Periodic Reporting for period 1 - MInfla-Tilc (Generation of therapeutic antibodies targeting type 2 Innate Lymphoid cells in asthma)
Période du rapport: 2020-01-01 au 2021-12-31
Asthma is a chronic respiratory disease that affects 300 million people worldwide and is expected to reach 400 million by 2025. Currently, there is no cure for this disease and only symptomatic treatments such as inhaled corticosteroids are available, but they are not always effective. These broad-spectrum immunosuppressive treatments have adverse effects due to off-target effects (negative impact on "beneficial" cells), as well as an overall dampening of immune responses that could be detrimental in the long term (decreased resistance to infections related to asthma exacerbations). The failure of long-term remission is due to the fact that the underlying immunopathology is not targeted.
We proposed to target innate lymphoid cells 2 (ILC2), a subset that is a major player in allergic asthma. ILC2 are abundantly present as tissue-resident cells in the lung, both in humans and mice. Strikingly, the induction of allergic asthma in a mouse model deficient in ILC2s is abolished. Furthermore, transfer of ILC2s into the same mouse recapitulates the pathology. Mechanistically, activated ILC2s are the main producer of type 2 cytokines that maintain the chronicity of asthma by recruiting other inflammatory and pathogenic cells, notably eosinophils, and ultimately drive hyperreactivity and mucus hypersecretion. In humans, ILC2 are more abundant in peripheral blood mononuclear cells (PBMCs) of patients with allergic asthma compared to healthy controls. They are also found in sputum and peripheral blood mononuclear cells of patients with severe and eosinophilic asthma compared to mild asthma. Collectively, these data highlight the importance of ILC2 in allergic inflammation and encourage us to target these cells for therapeutic purposes. MInfla-Tilc is a translational and integrated project aimed at launching a novel antibody (Ab) therapeutic treatment against ILC2 to control severe asthma.
Here, we generated a novel trispecific NK cell engager (NKCE) capable of specifically targeting ILC2 via CRTH2 cell surface expression and triggering cellular cytotoxicity of NK cells via CD16 and NKp46 binding properties. In parallel, we have also generated a mouse expressing the human CRTH2 gene as a replacement for the mouse gene. We are currently generating homozygous knock-in mice for the human gene (huCRTH2 KI mice) after backcrossing wild type mice with heterozygous mice. Finally, we have set up a lung inflammation protocol using the IL33 and papain combo to test the therapeutic impact of our first-in-class NKCE in hCRTH2 KI mice. Our model is ready to be used and we are waiting to obtain a significant batch of KI mice to perform the therapeutic trial with our anti-CRTH2 NKCE.
We proposed to target innate lymphoid cells 2 (ILC2), a subset that is a major player in allergic asthma. ILC2 are abundantly present as tissue-resident cells in the lung, both in humans and mice. Strikingly, the induction of allergic asthma in a mouse model deficient in ILC2s is abolished. Furthermore, transfer of ILC2s into the same mouse recapitulates the pathology. Mechanistically, activated ILC2s are the main producer of type 2 cytokines that maintain the chronicity of asthma by recruiting other inflammatory and pathogenic cells, notably eosinophils, and ultimately drive hyperreactivity and mucus hypersecretion. In humans, ILC2 are more abundant in peripheral blood mononuclear cells (PBMCs) of patients with allergic asthma compared to healthy controls. They are also found in sputum and peripheral blood mononuclear cells of patients with severe and eosinophilic asthma compared to mild asthma. Collectively, these data highlight the importance of ILC2 in allergic inflammation and encourage us to target these cells for therapeutic purposes. MInfla-Tilc is a translational and integrated project aimed at launching a novel antibody (Ab) therapeutic treatment against ILC2 to control severe asthma.
Here, we generated a novel trispecific NK cell engager (NKCE) capable of specifically targeting ILC2 via CRTH2 cell surface expression and triggering cellular cytotoxicity of NK cells via CD16 and NKp46 binding properties. In parallel, we have also generated a mouse expressing the human CRTH2 gene as a replacement for the mouse gene. We are currently generating homozygous knock-in mice for the human gene (huCRTH2 KI mice) after backcrossing wild type mice with heterozygous mice. Finally, we have set up a lung inflammation protocol using the IL33 and papain combo to test the therapeutic impact of our first-in-class NKCE in hCRTH2 KI mice. Our model is ready to be used and we are waiting to obtain a significant batch of KI mice to perform the therapeutic trial with our anti-CRTH2 NKCE.