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Fulfilling Paul Ehrlich’s Dream: therapeutics with activity on demand

Descripción del proyecto

¿Si pudiéramos matar las células enfermas sin dañar los tejidos normales?

Los científicos llevan décadas buscando la «bala mágica» que actúe selectivamente sobre las células causantes de enfermedades, pero los tratamientos actuales contra el cáncer y las enfermedades inflamatorias crónicas distan mucho de lograrlo. Aunque los anticuerpos monoclonales actúan contra dianas específicas, a menudo no son curativos como agentes únicos y el intento de «armarlos» con fármacos o citocinas ha generado niveles de toxicidad inaceptables. En este contexto, en el innovador proyecto ZAUBERKUGEL, financiado por el Consejo Europeo de Investigación, se propone una solución que podría suponer un cambio radical. Consiste en la liberación controlada de fármacos citotóxicos o el ensamblaje escalonado no covalente de citocinas. Para elaborar un perfil de respuesta a la terapia se utilizarán metodologías proteómicas innovadoras, basadas en el análisis del peptidoma del antígeno leucocitario humano. Este método encierra un potencial considerable para el tratamiento de enfermedades graves con agentes farmacéuticos de «actividad a demanda».

Objetivo

"Paul Ehrlich was the first scientist to postulate that if a compound could be made that selectively targeted disease-causing cells, then this agent could be used for the delivery of a toxin, which would enable a pharmacotherapy of unprecedented potency and selectivity. With this procedure, a ""magic bullet"" (Zauberkugel, his term for an ideal therapeutic agent) would be created, that killed diseased cells while sparing normal tissues.
The concept of a ""magic bullet"" was to some extent realized by the invention of monoclonal antibodies, as these molecules provide a very specific binding affinity to their cognate target. However, monoclonal antibodies used as single agents are typically not able to induce cures for cancer or chronic inflammatory diseases. More recently, intense academic and industrial research activities have aimed at “arming” monoclonal antibodies with drugs or cytokines, in order to preferentially deliver these therapeutic payloads to the site of disease. Unfortunately, in most cases, ""armed"" antibody products still cause unacceptable toxicities, which prevent escalation to potentially curative dose regimens.
In this Project, I outline a therapeutic strategy, which relies on the use of extremely specific tumor targeting agents, for the selective delivery of payloads, which can be conditionally activated at the site of disease. Methodologies for the conditional generation of active payloads include the stepwise non-covalent assembly of cytokines and the controlled release of cytotoxic drugs at suitable time points after injection, when the concentration of therapeutic agent in normal organs is acceptably low. Response to therapy will be profiled using innovative proteomic methodologies, based on HLA-peptidome analysis.
Pharmaceutical agents with “activity on demand” hold a considerable potential not only for the therapy of cancer, but also for the treatment of other serious diseases, including certain highly debilitating chronic inflammatory condition"

Régimen de financiación

ERC-ADG - Advanced Grant

Institución de acogida

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Aportación neta de la UEn
€ 2 000 000,00
Dirección
Raemistrasse 101
8092 Zuerich
Suiza

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Región
Schweiz/Suisse/Svizzera Zürich Zürich
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 2 000 000,00

Beneficiarios (1)