Summary
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.
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.
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| Web resources: | https://cordis.europa.eu/project/id/101080897 |
| Start date: | 01-06-2023 |
| End date: | 31-05-2028 |
| Total budget - Public funding: | 5 605 576,25 Euro - 5 605 576,00 Euro |
Cordis data
Original description
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.
Status
SIGNEDCall topic
HORIZON-HLTH-2022-DISEASE-06-02-two-stageUpdate Date
31-07-2023
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Organisations
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| SORBONNE UNIVERSITE (SU) (Coördinator)
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| COMMISSARIAT A L ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES (CEA)
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| ICOSAGEN CELL FACTORY OU
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| ILTOO PHARMA
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| INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
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| KING'S COLLEGE LONDON
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| MEDIZINISCHE UNIVERSITAET WIEN
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| UNIVERSITA DEGLI STUDI DI TRIESTE
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| UNIVERSITAT ZU LUBECK (UZL)
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| UNIVERSITATSKLINIKUM SCHLESWIG-HOLSTEIN