A human monoclonal antibody to a novel ovarian cancer target inhibits tumor growth

B59 We identified a novel human cell surface protein, AGS-8, which is expressed in >70% of ovarian cancers, predominantly in advanced stages of serous adenocarcinoma. Amongst normal tissues, AGS-8 expression is restricted to testis and the red pulp of spleen. In vitro studies with AGS-8 expressing cells indicated an involvement of AGS-8 in tumor cell survival, migration, invasion and cell-cell interaction. Furthermore, a purified AGS-8 extracellular domain (ECD) protein mediated Ca 2+ -dependent binding to human umbilical vein endothelial cells (HUVEC), supported their survival and induced tube formation in vitro . Recombinant expression of AGS-8 in murine fibroblasts was oncogenic, leading to aggressive tumor growth and metastasis in mice. Additionally, these cells induced significant angiogenesis when implanted in vivo . Recombinant AGS-8 expression in ovarian carcinoma cells (OVCAR-5) led to enhancement of their intrinsic tumor growth in vivo .
 XenoMouse ® technology was employed to generate a panel of high affinity fully human monoclonal antibodies (MAbs) to AGS-8, targeting diverse epitope groups. One MAb that exhibited potent inhibitory activity in all functional assays was AGS-8M4, an IgG 1 κ MAb with a Kd = 5 x 10 -9 M for cell surface AGS-8. AGS-8M4 dose-dependently inhibited tube formation in vitro . In addition, AGS-8M4 inhibited the migration, invasion and cell-cell interaction of AGS-8 expressing cells. Significant anti-tumor efficacy of AGS-8M4 in vivo was observed in both recombinant models and in endogenous models, either during tumor formation or in well-established tumors. Efficacy of AGS-8M4 was maintained after MAb de-glycosylation, indicating an intrinsic anti-tumor activity of the MAb without significant contribution by immune effector functions. AGS-8M4 inhibited lung metastases in the 3T3/AGS-8 tumor model, further suggesting a role of AGS-8 in tumor cell migration and invasion. Studies evaluating the anti-tumor efficacy of AGS-8M4 with drug combinations are underway. Together, these data establish AGS-8 as a novel and attractive ovarian cancer target and AGS-8M4 as a potential therapeutic MAb for this cancer indication.