Towards a new treatment targeting choroidal neovascularization in wet age-related macular degeneration – TARMAC-17

Wet age-related macular degeneration (WAMD), characterized by the neo-vascularization of the retro-foveolar choroid, leads to blindness within few years. This disease is related to angiogenesis mediated by the Vascular Endothelial Growth Factor A (VEGF) and to inflammation. The only available treatments consists in monthly intra-vitreal injections of antibodies directed against VEGF (ranibizumab (Lucentis®), bevacizumab (Avastin®)), or extracellular portions of VEGF receptors 1and 2 that “trap” VEGF, VEGF-B and placental growth factor (aflibercept (Eylea®)). Despite their relative success, these drugs only delay progression to blindness. Therefore, retinal specialists acknowledge the need for additional interventions. Indeed, 30% of the patients are insensitive to these therapies and no means are available to predict their degree of response. Moreover, the chronic use of anti-VEGF-agents may induce retinal atrophy.
Several Phase 3 clinical trials in 2016 explored the efficacy of Fovista, an inhibitor of both VEGF and platelet-derived growth factor (PDGF). Although this innovative approach showed promising results Phase 3 clinical trials – during which it was administered in combination with Lucentis – showed that Fovista was not effective.
We hypothesize that these failures are due to the redundancy of pro-angiogenic factors and to activation of alternative signaling pathways. Importantly, anti-VEGF/PDGF/PlGF therapies do not avoid the inflammation, which also characterizes WAMD. Inflammation and angiogenesis are integrated processes and several cytokines are pro-inflammatory and pro-angiogenic factors.
We focused this project on CXCL cytokines because the leading member of this family of cytokines, interleukin 8/CXCL8 and other members of the CXCL family (CXCL1, 7) (i) are abundantly secreted where VEGF is produced; (ii) its expression is comparable to those of VEGF; (iii) the molecular factors that stimulate VEGF expression also up-regulate CXCL 1, 7, 8 expression. The CXCL cytokine family is divided in two subclasses: ELR+CXCL and ELR-CXCL; the ELR+CXCLs (CXCL1,2,3,5,6,7,8) are pro-angiogenic/pro-inflammatory, whereas ELR-CXCLs are anti-angiogenic/anti-inflammatory. Angiogenesis is not an on/off mechanism but rather a balanced ratio of cytokines exerting a positive and negative effect. Hence, an equilibrated ratio of both subclasses of cytokines maintains a physiological angiogenic pattern. The ELR+CXCL exert their effects through G-protein coupled receptors, CXCR1 and CXCR2 that are present at the surface of endothelial and immune cells. In this project, we hypothesized that ELR+CXCL are as important as VEGF for the development of angiogenesis and inflammation in WAMD.
Hence, our objectives will be dedicated to:
1. The development of two complementary therapeutic strategies through; i)the optimization of potent small molecule inhibitors of CXCR1/2 (lead optimization); ii) the development of bispecific antibodies targeting VEGF and relevant ELR+CXCL cytokines
2. The development of a non-invasive diagnostic kit to determine patients that will benefit of anti-VEGF therapies.
It is worth noting that a combination of drugs and antibodies would be of great interest and should be deeply addressed in this project. The final goal is to improve the general outcome of patients and to delay vision loss for therapeutic, psychological and economical purposes.
This project will be developed by a multidisciplinary consortium of specialists in patients’ treatment (head of ophthalmology department Nice Hospital), angiogenesis and resistance to anti-VEGF therapy within an internationally recognized Institute (Institute for research on cancer and aging of Nice), drugs design and development in another internationally recognized chemistry institute (Institute of Chemistry of Nice).