Complement in Immune and Inflammatory Disorders: Therapeutic Interventions (original) (raw)

With the awareness that immune-inflammatory crosstalk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. While prevalent conditions such as age-related macular degeneration have attracted the most attention, the diverse array of complement-mediated pathologies, with distinct underlying mechanisms, demands a multifaceted arsenal of therapeutic strategies. Fortunately, efforts in recent years have not only introduced the first complement inhibitors to the clinic but also filled the pipelines with promising candidates. With a focus on immunomodulatory strategies, this review discusses complement-directed therapeutic concepts and highlights promising candidate molecules. Many concepts of modern drug discovery have deep roots in immunology research, with Paul Ehrlich's notions of the "magic bullet" and his "side-chain theory" being among the most prominent examples (1). The connection between these two disciplines has even intensified in recent years in view of biological drugs such as mAb's. Therapeutic immune modulation is increasingly recognized as a promising strategy for tackling inflammatory diseases, yet is in need of more selective modulators that help restore the immune balance and resolve inflammation (2). Fueled by the discovery of new functional roles, immune crosstalk mechanisms, and a growing number of disease associations (see accompanying review (3)), complement has emerged as focal point of interest in immunomodulatory and anti-inflammatory strategies (4). The variety of intervention points and high number of extracellular targets within the complement cascade (Fig. 1), the availability of potent natural inhibitor templates, and a spike in structure-function insight have all contributed to rapid advances in the field of complement-related drug discovery. While only two drugs with connection to complement are currently available in the clinic, ongoing research efforts have produced a plethora of innovative and diverse drug candidates that demonstrate great promise in many clinical conditions. In the following sections, we provide an overview of current therapeutic strategies and highlight drug candidates that are in preclinical or clinical development.