Lrg-1 antagonists: Direct effect upon cancer cells
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The formation of new blood vessels by angiogenesis is a key feature of number of diseases including Age-related Macular Degeneration (AMD), Proliferative Diabetic Retinopathy (PDR), atherosclerosis, rheumatoid arthritis and cancer. Vascular Endothelial Growth Factors (VEGFs) and their receptors have been previously identified as targets for therapy of these diseases but their success in human therapy is limited with adverse side effects upon long term use.
Researchers at UCL Institute of Ophthalmology have now identified a novel protein Lrg1 which acts in the pathogenic angiogenesis pathway. An antibody therapy has been developed against Lrg1 and is currently in pre-clinical development.
The Technology and its Advantages
Researchers at UCL Institute of Ophthalmology have identified Lrg1 (leucine-rich alpha-2-glycoprotein-1) as a player in angiogenesis, tumour development, migration and aberrant scaring. Lrg1 is a secreted glycoprotein that stimulates angiogenesis by modulating the activity of TGFß. UCL researchers showed that antibodies against Lrg1 block lesion formation in the mouse model of laser-induced choroidal neovascularisation (CNV) (Wang et al., 2013, Nature, 499(7458):306-11). Significantly, in the mouse model of oxygen-induced retinopathy they observed that Lrg1 is involved specifically in the development of pathological vascular tufts, but not the normal vessel growth that occurs during the revascularisation phase. Collectively, these data revealed that Lrg1 is required for pathological angiogenesis, identifying Lrg1 as a therapeutic target for diseases such as wet AMD and cancer, in which aberrant blood vessel growth occurs.
The team developed a series of monoclonal antibodies against Lrg1. The lead candidate has been humanised and de-immunised and funding has been secured to develop the CMC process to GMP standards, perform pre-clinical toxicology studies and Phase IIa trial.
Targeting Lrg1 offers an alternative over currently used anti-VEGFs. These compounds have efficacy in wet AMD, diabetic retinopathy and cancer, but there is a significant fraction of patients who either fail to respond to VEGF blockade or who become refractory. The currently used VEGF blockers are known to have adverse effects in ocular indications, most likely because VEGF has a homeostatic role in neuronal cells, and this may limit long-term drug administration. In cancer, systemic administration of Avastin is associated with an increased risk of cardiovascular events, haemorrhage and stroke.
Currently the anti-angiogenic therapeutic market is dominated by the anti-VEGFs, in particular Avastin, Lucentis and Eylea.
Although Wet AMD, which results from the abnormal growth of blood vessels accounts for only 10-15% of all AMD cases, it is responsible for more than 80% of AMD-related vision loss. Datamonitor Healthcare estimates that sales of drugs for wet AMD across the US and five major EU markets (France, Germany, Italy, Spain, and the UK) will reach almost $5.8bn by 2023.
Diabetic retinopathy is the leading cause of blindness in adults of working age affecting 11.5M people in the seven major markets in 2010. According to Grand View Research Inc, global DR market is expected to reach $10.11bn by 2022.
Global cancer prevalence is driven by the aging population and even though cancer is not a single, homogenous disease, TGFß has been implicated in many cancer types – making this therapeutic approach suitable for many cancer indications. The global market for cancer is expected to reach $147bn by 2018, according to a report by the IMS Institute for Healthcare Informatics.
Collectively these three main indications for which Lrg1 antagonists could be used can be estimated to achieve ca. $160bn market potential.
Intellectual Property Status
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