Ptk7 as a direct and tumor stroma target in multiple solid malignancies

1526 Ptk7 shares homology with the receptor tyrosine kinases and contains extracellular immunoglobulin like domains. It is predicted to lack kinase activity as it is missing one of the conserved catalytic amino acids and is therefore classified as a pseudokinase. Ptk7 clearly has a role in embryonic development as seen in mouse knock-out and expression analyses. There have been sporadic reports of the expression of ptk7 in cancers, mostly through mRNA analyses. We identified ptk7 as a potential target for multiple solid malignancies through proteomic analyses of cancer cell lines where it was identified in cell lines representing different tumor types. mRNA studies showed ptk7 to be upregulated in many clinical cancer specimens and virtually absent from normal adult organs except fibroblasts in some tissues. This observation was confirmed by IHC which showed ptk7 to be highly expressed in many cancer types including lung, ovarian, pancreatic, colon, renal and breast. Interestingly the staining of cancer tissues occurs either in the cancer cells themselves, or in the tumor activated stroma, but very rarely in both. The clinical prevalence of ptk7 in these solid malignancies is >80% for all types when both regions of positive staining are considered. Furthermore, over-expression of ptk7 enhances the invasive properties of cells. Thus ptk7 represents an extremely attractive protein for targeted anti cancer therapies. To exploit this we have developed a panel of fully human antibodies specific for ptk7. These antibodies are internalized on receptor binding and, when conjugated to toxins, effectively kill cancer cells in vitro. The ptk7 antibodies cross-react with the mouse protein and preliminary toxicity studies with antibody drug conjugates in mice show no adverse target related events. We are developing 2 types of in vivo models to examine activity of anti ptk7 antibody-drug-conjugates : 1) where ptk7 is expressed on the cancer cells, and 2) where ptk7 is expressed on tumor associated stromal cells.