Periodic Reporting for period 1 - TiilT (Preclinical development of a 3rd-generation interleukin-2 targeted to inflammatory sites)
Reporting period: 2023-06-01 to 2024-11-30
TiilT is funded by the European Union’s Horizon Europe Programme under Grant Agreement No. 101072435 and coordinated by Pr David Klatzmann of the Sorbonne University and Medical School. TiilT aims to develop a next-generation immunotherapy based on Treg stimulation.
Regulatory T cells (Tregs) play a crucial role in controlling immune responses and are key targets for the treatment of autoimmune and inflammatory diseases, including cardiovascular diseases such as atherosclerosis, vasculitis and myocardial infarction. Low doses of interleukin-2 (IL-2) can stimulate Tregs. Various forms of IL-2 are undergoing extensive clinical evaluation.
The aim of TiilT is to develop a next generation IL-2 targeted to sites of inflammation (IL-2IT) and to validate it for the treatment of inflammatory cardiovascular diseases.
Targeting inflammatory sites will be achieved by fusing IL-2 to antibodies (Abs) against oxidation specific epitopes (OSE), which are both universal markers and mediators of inflammation.
Led by key experts in the field, TiilT will validate the general concept of targeting therapeutic molecules to inflammatory sites and more specifically targeting IL-2 for the treatment of inflammatory cardiovascular diseases, and beyond.
Regulatory T cells (Tregs) play a crucial role in controlling immune responses and are key targets for the treatment of autoimmune and inflammatory diseases, including cardiovascular diseases such as atherosclerosis, vasculitis and myocardial infarction. Low doses of interleukin-2 (IL-2) can stimulate Tregs. Various forms of IL-2 are undergoing extensive clinical evaluation.
The aim of TiilT is to develop a next generation IL-2 targeted to sites of inflammation (IL-2IT) and to validate it for the treatment of inflammatory cardiovascular diseases.
Targeting inflammatory sites will be achieved by fusing IL-2 to antibodies (Abs) against oxidation specific epitopes (OSE), which are both universal markers and mediators of inflammation.
Led by key experts in the field, TiilT will validate the general concept of targeting therapeutic molecules to inflammatory sites and more specifically targeting IL-2 for the treatment of inflammatory cardiovascular diseases, and beyond.
By the end of reporting period 1, the following achievements can be underlined:
Workpackage 1 (WP1): we successfully identified and analyzed more than 20 different antibodies from various sources. By modifying sequences from these antibodies, we generated anti-OSE single-chain variable fragment (scFv) antibodies that were highly specific for their target molecules, as first demonstrated by ELISA and competition assays. These scFvs effectively bound to atherosclerotic plaques in both mice and humans, specifically targeting lipid-rich, acellular regions of plaques in advanced lesions.
Workpackage 2 (WP2): we explored the treatment modalities of IL-2IT administration and succeeded in generating valuable insights by developing two gene expression systems (AAVs and mRNA)
also explored the treatment modalities of IL-2IT administration. In fact, during this initial phase of the project, we successfully generated valuable insights with this regard by developing two gene expression systems (AAVs and mRNA)
Workpackage 3 (WP3): we have developed a pipeline for the preclinical evaluation of IL-2IT candidates, including safety, pharmacokinetics/pharmacodynamics (PK/PD), and biodistribution studies in animal models. Comprehensive PK/PD studies are being conducted in mice under both normal and inflammatory conditions. To date, four IL-2ITs have been fully characterized.
Workpackage 4 (WP4): initial results obtained in animal models are very promising showing a significant and selective increase in T regulatory (Treg) cells following administration of IL-2IT.
In addition, a successful arthritis model has been developed for efficacy studies.
Workpackage 5 (WP5): regarding dissemination and valorisation, members of the consortium have organized the 3rd edition of “The Promise of Interleukin-2 Therapy for Autoimmune and Inflammatory Diseases, Allergy, Transplantation, and Cancer” an international meeting, held from September 4 to 7, 2024, in Paris and which brought together leading scientists and pharmaceutical companies.
Workpackage 6 (WP6): this WP is dedicated to the management and governance of the project which has been successfully implemented and ensures smooth running of the activities throughout its duration.
