Descrizione del progetto
Mettere nel mirino i siti dell'infiammazione con una nuova immunoterapia
Le cellule T regolatorie (Treg) sono un sottogruppo di linfociti T con un ruolo chiave nella regolazione del sistema immunitario, poiché sopprimono le risposte immunitarie iperattive e mantengono la non responsività agli auto-antigeni. Le Treg stanno emergendo come strumenti clinici per il trattamento di malattie autoimmuni e infiammatorie, con basse dosi di interleuchina-2 (IL-2) attualmente in fase di valutazione per la loro attivazione. Finanziato dal programma ORIZZONTE, il progetto TiilT intende sviluppare IL-2 di terza generazione con proprietà migliorate. I ricercatori propongono di utilizzare anticorpi contro i marcatori pro-infiammatori per indirizzare le IL-2 ai siti di infiammazione. Questa nuova formulazione sarà testata in modelli preclinici e ottimizzata per l’uso nelle malattie cardiovascolari, come l’aterosclerosi e l’infarto del miocardio.
Obiettivo
As major players in the regulation of immune responses, regulatory T cells (Tregs) are important therapeutic targets for autoimmune and inflammatory diseases. Interleukin-2 (IL-2) used at low doses (IL-2LD) stimulate and expand Tregs in vivo. While 1st-generation native IL-2LD are currently under extensive clinical evaluation, pharmaceutical companies are developing 2nd-generation IL-2 muteins with improved half-life and activity.
We aim to develop 3rd-generation IL-2 specifically targeting inflammatory sites (IL-2IT) by using antibodies (Abs) against oxidation specific epitopes (OSE) that are both universal markers and mediators of inflammation. IL-2-OSE-Ab fusion proteins should allow dampening of local inflammation by a double-hit mechanism involving Ab neutralization of pro-inflammatory OSE and IL-2 stimulation of Tregs.
As a proof of concept, we designed a first IL-2IT in which an IL-2N88R mutein is fused to an scFv from a prototypic anti-OSE Ab. This IL-2IT (i) binds to IL-2 receptors and OSE, (ii) has an extended half-life and (iii) superior therapeutic efficacy compared to native IL-2 in mice.
Our general objectives are to design an optimized IL-2IT by testing combinations of different anti-OSE Ab with IL-2 and IL-2 muteins, and to complete its preclinical development in mice and macaques.
We will validate the use of IL-2IT in cardiovascular diseases (CVD), i.e. atherosclerosis, vasculitis, myocardial infarction and SLE-associated CVD, as these conditions have been shown to be improved by Treg infusions, native IL-2 and OSE-Abs in mice.
Carried by leading experts in the use IL-2, OSE-Abs, models of CVD, and clinical trials with native IL-2, the successful validation of an IL-2IT will open a new era for highly selective and effective immunotherapies based on Treg stimulation for diseases that represent a leading cause of death and morbidity. Furthermore, it will validate the broader concept of targeting any therapeutic molecule to inflammatory sites.
Campo scientifico
- medical and health scienceshealth sciencesinflammatory diseases
- natural scienceschemical scienceselectrochemistryelectrolysis
- medical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosis
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicineimmunologyimmunotherapy
Parole chiave
Programma(i)
Invito a presentare proposte
HORIZON-HLTH-2022-DISEASE-06-two-stage
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HORIZON-RIA - HORIZON Research and Innovation ActionsCoordinatore
75006 Paris
Francia