Human monoclonal antibodies to a novel kidney cancer antigen inhibit target-induced angiogenesis and tumor cell growth and migration in vitro Free

4108

We have identified a novel human cell surface protein, AGS-16, that is expressed in >95% of kidney cancers, predominantly in clear cell and papillary carcinomas. AGS-16 is expressed homogeneously at high levels in primary kidney cancers and in kidney metastases to lymph nodes and lung tissues. Amongst normal tissues, AGS-16 is expressed predominantly in kidney proximal tubules. In vitro studies with a purified extracellular domain (ECD) protein and AGS-16 expressing cells have indicated an involvement of AGS-16 in angiogenesis and tumor cell proliferation and migration. AGS-16 ECD induced human umbilical vein endothelial cell (HUVEC) tube formation on Matrigel in vitro, as well as their migration in a transwell chamber assay. RNAi silencing of AGS-16 expression in the kidney clear cell line RXF-393 and the liver cancer cell line HepG2 significantly reduced their proliferation, survival, migration and invasion. XenoMouse^® technology was employed to generate a large panel of high affinity fully human MAbs to AGS-16 with diverse isotypes (IgG₁κ, IgG₁λ, IgG₂κ). Among the MAbs that demonstrated potent activity in all of the in vitro assays described above was AGS-16M18, an IgG₁λ MAb with a Kd = 2.6 x 10^-10M for cell surface AGS-16. AGS-16 M18 inhibited proliferation and survival of both RXF-393 and HepG2 tumor cell lines in a dose-dependent manner. In addition, AGS-16M18 dose-dependently inhibited ECD-induced HUVEC tube formation. AGS-16M18 inhibited HepG2 cell migration and invasion in a short time period, which preceded the anti-proliferative effect of the MAb on these tumor cells. Completion of studies evaluating the anti-tumor efficacy of AGS-16M18 in vivo is underway. Together, these data establish AGS-16 as an attractive target for MAb-directed therapy of kidney cancer.