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1.
Br J Pharmacol ; 177(5): 1061-1076, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31648370

RESUMEN

BACKGROUND AND PURPOSE: Inhibition of the T- and B-cell interaction through the CD40/CD40 ligand (L) axis is a favourable approach for inflammatory disease treatment. Clinical studies of anti-CD40L molecules in autoimmune diseases have met challenges because of thromboembolic events and adverse haemostasis. VIB4920 (formerly MEDI4920) is a novel CD40L antagonist and Tn3 fusion protein designed to prevent adverse haemostasis and immunopharmacology. We evaluated the pharmacokinetics, activity and toxicity of VIB4920 in monkeys. EXPERIMENTAL APPROACH: Cynomolgus monkeys received i.v. or s.c. 5-300 mg·kg-1 VIB4920 or vehicle, once weekly for 1 month (Studies 1 and 2) or 28 weeks (Study 3). VIB4920 exposure and bioavailability were determined using pharmacokinetic analyses, and immune cell population changes via flow cytometry. Pharmacological activity was evaluated by measuring the animals' capacity to elicit an immune response to keyhole limpet haemocyanin (KLH) and tetanus toxoid (TT). KEY RESULTS: VIB4920 demonstrated linear pharmacokinetics at multiple doses. Lymphocyte, monocyte, cytotoxic T-cell and NK cell counts were not significantly different between treatment groups. B-cell counts reduced dose-dependently and the T-cell dependent antibody response to KLH was suppressed by VIB4920 dose-dependently. The recall response to TT was similar across treatment groups. No thromboembolic events or symptoms of immune system dysfunctionality were observed. CONCLUSIONS AND IMPLICATIONS: VIB4920 demonstrated an acceptable safety profile in monkeys. VIB4920 showed favourable pharmacokinetics, dose-dependent inhibition of a neoantigen-specific immune response and no adverse effects on immune function following long-term use. Our data support the use of VIB4920 in clinical trials.


Asunto(s)
Enfermedades Autoinmunes , Ligando de CD40 , Animales , Linfocitos B , Macaca fascicularis
2.
Sci Transl Med ; 11(489)2019 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-31019027

RESUMEN

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.


Asunto(s)
Autoanticuerpos/metabolismo , Autoinmunidad/fisiología , Ligando de CD40/metabolismo , Proliferación Celular/fisiología , Agregación Plaquetaria/fisiología , Artritis Reumatoide/metabolismo , Linfocitos B/metabolismo , Antígenos CD40/metabolismo , Voluntarios Sanos , Humanos
3.
Artículo en Inglés | MEDLINE | ID: mdl-23989160

RESUMEN

Tn3 proteins are a novel class of binding molecules based on the third fibronectin type III domain of human tenascin C. Target-specific Tn3 proteins are selected from combinatorial libraries in which three surface-exposed loops have been diversified. Here, the cocrystallization of two different Tn3 proteins in complex with CD40L, a therapeutic target for immunological disease, is reported. These crystal structures are the first to be reported of Tn3 proteins and will help to reveal how these engineered molecules achieve specific recognition of a cognate target.


Asunto(s)
Ligando de CD40/química , Fibronectinas/química , Péptidos/química , Secuencia de Aminoácidos , Sitios de Unión , Ligando de CD40/genética , Ligando de CD40/aislamiento & purificación , Cristalografía por Rayos X , Escherichia coli/genética , Fibronectinas/genética , Expresión Génica , Humanos , Datos de Secuencia Molecular , Biblioteca de Péptidos , Péptidos/genética , Péptidos/aislamiento & purificación , Unión Proteica , Estructura Secundaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Alineación de Secuencia
4.
Nat Immunol ; 8(5): 487-96, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17417641

RESUMEN

Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.


Asunto(s)
Proteína HMGB1/fisiología , Lupus Eritematoso Sistémico/inmunología , Oligodesoxirribonucleótidos/inmunología , Receptor para Productos Finales de Glicación Avanzada/fisiología , Receptor Toll-Like 9/metabolismo , Animales , Complejo Antígeno-Anticuerpo , Linfocitos B , Islas de CpG , Proteínas de Unión al ADN/inmunología , Células Dendríticas/citología , Células Dendríticas/metabolismo , Proteína HMGB1/biosíntesis , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Ratones , Ratones Endogámicos C57BL , Receptor para Productos Finales de Glicación Avanzada/biosíntesis , Receptores de Superficie Celular/metabolismo , Receptor Toll-Like 9/fisiología
6.
Bioorg Med Chem Lett ; 14(14): 3721-5, 2004 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-15203150

RESUMEN

A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.


Asunto(s)
Peso Corporal/efectos de los fármacos , Imidazoles/síntesis química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Animales , Sitios de Unión , Peso Corporal/fisiología , Células Cultivadas , Imidazoles/farmacología , Ratas , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-Actividad
7.
J Med Chem ; 47(7): 1602-4, 2004 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-15027849

RESUMEN

The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.


Asunto(s)
Benzamidinas/síntesis química , Emaciación/tratamiento farmacológico , Imidazoles/síntesis química , Neoplasias/complicaciones , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Administración Cutánea , Animales , Benzamidinas/química , Benzamidinas/farmacología , Emaciación/etiología , Imidazoles/química , Imidazoles/farmacología , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Trasplante Heterólogo
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