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

La presente invención describe un anticuerpo anti-factor B que bloquea la generación de la convertasa del C3 de la vía alternativa útil para prevenir o modular la activación o amplificación de la activación del complemento. Una forma concreta de este anticuerpo es el anticuerpo monoclonal anti-factor B producido por el hibridoma FB-28.4.2 depositado en ACECC el 13 de noviembre de 2012 con la referencia 12111301. Además, proporciona una composición farmacéutica útil para el tratamiento de enfermedades asociadas del complemento como por ejemplo, el síndrome hemolítico urémico atípico (aHUS) o la hemoglobinuria paroxística nocturna (HPN). Igualmente, se proporciona un complejo biotecnológico útil para la realización de ensayos para la identificación y diseño de medicamentos o composiciones farmacéuticas inhibidoras del complementoREIVINDICACIONES 1.- Anticuerpo anti-factor B que bloquea la generación de la convertasa del C3 de la vía alternativa útil para prevenir o modular la activación o amplificación de la activación del complemento caracterizado por que es capaz de reconocer específicamente un epítopo en el fragmento Ba del factor B y cuya secuencia aminoacídica de la cadena pesada presenta un porcentaje de homología de al menos el 95% respecto a la secuencia aminoacídica SEQ ID N01 y/o cuya secuencia aminoacídica de la región variable de la cadena pesada presenta un porcentaje de homología de al menos el 95% respecto a la secuencia aminoacídica la SEQ ID N04. 2.- Anticuerpo antl-factor B según la reivindicación 1 caracterizado por que es un anticuerpo monoclonal producido por un hibridoma. 3.- Anticuerpo anti-factor B según la reivindicación 1 caracterizado por que está producido por el hibridoma FB-28.4.2 depositado en ACECC el 13 de noviembre de 2012 con la referencia 12111301. 4.- Anticuerpo anti-factor B según la reivindicación 1 caracterizado por que comprende las regiones de reconocimiento del antígeno variables y/o hipervariables de las cadenas ligeras y/o pesadas, o bien de las propias cadenas ligeras y/o pesadas del anticuerpo anti-factor B según la reivindicación 3. 5.- Anticuerpo anti-factor B según la reivindicación 1 caracterizado por que comprende en la secuencia de aminoácidos de la cadena pesada la SEQ ID N01. 6.- Anticuerpo anti-factor B según la reivindicación 1 caracterizado por que comprende en la secuencia de aminoácidos de la región variable de la cadena pesada la SEQ ID N04. 7.- Anticuerpo anti-factor B según la reivindicación 1 caracterizado por que está constituido por un fragmento del anticuerpo monoclonal producido por el hibridoma FB-28.4.2 depositado en ACECC el 13 de noviembre de 2012 con la referencia 12111301. 8.- Anticuerpo anti-factor B según la reivindicación 7 caracterizado por que el fragmento es un fragmento Fab producido por digestión con papaína. 9.- Hibridoma FB-28.4.2 depositado en ACECC el 13 de noviembre de 2012 con la referencia 12111301. 10.- El uso del hibridoma según la reivindicación 9 para la producción del anticuerpo monoclonal anti-factor B según la reivindicación 3. 11.- Uso de un anticuerpo según una cualquiera de las reivindicaciones 1 a la 8 en la elaboración de un medicamento o una composición farmacéutica para el tratamiento de un desorden o una enfermedad asociada al complemento. 12.- Composición farmacéutica antagonista del factor B del complemento útil para el tratamiento de una enfermedad asociada del complemento caracterizada por que comprende el anticuerpo anti-factor B según una cualquiera de las reivindicaciones 1 a la 8 con portadores farmacéuticamente aceptables. 13.- Composición farmacéutica según la reivindicación 12 caracterizada por que la enfermedad asociada al complemento pertenece al siguiente grupo: artritis reumatoide (AR), lupus eritematoso sistémico (LES), glomerulonefritis, esclerosis múltiple (EM), isquemia / repercusión, glomerulopatías por depósito aislado de C3 (C3G), síndrome hemolítico urémico atípico (aHUS), enfermedad hemoglobinuria paroxística nocturna (HPN) y degeneración macular asociada a la edad (AMD). 14.- Uso de la composición farmacéutica según las reivindicaciones 12 y 13 útil en una cantidad terapéuticamente eficaz para el tratamiento de una enfermedad asociada al complemento. 15.- Uso de la composición farmacéutica según la reivindicación 14 caracterizado por que la enfermedad asociada al complemento perteneciente al siguiente grupo: artritis reumatoide (AR), lupus eritematoso sistémico (LES), glomerulonefritis, esclerosis múltiple (EM), isquemia / repercusión, glomerulopatías por depósito aislado de C3 (C3G), síndrome hemolítico urémico atípico (aHUS), enfermedad hemoglobinuria paroxística nocturna (HPN) y degeneración macular asociada a la edad (AMD). 16.- Uso de la composición según las reivindicaciones 14 y 15 caracterizado por que la composición farmacéutica puede administrase en combinación con otros agentes terapéuticos. 17.- Complejo biotecnología) útil para la realización de ensayos biotecnológicos caracterizado por que comprende el factor B y el anticuerpo anti-factor B según una cualquiera de las reivindicaciones 1 a la 8. 18.- Uso de! anticuerpo anti-factor B según una cualquiera de las reivindicaciones 1 a la 8 para la elaboración del complejo biotecnológico según la reivindicación 17. 19.- Uso de! complejo biotecnológico de la reivindicación 17 en la elaboración de ensayos biotecnológicos para la identificación y diseño de medicamentos o composiciones 10 farmacéuticas inhibidoras de la formación de la convertasa de! C3 de la vía alternativa y de la activación de! complemento.Cuando una patente se hace internacional, se puede encontrar en el idioma de cada país en que se ha solicitado. En Espacenet se tiene acceso a los documentos en cada idiomaConsejo Superior de Investigaciones Científicas; Instituto de Salud Carlos IIISolicitud de patent

