Targeting M-CSF with MCS110: A Novel Monoclonal Antibody Approach for Tumor-Induced Osteolysis Therapy

The AACR Annual Meeting held from April 18-22, 2009 in Denver, CO, discussed a significant study on the role of Macrophage colony-stimulating factor (M-CSF), also referred to as CSF-1, in osteoclast differentiation from monocytic lineage precursors. It is believed that in cancer patients with bone metastases, M-CSF secretion by tumor cells or stroma leads to abnormal osteoclastogenesis, which increases osteoclast cell count, excessive bone degradation, and skeletal-related events such as bone pain and fractures.

MCS110, a high-affinity human-engineered monoclonal antibody, has been shown to block M-CSF's ability to stimulate cell proliferation and inhibit M-CSF-stimulated phosphorylation of the M-CSF receptor, CSF-1R. The antibody effectively halts the osteoclast differentiation process in vitro and has been tested in vivo in cynomolgus monkeys, where it resulted in a sustained loss of serum M-CSF bioactivity and a decrease in bone resorption markers.

Further research in murine xenograft tumor-induced osteolysis (TIO) models, involving human tumor cell lines injected into immune-compromised mice, demonstrated that MCS110 significantly reduced the incidence and severity of bone lesions by up to 70% compared to control antibodies. The treatment did not affect tumor burden, but when combined with zoledronic acid, it showed enhanced activity.

The study also explored the presence of soluble forms of CSF-1R in cancer patient sera as potential biomarkers for targeted drug therapies. A soluble CSF-1R was found to be released during in vitro osteoclastogenesis, and its circulating form was detected in human samples. Treatment with anti-M-CSF antibodies resulted in a decrease in the circulating soluble CSF-1R concentration, whereas bisphosphonates had no effect. The soluble CSF-1R level was reduced in monkeys treated with MCS110, correlating with a reduction in bone resorption markers.

These findings support the initiation of clinical trials for MCS110 in patients with bone metastases to evaluate its potential to inhibit abnormal osteoclastogenesis and skeletal-related events. The soluble form of CSF-1R may serve as a clinical biomarker for MCS110's action, particularly useful in patients with suppressed bone turnover markers due to bisphosphonate treatment.