Abstract 3947: AMG 161, a fully human monoclonal antibody to human RANKL, inhibits tumor-induced osteoclastogenesis and reduces skeletal tumor burden in mice that express chimeric (murine / human) RANKL.

Abstract

Abstract Tumor cells can induce RANKL expression in the bone stroma, causing activation of osteoclasts which consequently mediate bone breakdown and subsequent tumor proliferation. RANKL is an essential mediator of osteoclast function and survival. RANKL inhibition by OPG-Fc can prevent tumor-induced osteolysis, decrease skeletal tumor burden, and increase survival in preclinical models. Denosumab is an anti-huRANKL antibody approved for the prevention of skeletal-related events due to bone metastases from solid tumors. Selective anti-huRANKL antibodies do not bind murine RANKL, therefore efficacy cannot be tested in typical mouse models. We developed a breast cancer bone metastasis model in mice in which exon 5 from murine RANKL was replaced with its human ortholog (“mu/huRANKL”). We tested the effect of AMG 161, an antibody which binds huRANKL and chimeric mu/huRANKL, on tumor burden and associated osteoclasts. After intra-cardiac injection of MCF-7Luc breast carcinoma cells, hind limb metastases formed and tumor burden was tracked by bioluminescence imaging (BLI). AMG 161 (0.3 or 3.0 mg/kg, 2x/week), OPG-Fc (3.0 mg/kg, 2x/week) or vehicle were administered beginning 10 days post tumor injection to treat established bone metastases until study termination at day 31. AMG 161 resulted in a dose-dependent decrease in skeletal tumor burden (3.0 mg/kg: 84% decrease vs. control p=0.0052) similar to that observed with OPG-Fc (85% decrease vs. control, p=0.0038). Histological analysis at the end of the study showed reductions in skeletal tumor burden consistent with the BLI. AMG 161 treatment resulted in a significant decrease in tumor-associated osteoclasts (TRAP staining) and inhibition of osteolytic lesions (X-ray). The inhibition of tumor burden by the anti-RANKL antibody was indirect via osteoclast inhibition since MCF-7Luc cells do not express RANK, and RANKL inhibition does not affect subcutaneous growth of MCF-7Luc cells. These data support the efficacy of anti-RANKL antibody treatment to inhibit tumor-induced osteoclastogenesis and to block the growth of bone metastases. Citation Format: Jude R. Canon, Rebecca Bryant, Martine Roudier, William C. Dougall. AMG 161, a fully human monoclonal antibody to human RANKL, inhibits tumor-induced osteoclastogenesis and reduces skeletal tumor burden in mice that express chimeric (murine / human) RANKL. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3947. doi:10.1158/1538-7445.AM2013-3947