Specific targeting of the drivers of fibrotic diseases of the kidney and lung – FibrotargLungKidney

b.1 Hypothesis

Our hypothesis stipulates that ELR+CXCL/CXCR1/2 play a crucial role in fibrosis and that targeting CXCR1/2 can stop inflammation, mesenchymal cell activation, angiogenesis, and fibrosis. Interfering with the VEGFC pathway, which is also linked to CXCR1/2 signaling, may be effective in its own right or may further enhance the efficacy of RCT001.

b.2 Objectives

Our project is clearly translational. The partners in this project, who have complementary expertise and material, aim to show that CXCR1/2/ELR+CXCL cytokines and VEGFC/receptors/coreceptors pathways correlate with the aggressiveness of renal and pulmonary fibrosis in patient samples. We will characterize the effects of RCT001 and/or anti-VEGFC Mab on preclinical models of lung and kidney fibrosis and decipher their mechanisms of action. Roca Therapeutics and Kekkan Biologics will be responsible for the preclinical CMC and GLP tox studies to enable two innovative therapies to enter the clinic in pathological situations with unmet medical need.

c. Methodology

c.1. Patient samples

c.2. Preclinical mouse models

Chronic Kidney Disease (CKD) & Idiopathic Pulmonary Fibrosis (IPF).

c.3. Task 1: Impact of RCT001 and anti-VEGFC Mab in vitro on ROS, senescence, and fibrosis in vitro

c.4. Task 2: Effect of RCT001 and anti-VEGFC Mab treatment on the biology and reprogramming of M2 macrophages

c.5. Task 3: Targeting the profibrotic environment in murine models of IPF and CKD

c.6 & c7. Task 4: Analysis of patient samples, preclinical CMC , GLP toxicology studies for RCT001 (c.6) and anti-VEGFC Mabs (c.7)

c2 -> Mouse models are developed, validated and available. Samples have been taken and are currently being analyzed.

c3 -> RCT001 inhibits oxidative stress and fibrosis in vitro.

C4 -> RCT001 inhibits M2 macrophage polarization and induces their reprogramming. RCT001 inhibits macrophage secretion of cytokines involved in fibrosis. The VEGFC antibody is currently being evaluated for macrophage polarization.

C5 -> RCT001 and anti-VEGFC Mabs are currently undergoing animal testing.

C6 -> Studies in progress

our goal is to characterize the role of ELR+CXCL1/2 and the VEGFC signaling in all the mechanisms involved in development of IPF or CKD (ROS, senescence, fibrosis). RCT001, a CXCR1/2 inhibitor develop by RC, and/or anti-VEGFC antibodies developed by KB should prevent and/or treat IPF/CKD. RC and KB will manage the necessary developments (CMC & regulatory toxicology) to start a phase 1/2 clinical trial at the end of the study.

Background
Accumulation of extracellular matrix, recruitment of inflammatory macrophages and neutrophils secreting reactive oxygen species (ROS), and cytokines are characteristic of idiopathic pulmonary fibrosis (IPF) and renal fibrosis (RF). Signaling cascades triggered by TGF beta and involving cytokines and profibrotic factors are important therapeutic targets. The pro-inflammatory/pro-angiogenic chemokines ELR+CXCL and their receptors CXCR1/2 play a key role in promoting pulmonary fibrosis and nephropathy. In addition, VEGFC, a key driver of lymphangiogenesis produced by proinflammatory M2 macrophages, is critical for fibrosis via a cross-talk with TGF beta and ELR+CXCL stimulate lymphangiogenesis via VEGFC. To develop small therapies targeting these processes, the coordinator founded start-ups Roca therapeutics (RT) and Kekkan Biologics (KB). RT developed CXCR1/2 inhibitors and its drug candidate RCT001, and KB licensed the coordinator team's anti-VEGFC monoclonal antibodies. RCT001 inhibits the production of ROS, inflammation and fibrosis, is non-toxic to normal cells, stable, has good bioavailability and half-life. Anti-VEGFC Mab inhibits the proliferation of fibroblasts.

Hypothesis
Our hypothesis stipulates that ELR+CXCL/CXCR1/2 play a crucial role in fibrosis and that targeting CXCR1/2 can stop inflammation, mesenchymal cell activation, angiogenesis, and fibrosis. Interfering with the VEGFC pathway, which is also linked to CXCR1/2 signaling, may be effective in its own right or may further enhance the efficacy of RCT001. We believe that targeting two interconnected signaling pathways involved in chronic inflammation and abnormal lymphangiogenesis may represent innovative therapies.

Methodology
This translational project is based on the study of patient samples and the correlation between the presence of players in the ELR+CXCL/CXCR1/2 and VEGFC signaling pathways and the severity of IPF and/or RF. The effects of inhibiting both pathways individually or in combination on M2 macrophage polarisation and their ability to inhibit ROS formation will be tested in models of epithelial and endothelial cells and fibroblasts. The relevance of the two targetings will be evaluated functionally or biologically in models of IPF and RF in vivo.

Expected results
Pulmonary and renal fibrosis are currently at therapeutic impasses. Innovative therapies are urgently needed. Our patented molecules, backed by two start-ups, mean hope for patients. The two start-ups will licence the application patents for these inhibitors to carry out all the necessary steps to enter the clinical phase.