Absence of CD59 in guinea pigs: Analysis of the Cavia porcellus genome suggests the evolution of a CD59 pseudogene

CD59 is a membrane-bound regulatory protein that inhibits the assembly of the terminal membrane attack complex (C5b-9) of complement. From its original discovery in humans almost 30 years ago, CD59 has been characterized in a variety of species, from primates to early vertebrates, such as teleost fish. CD59 is ubiquitous in mammals; however, we have described circumstantial evidence suggesting that guinea pigs (Cavia porcellus) lack CD59, at least on erythrocytes. In this study, we have used a combination of phylogenetic analyses with syntenic alignment of mammalian CD59 genes to identify the only span of genomic DNA in C. porcellus that is homologous to a portion of mammalian CD59 and show that this segment of DNA is not transcribed. We describe a pseudogene sharing homology to exons 2 through 5 of human CD59 present in the C. porcellus genome. This pseudogene was flanked by C. porcellus homologs of two genes, FBXO3 and ORF91, a relationship and orientation that were consistent with other known mammalian CD59 genes. Analysis using RNA sequencing confirmed that this segment of chromosomal DNA was not transcribed. We conclude that guinea pigs lack an intact gene encoding CD59; to our knowledge, this is the first report of a mammalian species that does not express a functional CD59. The pseudogene we describe is likely the product of a genomic deletion event during its evolutionary divergence from other members of the rodent order

The human CD53 gene, coding for a four transmembrane domain protein, maps to chromosomal region 1p13

The rat OX44/CD53 protein is the prototypic member of a"novel" family of proteins. These proteins are characterizedby four highly hydrophobic transmembrane domains, twosmall extracellular domains, one of which is extensively N-glycosylated,and both the amino and the carboxy terminus intracytoplasmic.This work has been supported by grants from Fundación Ramón Areces and CICYT (SAL90-0209 and SAL91-0043) to P.A.L. and FIS(92-0889) to S.R.CS

The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity

38 p.- 7 fig.Mutations and polymorphisms in the gene encoding factor H (CFH) have been associated with atypical haemolytic uraemic syndrome, dense deposit disease and age-related macular degeneration. The disease-predisposing CFH variants show a differential association with pathology that has been very useful to unravel critical events in the pathogenesis of one or other disease. In contrast, the factor H (fH)-Ile62 polymorphism confers strong protection to all three diseases. Using ELISA-based methods and surface plasmon resonance analyses, we show here that the protective fH-Ile62 variant binds more efficiently to C3b than fH-Val62 and competes better with factor B in proconvertase formation. Functional analyses demonstrate an increased cofactor activity for fH-Ile62 in the factor I-mediated cleavage of fluid phase and surface-bound C3b; however, the two fH variants show no differences in decay accelerating activity. From these data, we conclude that the protective effect of the fH-Ile62 variant is due to its better capacity to bind C3b, inhibit proconvertase formation and catalyze inactivation of fluid-phase and surface-bound C3b. This demonstration of the functional consequences of the fH-Ile62 polymorphism provides relevant insights into the complement regulatory activities of fH that will be useful in disease prediction and future development of effective therapeutics for disorders caused by complement dysregulationThis work was supported by MRC Project Grant Ref 84908 (to C.L.H. and B.P.M.), Ministerio de Ciencia e Innovación Ref SAF 2005-00913 (to S.R.deC.) the CIBER de Enfermedades Raras and Fundación Renal Iñigo Alvarez de Toledo (to S.R.deC.).Peer reviewe

Blocking Complement Factor B Activation Reduces Renal Injury and Inflammation in a Rat Brain Death Model

Introduction: The majority of kidneys used for transplantation are retrieved from brain-dead organ donors. In brain death, the irreversible loss of brain functions results in hemodynamic instability, hormonal changes and immunological activation. Recently, brain death has been shown to cause activation of the complement system, which is adversely associated with renal allograft outcome in recipients. Modulation of the complement system in the brain-dead donor might be a promising strategy to improve organ quality before transplantation. This study investigated the effect of an inhibitory antibody against complement factor B on brain death-induced renal inflammation and injury. Method: Brain death was induced in male Fischer rats by inflating a balloon catheter in the epidural space. Anti-factor B (anti-FB) or saline was administered intravenously 20 min before the induction of brain death (n = 8/group). Sham-operated rats served as controls (n = 4). After 4 h of brain death, renal function, renal injury, and inflammation were assessed. Results: Pretreatment with anti-FB resulted in significantly less systemic and local complement activation than in saline-treated rats after brain death. Moreover, anti-FB treatment preserved renal function, reflected by significantly reduced serum creatinine levels compared to saline-treated rats after 4 h of brain death. Furthermore, anti-FB significantly attenuated histological injury, as seen by reduced tubular injury scores, lower renal gene expression levels (>75%) and renal deposition of kidney injury marker-1. In addition, anti-FB treatment significantly prevented renal macrophage influx and reduced systemic IL-6 levels compared to saline-treated rats after brain death. Lastly, renal gene expression of IL-6, MCP-1, and VCAM-1 were significantly reduced in rats treated with anti-FB. Conclusion: This study shows that donor pretreatment with anti-FB preserved renal function, reduced renal damage and inflammation prior to transplantation. Therefore, inhibition of factor B in organ donors might be a promising strategy to reduce brain death-induced renal injury and inflammation.Nephrolog

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

National identity predicts public health support during a global pandemic

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale