Recent approval of the first human
complement pathway-directed
therapeutics, along with high-profile genetic association studies, has catalyzed renewed
biopharmaceutical interest in developing drugs that modulate the
complement system. Substantial challenges remain, however, that must be overcome before widespread application of
complement inhibitors in inflammatory and
autoimmune diseases becomes possible. Among these challenges are the following: (1) defining the
complement pathways and effector mechanisms that cause tissue injury in humans and determining whether the relative importance of each varies by disease, (2) blocking or modulating, using traditional small molecule or
biologic approaches, the function of
complement proteins whose circulating levels are very high and whose turnover rates are relatively rapid, especially in the setting of acute and chronic
autoimmune diseases, and (3) avoiding infectious complications or impairment of other important physiological functions of
complement when using systemically active
complement-blocking agents. This chapter will review data that address these challenges to therapeutic development, with a focus on the development of a novel strategy of blocking specific
complement pathways by targeting inhibitors using a recombinant portion of the human
complement receptor type 2 (CR2/CD21) which specifically targets to sites of local
complement C3 activation where C3 fragments are covalently fixed. Recently, the first of these CR2-targeted
proteins has entered human phase I studies in the human disease
paroxysmal nocturnal hemoglobinuria. The results of murine translational studies using CR2-targeted inhibitors strongly suggest that a guiding principle going forward in
complement therapeutic development may well be to focus on developing strategies to modulate the pathway as precisely as possible by physically localizing therapeutic inhibitory effects.