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

Fei Liu1, Stefan Wawersik1, Stephen Tomlinson2,3

  • 1Q32 Bio Inc., Waltham, MA, United States.

Journal of Immunology (Baltimore, Md. : 1950)
|April 21, 2025
PubMed

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.

Keywords:
complementcomplement regulatorstissue-targeted therapeutics

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