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

Frontiers in Immunology, vol. 15, pp. 1288597

Abstract

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.

Authors 16

1. Haiyu Wang Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

2. Fleur S. van de Bovenkamp Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

3. Douwe J. Dijkstra Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

4. Leoni Abendstein Aachen Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands

5. Nicole V. Borggreven Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

6. Jos Pool Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

7. Rob Zuijderduijn Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

8. Christoph Gstöttner Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands

9. Kyra A. Gelderman

   Sanquin

   Affiliation as printed

   Sanquin Diagnostic Services, Amsterdam, Netherlands

10. Timon Damelang

    Utrecht University · Sanquin

    Affiliation as printed

    Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands

    Sanquin Research, Department of Experimental Immunohematology, Amsterdam, Netherlands

11. Gestur Vidarsson

    Utrecht University · Sanquin

    Affiliation as printed

    Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands

    Sanquin Research, Department of Experimental Immunohematology, Amsterdam, Netherlands

12. Anna Marie Blom

    Lund University

    Affiliation as printed

    Department of Translational Medicine, Section of Medical Protein Chemistry, Lund University, Malmö, Sweden

13. Elena Domínguez‐Vega Aachen Center for Proteomics and Metabolomics

    Leiden University Medical Center

    Affiliation as printed

    Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands

14. Paul W.H.I. Parren Aachen Department of Immunology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

    Gyes BV, Utrecht, Netherlands

15. Thomas Harry Sharp Aachen Department of Cell and Chemical Biology

    Leiden University Medical Center

    Affiliation as printed

    Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands

16. Leendert Adrianus Trouw corresponding Aachen Department of Immunology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Immunology, Leiden University Medical Center, Leiden, Netherlands