Target: RON (Recepteur d’Origine Nantais/ Macrophage Stimulating 1 Receptor)
ASLAN005 is a novel monoclonal antibody targeted against the human RON (Recepteur d’Origine Nantais) receptor tyrokinase, which is both an immuno-oncology target, as well as a growth and survival factor in multiple tumour types. RON is closely related to cMET but with highly differentiated biology. Relevant to its role as an immuno-oncology target, RON is central in the control of the macrophage population and enhancement of host immune surveillance. RON has three primary roles:
RON activation in tumour cells promotes aggressive disease, early metastasis and preferential metastasis to bone and bone loss via upregulation of osteoclast function (Kretschmann et al, 2010). Based on ASLAN’s collaboration with Professor Alana Welm (University of Utah, Huntsman Cancer Institute), knockout of RON in a metastatic breast cancer model resulted in upregulation of TNFα in circulating macrophages and an increase in tumour specific cytotoxic T-cells that reduced tumour metastasis to the lung.
Once stimulated, RON receptors down-regulate pro-inflammatory signals via the Toll-like receptors and cytokine cascade and promote wound healing. Approximately 50% of gastric cancer, breast cancer and lung cancer tumours use the RON axis to switch off the immune response in their local tumour microenvironment in order to evade detection via host immune surveillance.
RON signalling in Tumour-associated Macrophages (TAMs) induces differentiation towards pro-tumoural M2 macrophage phenotype. Blockade of the RON receptor on the macrophage has also been shown to increase TAMs in the tumour microenvironment leading to clearance of tumour cells via the host immune response, and a phenotypic change from tumour supporting M2 macrophages to inflammatory and tumour aggressive M1 macrophages. The latter may be very important as an enhancement of immune defence against cancer, and may be complementary to other immuno-oncology therapies such as PD1 inhibitors.
As a marker of tumour cells, RON is overexpressed in a range of solid tumour types but is not normally amplified or mutated (Kretschmann et al, 2010). The ligand for RON is macrophage stimulatory protein (MSP, also known as Hepatocyte Growth Factor-Like protein [HGFL]). Approximately 73% of gastric/gastroesophageal cancers overexpress RON/MSP and RON ‘high’ patients have substantially worse overall survival with a median 14 vs. >80 months (Catenacci et al, 2011). 16% of cholangiocarcinoma are RON/cMET ‘high’ and again these patients have a much worse overall and disease free survival (Yao et. al., 2013, Watanabi et. al., 2015). Similarly, RON/ MSP high tumours are present in approximately 50% of breast and lung cancers (NSCLC). The RON signalling pathway is believed to be an important growth and survival pathway in cancer, and hence an attractive anti-tumour target.
ASLAN005 was licensed from the p53 Laboratory at Singapore’s Agency for Science, Technology and Research (A*STAR). ASLAN005 will be advanced towards clinical trials through a three-year research collaboration between ASLAN and A*STAR.
ASLAN will develop and commercialise ASLAN005 worldwide and intends to commence clinical studies in 2018.
The Agency for Science, Technology and Research (A*STAR) is Singapore’s lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit society. As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. The research creates economic growth and jobs for Singapore, and enhances lives by contributing to societal benefits such as improving outcomes in healthcare, urban living, and sustainability.
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