Volociximab - α5β1 Antagonist

Approximately one third of patients with wet AMD gain significant vision (3 lines or more improvement on an ETDRS chart) after receiving the current standard-of-care regimen of anti-VEGF monontherapy. Limitations of a monotherapy anti-VEGF approach include:

  • Lack of neovascular regression
  • Persistent underlying inflammation
  • Continued neovascularization due to the presence of other angiogenic growth factors such as bFGF, IL-8 etc.

Inhibition of downstream signaling which interferes with endothelial cell survival independent of growth factor stimulation (i.e. VEGF, bFGF, IL-8) may result in an enhanced anti-angiogenic response and neovascular regression.

One such downstream signaling event is the interaction of the endothelial transmembrane receptor α5β1 integrin with the extracellular matrix (ECM) ligand fibronectin. Interaction between activated and proliferating endothelial cells with extracellular matrix (ECM) proteins via this α5β1 integrin mediated mechanism regulates multiple key endothelial cellular processes involved in angiogenesis. Over twenty years of scientific studies from independent labs support the key role of the α5β1 integrin-fibronectin interaction in angiogenesis. Therefore, interruption of this α5β1 integrin-fibronectin signal offers an attractive opportunity for an anti-angiogenic attack independent of specific upstream growth factor stimulation.

Volociximab blocks the binding of α5β1 integrin to fibronectin

Volociximab, a high-affinity monoclonal antibody (Mab), binds to α5β1 integrin and blocks the binding of α5β1 integrin to fibronectin, thereby inhibiting a pivotal interaction required for angiogenesis. Volociximab administration has resulted in strong inhibition of rabbit and primate retinal neovascularization. In cynomolgus monkeys with laser-induced choroidal neovascularization (CNV), volociximab significantly inhibited CNV proliferation and reduced the degree of lesion formation. In a rabbit model, volociximab administered either intravenously or intravitreally prior to the onset of neovascularization significantly reduced angiogenesis as compared to control. Similar anti-angiogenic efficacy with volociximab has also been shown in multiple preclinical models of tumor angiogenesis.

A phase 1 open-label, multicenter study of volociximab, in combination with an anti-VEGF agent (Lucentis®), in patients with wet AMD is ongoing.