CORDIS - EU research results
CORDIS

Preclinical development of a 3rd-generation interleukin-2 targeted to inflammatory sites

Project description

Targeting inflammatory sites with novel immunotherapy

Regulatory T cells (Tregs) are a subset of T lymphocytes with a key role in regulating the immune system by suppressing overactive immune responses and maintaining unresponsiveness to self-antigens. Tregs are emerging as clinical tools for the treatment of autoimmune and inflammatory diseases, with low doses of interleukin-2 (IL-2) being evaluated for their activation. Funded by the HORIZON programme, the TiilT project aims to develop third-generation IL-2 with improved properties. Researchers propose using antibodies against pro-inflammatory markers to target IL-2 to inflammation sites. This new formulation will be tested in preclinical models and optimised for use in cardiovascular diseases, such as atherosclerosis and myocardial infarction.

Objective

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.

Coordinator

SORBONNE UNIVERSITE
Net EU contribution
€ 796 000,00
Address
21 RUE DE L'ECOLE DE MEDECINE
75006 Paris
France

See on map

Region
Ile-de-France Ile-de-France Paris
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 796 000,00

Participants (8)

Partners (1)