Targeted complement inhibition using bispecific antibodies that bind local antigens and endogenous complement regulators.

Autor:	Wang H; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands., van de Bovenkamp FS; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands., Dijkstra DJ; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands., Abendstein L; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands., Borggreven NV; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands., Pool J; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands., Zuijderduijn R; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands., Gstöttner C; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands., Gelderman KA; Sanquin Diagnostic Services, Amsterdam, Netherlands., Damelang T; Sanquin Research, Department of Experimental Immunohematology, Amsterdam, Netherlands.; Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands., Vidarsson G; Sanquin Research, Department of Experimental Immunohematology, Amsterdam, Netherlands.; Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands., Blom AM; Department of Translational Medicine, Section of Medical Protein Chemistry, Lund University, Malmö, Sweden., Domínguez-Vega E; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands., Parren PWHI; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands.; Gyes BV, Utrecht, Netherlands., Sharp TH; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands., Trouw LA; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 May 16; Vol. 15, pp. 1288597. Date of Electronic Publication: 2024 May 16 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1288597
Abstrakt:	Complement activation protects against infection but also contributes to pathological mechanisms in a range of clinical conditions such as autoimmune diseases and transplant rejection. Complement-inhibitory drugs, either approved or in development, usually act systemically, thereby increasing the risk for infections. We therefore envisioned a novel class of bispecific antibodies (bsAbs) which are capable of site-directed complement inhibition by bringing endogenous complement regulators in the vicinity of defined cell surface antigens. Here, we analyzed a comprehensive set of obligate bsAbs designed to crosslink a specific target with either complement regulator factor H (FH) or C4b-binding protein (C4BP). The bsAbs were assessed for their capacity to inhibit complement activation and cell lysis in an antigen-targeted manner. We observed that the bsAbs inhibited classical, lectin, and alternative pathway complement activation in which sufficient endogenous serum FH and C4BP could be recruited to achieve local inhibition. Importantly, the bsAbs effectively protected antigen-positive liposomes, erythrocytes, and human leukocytes from complement-mediated lysis. In conclusion, localized complement inhibition by bsAbs capable of recruiting endogenous human complement regulators (such as FH or C4BP) to cell surfaces potentially provides a novel therapeutic approach for the targeted treatment of complement-mediated diseases. Competing Interests: Author PWHIP was employed by Gyes BV. FSB, PWHIP, and LAT are listed as inventors on a patent application regarding the application of targeted complement inhibition. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Wang, van de Bovenkamp, Dijkstra, Abendstein, Borggreven, Pool, Zuijderduijn, Gstöttner, Gelderman, Damelang, Vidarsson, Blom, Domínguez-Vega, Parren, Sharp and Trouw.)
Databáze:	MEDLINE
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