Rilotumumab, a mab against human Hepatocyte growth factor for the treatment of cancer

Tyrosine kinase receptors and their ligands have become appealing candidates as molecular therapeutic agents for the treatment of cancer. Hepatocyte growth factor (HGF) and its receptor, mesenchymal-epithelial transition factor (c-Met), play a role in many human tumors, promoting cell proliferation and invasion, as well as resistance to apoptosis. Rilotumumab, being developed by Amgen Inc, is a humanized mAb directed against HGF, and is thus able to interfere with the interaction between HGF and c-Met to prevent c-Met activation. In preclinical studies, rilotumumab effectively blocked c-Met phosphorylation, inhibiting c-Met-activated downstream signaling pathways. In phase I clinical trials, rilotumumab was well tolerated at doses up to 20 mg/kg every 2 weeks. Data from preclinical studies and a phase Ib trial demonstrated that rilotumumab had an additive effect when combined with chemotherapeutic agents, leading to the initiation of several phase II trials that are enrolling patients with different tumor types to assess combinations of rilotumumab with chemotherapeutic regimens, as well as with other mAbs. Which tumor types might beneft most from treatment with rilotumumab remains to be determined, and the identifcation of candidate patients will be a critical issue for the further development of this drug.