AI Article Synopsis

  • The complement system is vital for the immune response, tagging pathogens and dying cells for removal, but its dysfunction can lead to disease.
  • C3b is a key fragment within this system that enhances activation, making it a desirable target for treatments.
  • Researchers developed a modified nanobody (EWE-hC3Nb1) that specifically binds to C3 degradation products, leading to new fusion proteins (EWEnH and EWEµH) that effectively inhibit C3b activity and show potential for use in rodent models of diseases related to complement dysfunction.

Article Abstract

The complement system is a part of the innate immune system, where it labels intruding pathogens as well as dying host cells for clearance. If complement regulation is compromised, the system may contribute to pathogenesis. The proteolytic fragment C3b of complement component C3, is the pivot point of the complement system and provides a scaffold for the assembly of the alternative pathway C3 convertase that greatly amplifies the initial complement activation. This makes C3b an attractive therapeutic target. We previously described a nanobody, hC3Nb1 binding to C3 and its degradation products. Here we show, that extending the N-terminus of hC3Nb1 by a Glu-Trp-Glu motif renders the resulting EWE-hC3Nb1 (EWE) nanobody specific for C3 degradation products. By fusing EWE to N-terminal CCP domains from complement Factor H (FH), we generated the fusion proteins EWEnH and EWEµH. In contrast to EWE, these fusion proteins supported Factor I (FI)-mediated cleavage of human and rat C3b. The EWE, EWEµH, and EWEnH proteins bound C3b and iC3b with low nanomolar dissociation constants and exerted strong inhibition of alternative pathway-mediated deposition of complement. Interestingly, EWEnH remained soluble above 20 mg/mL. Combined with the observed reactivity with both human and rat C3b as well as the ability to support FI-mediated cleavage of C3b, this features EWEnH as a promising candidate for studies in rodent models of complement driven pathogenesis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352930PMC
http://dx.doi.org/10.3389/fimmu.2022.872536DOI Listing

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