Abstract 3875: Exploiting the Anticalin therapeutic protein platform for the treatment of cMet ligand-independent and dependent tumors - discovery and characterization of a highly specific and potent c-Met antagonist with drug-like properties
Authors: Gille Hendrik , Matschiner Gabriele , Hülsmeyer Martin , Joffroy Christian , Aiba Rachida Siham Bel , Christian Hans-Jürgen , Trentmann Stefan , Hohlbaum Andreas M. , Jensen Kristian , Audoly Laurent , Olwill Shane A. 
Published: August 2012

Background: Activation of the c-Met oncogenic pathway has been implicated in the development of aggressive cancers which are difficult to treat with current chemotherapies. Dimerization of c-Met receptor upon binding of Hepatocyte Growth Factor (HGF) leads to the stimulation of proliferative, migratory and survival pathways implicated in tumor development. Moreover it has recently been discovered that patients who become resistant / nonresponsive to therapies such as EGFR or VEGF inhibitors often show an enhanced c-Met expression. This has led to an increased interest in developing novel therapies that target the c-Met pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of small biologics, are hypothesized to be ‘fit for purpose’ for developing highly specific and potent antagonists of cancer pathways. A monovalent Anticalin c-Met antagonist displaying efficacy in both ligand-dependent and independent cancer models has been developed. Methods/Results: Here we describe the in vitro and in vivo characterisation of the Anticalin c-Met antagonist PRS-110. In protein-based binding assays PRS-110 specifically binds to c-Met with high affinity and blocks HGF interaction (IC50 3.4 ± 0.7 nM). HUVEC cell proliferation assays demonstrated that PRS-110 efficiently antagonizes HGF-mediated growth. As a monovalent antagonist PRS-110 does not induce the c-Met pathway in the absence of ligand by receptor dimerization - an unwanted activation that can occur with bivalent antibodies. In mice, rats and non-human primates, PEGylated PRS-110 displayed favourable plasma elimination half-life profiles of 41 hours, 61 hours and 72 hours (T½α) respectively, with no signs of macrotoxicity. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in multiple xenograft models representative of ligand-dependent and ligand-independent c-Met activation. Analysis of c-Met protein levels on xenograft biopsy samples demonstrated a significant reduction in total c-Met (p&lt;0.01) and pMet (p&lt;0.01) following therapy with PRS-110. Furthermore, safety profiling using in silico epitope analysis and ex vivo human donor PBMC screening demonstrated a low risk of potential immunogenicity when compared to other approved biologic agents. Conclusion: Inhibition of the c-Met pathway by PRS-110 leads to attenuation of cell proliferation, dose-dependent tumour growth inhibition and a reduction in c-Met phosphorylation. Taken together these data indicate that the c-Met inhibitor PRS-110 has potentially broad anticancer activity which warrants evaluation in patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3875. doi:1538-7445.AM2012-3875