Tissue-targeted regulators of complement for amelioration of human disease: rationale and novel therapeutic strategies

The complement system is an essential part of innate immunity, and dysregulated complement is an underlying driver in many inflammatory and autoimmune diseases. Currently approved complement-focused therapeutics rely on systemic blockade of complement activation, but a major challenge with this approach is that complement components exist in high abundance and undergo rapid systemic turnover, creating a large pharmacologic sink. To improve the arsenal of complement therapies, tissue-targeting has emerged as a strategy to re-regulate complement in diseased tissue, while limiting systemic blockade. This approach, which is based on directing complement modulators to tissues through the recognition of tissue-fixed activated complement fragments, tissue-specific epitopes, or injury-associated neoepitopes, has the potential for enhanced potency and durability and reduced infection risk. In this review, we discuss the rationale for tissue-targeted complement therapies, the strategies taken to achieve local regulation, current state of preclinical and clinical stage tissue-targeted therapeutics, and potential future directions.