5th World Congress on Cancer Therapy
Georgia State University, USA
Title: Development of protein agent targeting Integrins αvβ3 at a novel site by rational protein design
Biography: Zhi-Ren Liu
Due to abnormal expression of integrins αv3 in various disease conditions, this integrin pair has been a focus as targets for drug development. Studies yield a few successful examples. Among them are various antibodies against the integrins, and most recently, Cilengitide, a RGD-based peptidomimetic.Nevertheless, most of current approaches focus on ligand-binding with goal of inhibition of integrin functions.A major draw-back of targeting ligand-binding of integrins is activation of integrin signaling by the developed agent, which largely limit the clinical success of the integrin ligand based antagonist/agonist. We report here development of a new class of therapeutically protein agent (Ref to as ProAgio) by rational protein design using a stable host protein. ProAgio is designed to target integrins αv3 at a novel site. ProAgio exhibits a strong in vitro activity in induction of apoptosis of integrin αv3 expressing cells. ProAgio induces apoptosis by recruiting and activating caspase 8 to the cytoplasmic domain of the targeted integrins. Tests with tumor xenograft s show that ProAgio strongly inhibits tumor growth. Histology analyses indicate that tumor vessels are reduced, while the established vasculatures are not aff ected. Th e results confi rm targeting of integrin αv3 as an anti-angiogenic agent. Toxicity analyses demonstrate that ProAgio is not toxic to mouse at very high doses. Our study develops an eff ective integrin targeting agent via a novel mechanism of action. Our approach provides a new platform for development of therapeutics by targeting integrins.