Video Experimental Relacionado
Updated: Aug 18, 2026
16:07
Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method
Published on: September 16, 2017
La inactivación de la señalización del TNF por variantes de TNF dominantes negativas diseñadas racionalmente
Paul M Steed1, Malú G Tansey, Jonathan Zalevsky
1Xencor, 111 West Lemon Avenue, Monrovia, CA 91016, USA.
Science (New York, N.Y.)
|September 27, 2003
Resumen
Los científicos diseñaron proteínas variantes del factor de necrosis tumoral (TNF) para neutralizar el TNF nativo. Esta estrategia inactiva el TNF por secuestro, ofreciendo un nuevo enfoque potencial para la bioterapia antiinflamatoria.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Inmunología Inmunología.
- Biología Estructural Biología estructural.
Sus antecedentes:
- El factor de necrosis tumoral (TNF) es un regulador crítico de la inflamación.
- La señalización desregulada del TNF está implicada en numerosas condiciones patológicas.
- Dirigirse al TNF es una estrategia clave en el tratamiento de enfermedades inflamatorias.
Objetivo del estudio:
- Para diseñar proteínas TNF variantes capaces de inhibir la actividad nativa del TNF.
- Desarrollar una nueva estrategia para inactivar el TNF a través de la formación de complejos proteicos.
- Explorar el potencial de las variantes dominantes negativas del TNF como bioterapéuticos antiinflamatorios.
Principales métodos:
- El diseño de proteínas basado en la estructura se empleó para diseñar nuevas variantes de TNF.
- Las variantes diseñadas fueron diseñadas para formar heterotrimeros con TNF nativo.
- Se evaluó la consecuencia funcional de estos heterotrimeros en la unión y señalización del receptor TNF.
Principales resultados:
- Las variantes de TNF diseñadas forman rápidamente complejos heterotriméricos con el TNF nativo.
- Estos complejos secuestran eficazmente el TNF nativo, impidiendo la unión al receptor.
- La estrategia demostró la atenuación de la patología mediada por TNF en modelos animales.
- Los TNF dominantes negativos diseñados mostraron potencial como agentes antiinflamatorios.
Conclusiones:
- Las variantes de TNF dominantes negativas pueden diseñarse racionalmente para inhibir la función del TNF.
- La inactivación del TNF a través del secuestro presenta una estrategia terapéutica viable para las condiciones inflamatorias.
- Este enfoque puede ser extensible a otras citocinas multiméricas dentro de la superfamilia TNF.
Videos de Conceptos Relacionados
02:26NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
01:15Receptor Downregulation in MVBs
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
01:24T Cell Types and Functions
When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
01:24Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
Tumor Necrosis Factor (TNF), a proinflammatory cytokine, contributes significantly to the inflammation seen in Crohn's disease. It exists as soluble TNF and membrane-bound TNF, with actions mediated through TNF receptors (TNFR). TNFR activation leads to the release of proinflammatory cytokines, T-cell activation, collagen production, and leukocyte migration, all contributing to inflammation in Crohn's disease. Anti-TNF monoclonal antibodies, namely infliximab (Remicade), adalimumab (Humira),...