Overall, TiilT is progressing well towards its objectives. In the coming period, a maximum of four IL-2IT candidates will be selected by consensus for further evaluation in animal models of cardiovascular diseases.
Workpackage 1 (WP1): we successfully identified and analyzed more than 20 different antibodies from various sources. By modifying sequences from these antibodies, we generated anti-OSE single-chain variable fragment (scFv) antibodies that were highly specific for their target molecules, as first demonstrated by ELISA and competition assays. These scFvs effectively bound to atherosclerotic plaques in both mice and humans, specifically targeting lipid-rich, acellular regions of plaques in advanced lesions.
Workpackage 2 (WP2): we explored the treatment modalities of IL-2IT administration and succeeded in generating valuable insights by developing two gene expression systems (AAVs and mRNA)
also explored the treatment modalities of IL-2IT administration. In fact, during this initial phase of the project, we successfully generated valuable insights with this regard by developing two gene expression systems (AAVs and mRNA)
Workpackage 3 (WP3): we have developed a pipeline for the preclinical evaluation of IL-2IT candidates, including safety, pharmacokinetics/pharmacodynamics (PK/PD), and biodistribution studies in animal models. Comprehensive PK/PD studies are being conducted in mice under both normal and inflammatory conditions. To date, four IL-2ITs have been fully characterized.
Workpackage 4 (WP4): initial results obtained in animal models are very promising showing a significant and selective increase in T regulatory (Treg) cells following administration of IL-2IT.
In addition, a successful arthritis model has been developed for efficacy studies.
Workpackage 5 (WP5): regarding dissemination and valorisation, members of the consortium have organized the 3rd edition of “The Promise of Interleukin-2 Therapy for Autoimmune and Inflammatory Diseases, Allergy, Transplantation, and Cancer” an international meeting, held from September 4 to 7, 2024, in Paris and which brought together leading scientists and pharmaceutical companies.
Workpackage 6 (WP6): this WP is dedicated to the management and governance of the project which has been successfully implemented and ensures smooth running of the activities throughout its duration.
Overall, TiilT is progressing well towards its objectives. In the coming period, a maximum of four IL-2IT candidates will be selected by consensus for further evaluation in animal models of cardiovascular diseases.
TiilT aims to revolutionise immunotherapy by addressing high-burden diseases and conditions with unmet medical need. Its primary outcome is the validation of a novel approach: targeting therapeutic molecules to sites of inflammation, specifically using IL-2 as a treatment for inflammatory cardiovascular diseases.
By demonstrating the biological properties and efficacy of IL-2IT, TiilT will lay the groundwork for the development of new immunotherapies for inflammatory diseases. The project will generate valuable resources, including innovative in vitro models, toxicity and biodistribution data in mice and primates, and animal models for the evaluation of therapeutic efficacy. These results will have a significant impact for the field, enabling researchers to advance their own targeted therapeutic molecules.
TiilT will provide preclinical validation of the concept, paving the way for industrial projects and enabling the initiation of first-in-human trials immediately upon project completion, opening a new frontier in immunotherapy and creating opportunities for the life sciences industry.
Our ultimate goal is to improve patient care and the treatment of chronic inflammatory diseases and acute inflammation. Our work will have a direct impact on patient care, starting with those suffering from conditions within our scope and beyond. All of these diseases are major health threats with high unmet medical needs and affect a large proportion of society.
By demonstrating the biological properties and efficacy of IL-2IT, TiilT will lay the groundwork for the development of new immunotherapies for inflammatory diseases. The project will generate valuable resources, including innovative in vitro models, toxicity and biodistribution data in mice and primates, and animal models for the evaluation of therapeutic efficacy. These results will have a significant impact for the field, enabling researchers to advance their own targeted therapeutic molecules.
TiilT will provide preclinical validation of the concept, paving the way for industrial projects and enabling the initiation of first-in-human trials immediately upon project completion, opening a new frontier in immunotherapy and creating opportunities for the life sciences industry.
Our ultimate goal is to improve patient care and the treatment of chronic inflammatory diseases and acute inflammation. Our work will have a direct impact on patient care, starting with those suffering from conditions within our scope and beyond. All of these diseases are major health threats with high unmet medical needs and affect a large proportion of society.