Abstract 3621: A monovalent Anticalin antagonist: A novel approach for inhibition of c-Met-dependent tumor growth
Authors: Hendrik Gille, Gabriele Matschiner, Martin Hülsmeyer, Rachida S. Bel Aiba, Hans-Jürgen Christian, Stefan Trentman, Andrea Allersdorfer, Andreas M. Hohlbaum, Kristian Jensen, Laurent P. Audoly
Journal: Cancer Research (2011)

Abstract The c-MET receptor has important functions in embryonic development and adult organ regeneration but its tyrosine kinase activity is often aberrantly activated in human malignancies. Activation is associated with enhanced tumor cell proliferation, migration and the promotion of an invasive cell phenotype resulting in increased metastasis and diminished survival. Both animal studies and clinical studies suggest that inhibition of this oncogene product could be beneficial and small molecules that target the enzyme activity of the kinase receptor and biologics that block the HGF/cMet pathway are under development. Each of these has advantages and disadvantages in reducing the activity of this pathway. While the current biologics in clinical development display target specificity rarely achievable with small molecule inhibitors they are costly and often times complex to develop/manufacture, often lack the penetration of small molecules, and under some circumstances can have partial agonist activity. While small molecules are generally inexpensive to produce, specificity and toxicity, especially with kinase inhibitors, remains a problem. To address the possible limitations of these current therapeutic strategies directed at attenuation of this important oncogenic pathway, we present an alternative approach, the development of a cMet Anticalin (PRS-110). Anticalins are targeted muteins based on the lipocalin protein scaffold and represent a new class of biologics. All lipocalins are made up of a single beta-barrel domain with four loops protruding from the opening of the calyx although they share limited sequence identity. The lipocalin family has naturally evolved to perform various binding functions. The loop residues of human tear lipocalin were randomized to generate a combinatorial library and successive rounds of panning and screening were employed to generate an Anticalin with high affinity and specificity for c-MET. We show that this cMet Anticalin binds to cells expressing this kinase receptor with both high affinity and specificity. Importantly, we show, using a xenograft strategy, that the cMet Anticalin inhibits the growth of established tumors expressing this receptor. Because of the small size and stable three-dimensional structure, this molecule can be produced and purified from E. coli with limited steps, high titer, and a line of sight to late stage development manufacturability and product launch. In summary, our data suggest that the cMet Anticalin displays the specificity of anti cMet/HGF antibodies, but because of its structure, and small size it exemplifies some of the advantages of small molecules directed at this important tumor target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3621. doi:10.1158/1538-7445.AM2011-3621