Abstract A152: Novel autotaxin inhibitory antibodies block lysophosphatidic acid production in plasma and tumour cell proliferation in vitro

Autotaxin (ATX) is a secreted phosphodiesterase that cleaves lysophosphatidylcholine (LPC) in serum to produce lysophosphatidic acid (LPA). LPA can signal through a family of GPCR receptors to mediate cell proliferation, migration and survival in cancer cells. Blocking the enzymatic activity of ATX is proposed to have anti-tumour activity by reducing levels of LPA and preventing signaling through the LPA receptor family. A number of synthetic inhibitors have been developed to understand the role in ATX in driving carcinogenesis and these encompass lipid substrate mimetics as well as inhibitors identified from small molecule library screens. Some of these compounds demonstrate low nM activity in vitro and a subset have shown some in vivo activity although none have progressed into the clinic. We sought to identify novel selective ATX antibodies with low nM affinity, which fully inhibited ATX enzyme activity of human, cyno and mouse ATX protein. Using an ATX enzyme inhibition assay we identified and characterised two ATX antibodies, 9E10 and 18B7 which, interestingly, had different binding mechanisms of inhibition and showed potent cross-species inhibition of ATX in vitro. We measured human and mouse ATX expression levels across of panel of xenograft models and verified ATX activity by measuring cleavage of an ATX substrate using conditioned media from these cells. 9E10 and 18B7 antibodies were shown to inhibit the activity of secreted ATX and prevent cleavage of an ATX substrate. 9E10 and 18B7 showed significant inhibition of LPC stimulated cell growth and IL-8 secretion in a range of ATX and/or LPA responsive tumour cell lines. In ex vivo plasma ATX activity assays, treatment of mouse or human plasma with the ATX antibodies inhibited the increase in LPA levels that are observed over time when serum samples are incubated at 37°C. In summary we have identified highly selective ATX antibody inhibitors which will be useful tools to explore the role of ATX in tumour growth and invasion. Citation Format: Sarah Ross, Scott Collins, Jelena Jovanovic, Jane Kendrew, Simon Barry, Swami Rathanaswami, Blakey David, Hazel Weir. Novel autotaxin inhibitory antibodies block lysophosphatidic acid production in plasma and tumour cell proliferation in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A152.