Nanobodies Provide Insight Into the Molecular Mechanisms of the Complement Cascade and Offer New Therapeutic Strategies

Abstract

The complement system is part of the innate immune response, where it provides immediate protection from infectious agents and plays a fundamental role in homeostasis. Complement dysregulation occurs in several diseases, where the tightly regulated proteolytic cascade turns offensive. Prominent examples are atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria and Alzheimer’s disease. Therapeutic intervention targeting complement activation may allow treatment of such debilitating diseases. In this review, we describe a panel of complement targeting nanobodies that allow modulation at different steps of the proteolytic cascade, from the activation of the C1 complex in the classical pathway to formation of the C5 convertase in the terminal pathway. Thorough structural and functional characterization has provided a deep mechanistic understanding of the mode of inhibition for each of the nanobodies. These complement specific nanobodies are novel powerful probes for basic research and offer new opportunities for in vivo complement modulation.

Structure of the integrin receptor αMβ2 headpiece in complex with a function-modulating nanobody

“…In general, a nanobody is a versatile module that is easily humanized and targeted to specific tissues and cell types by fusion to other proteins. Fusion may also increase the short circulation time of unmodified nanobodies, reviewed in (60). Animal experiments could investigate the in vivo utility of properly modified hCD11bNb1 as a highly specific α M β 2 agonist, but such studies are complicated by the lack of cross-reactivity with the murine αI domain.…”