MACROFIBRO

Lung fibrosis is a severe disease that develops after a viral infection, in response to aerosolized environmental toxins, in patients with a chronic inflammatory disease, or without any identified cause (idiopathic pulmonary fibrosis). It is also a complication of several commonly used therapeutic approaches in cancer, such as bleomycin treatment leading to death of 1–2% of treated patients. Chest irradiation to treat breast or lung cancer, or mediastinal lymphoma, has been associated also with a risk of lung fibrosis. The combination of immune checkpoint inhibitors with radiotherapy, which should become the gold standard in some oncology indications, could increase the number of patients presenting fibrosis. No current treatment has proven effective in stopping progression of the disease. Irradiation has been shown in many studies to induce monocyte/macrophage infiltration in tumors, limiting the efficacy of radiotherapy. Fibrosis occurs due to the transition of M1 macrophages to anti-inflammatory pro-fibrotic M2 macrophages. Colony-stimulating factor-1 (CSF-1) is a main cytokine inducing the differentiation of macrophages polarized towards the M2-type. Given the role of M2- macrophages in lung fibrosis development, modulation of their polarization could prevent the disease occurrence. CD115 (or CSF-1R) is the unique cell-surface receptor of CSF-1, expressed by all myeloid cell populations. The CD115 signaling pathway is required for macrophage differentiation and polarization towards the M2-type. ELB041 is a humanized monoclonal antibody (mAb) to CD115 developed by ElsaLys Biotech. It inhibits the differentiation of M2-type macrophages, without depleting myeloid cell populations and without increasing circulating CSF-1 levels. It also inhibits the production of CCL2, a main chemokine implicated in fibrosis development. Based on its unique mode of action, ELB041 is likely to show a better efficacy/safety ratio than any other anti-CD115 mAb in development. Because ELB041 does not cross-react with murine CD115, a transgenic mouse strain humanized for CD115 has been generated on the C57BL/6 genetic background. These CD115-humanized mice will be used to investigate the effects of ELB041 on the inhibition of lung fibrosis in two relevant preclinical models: (1) bleomycin-induced and (2) radiation-induced lung fibrosis. Bleomycin-induced lung fibrosis is a commonly used mouse model to explore the pathogenesis of this disease. C57BL/6 mice are treated by intratracheal injections of bleomycin sulphate, which induces lung fibrosis. According to this model, macrophages play an important role in the pathogenesis of lung fibrosis. We will extend these observations to an irradiation-induced lung fibrosis model. In this model, mice develop a marked pulmonary fibrosis starting from week 16 post-irradiation. These preclinical models are highly relevant to study the effects of ELB041 on lung fibrosis and more generally on the implication of M2-macrophages in this process. In both models, we anticipate that impairment of M2 macrophage polarization by ELB041 will reduce the extent of lung fibrosis. To ensure that the preclinical fibrosis models will be performed using the most relevant markers of ELB041 activity as read-outs and at the optimal dose of ELB041, preliminary experiments will first be performed in vitro and in vivo. In vitro, we will analyze whether ELB041 may regulate known biomarkers of fibrosis produced by human macrophages, such as TGF?. In CD115-humanized mice, we will set up a “mechanistic model” designed to (i) analyze the biomarkers (cytokines, myeloid cell populations) modulated by in vivo CSF-1 treatment, (ii) study the effects of ELB041 on these biomarkers, and (iii) determine the efficacious dose of ELB041 affecting these biomarkers. These results will constitute a strong basis for evaluating the potential of ELB041 in the bleomycin- and irradiation-induced fibrosis models.