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DNA Nanostructure-Templated Antibody Complexes Provide Insights into the Geometric Requirements of Human Complement Cascade Activation.
Abendstein, Leoni; Noteborn, Willem E M; Veenman, Luc S; Dijkstra, Douwe J; van de Bovenkamp, Fleur S; Trouw, Leendert A; Sharp, Thomas H.
Afiliación
  • Abendstein L; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
  • Noteborn WEM; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
  • Veenman LS; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
  • Dijkstra DJ; Department of Immunology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
  • van de Bovenkamp FS; Department of Immunology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
  • Trouw LA; Department of Immunology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
  • Sharp TH; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
J Am Chem Soc ; 146(19): 13455-13466, 2024 May 15.
Article en En | MEDLINE | ID: mdl-38703132
ABSTRACT
The classical complement pathway is activated by antigen-bound IgG antibodies. Monomeric IgG must oligomerize to activate complement via the hexameric C1q complex, and hexamerizing mutants of IgG appear as promising therapeutic candidates. However, structural data have shown that it is not necessary to bind all six C1q arms to initiate complement, revealing a symmetry mismatch between C1 and the hexameric IgG complex that has not been adequately explained. Here, we use DNA nanotechnology to produce specific nanostructures to template antigens and thereby spatially control IgG valency. These DNA-nanotemplated IgG complexes can activate complement on cell-mimetic lipid membranes, which enabled us to determine the effect of IgG valency on complement activation without the requirement to mutate antibodies. We investigated this using biophysical assays together with 3D cryo-electron tomography. Our data revealed the importance of interantigen distance on antibody-mediated complement activation, and that the cleavage of complement component C4 by the C1 complex is proportional to the number of ideally spaced antigens. Increased IgG valency also translated to better terminal pathway activation and membrane attack complex formation. Together, these data provide insights into how nanopatterning antigen-antibody complexes influence the activation of the C1 complex and suggest routes to modulate complement activation by antibody engineering. Furthermore, to our knowledge, this is the first time DNA nanotechnology has been used to study the activation of the complement system.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN / Inmunoglobulina G / Activación de Complemento / Nanoestructuras Límite: Humans Idioma: En Revista: J Am Chem Soc Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN / Inmunoglobulina G / Activación de Complemento / Nanoestructuras Límite: Humans Idioma: En Revista: J Am Chem Soc Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos