plasma, to perform fuctional assays.

Finally, we have functionally characterized some of the variants associated with AMD, aHUS and DDD. On the one hand, the common polymorphisms of fB, Arg32Trp/Gln, and of fH, Val62Ile, whose situation in the protein directly influences the formation and regulation of C3 convertase. On the other hand, the rare variants of fH, Ser890Ile / Val1007Leu, which have been repeatedly associated with aHUS, DDD and AMD. We have designed a set of functional assays which reveal the molecular basis of the association of these variants with disease, and provide information on the pathological mechanisms by which complement dysregulation is more or less involved in the development disease.