Humanized Cobra Venom Factor: Experimental Therapeutics for Targeted Complement Activation and Complement Depletion

Carl-Wilhelm      Vogel; David   C.   Fritzinger

Abstract

Cobra Venom Factor (CVF) is the complement-activating protein in cobra venom. CVF is a structural and functional analog of complement component C3. In serum, CVF forms a physicochemically stable and control-resistant C3/C5 convertase that continuously activates C3 and C5, ultimately leading to depletion of serum complement. As CVF can be safely administered to vertebrate animals, it has become an important tool for complement depletion to study the biological functions of complement and its role in the pathogenesis of disease. CVF has also been used for targeted complement activation by chemically coupling it to monoclonal antibodies. Complement depletion is an attractive concept for pharmacological intervention in diseases where complement activation is part of the pathogenetic mechanism. Toward that end, the structural homology of CVF and C3 has been exploited by creating hybrid proteins in which short portions of C3 sequence have been exchanged with corresponding portions of CVF that introduce the desired ability of forming a stable convertase into human C3. These human C3 derivatives are “humanized CVF” proteins that represent an attractive biopharmaceutical for therapeutic complement depletion.

Keywords: Cobra Venom Factor, CVF, complement, complement system, complement depletion, complement inhibition, alternative pathway, C3 convertase, protein humanization