Moss-produced human complement factor H with modified glycans has an extended half-life and improved biological activity

Frontiers in Immunology, vol. 15, pp. 1383123

Abstract

Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring the balance of an overactive complement system while preserving its normal physiological functions. Until now, the systemic treatment of complement-associated disorders with FH has been deemed unfeasible, primarily due to high production costs, risks related to FH purified from donors’ blood, and the challenging expression of recombinant FH in different host systems. We recently demonstrated that a moss-based expression system can produce high yields of properly folded, fully functional, recombinant FH. However, the half-life of the initial variant (CPV-101) was relatively short. Here we show that the same polypeptide with modified glycosylation (CPV-104) achieves a pharmacokinetic profile comparable to that of native FH derived from human serum. The treatment of FH-deficient mice with CPV-104 significantly improved important efficacy parameters such as the normalization of serum C3 levels and the rapid degradation of C3 deposits in the kidney compared to treatment with CPV-101. Furthermore, CPV-104 showed comparable functionality to serum-derived FH in vitro, as well as similar performance in ex vivo assays involving samples from patients with atypical hemolytic uremic syndrome, C3 glomerulopathy and paroxysomal nocturnal hematuria. CPV-104 – the human FH analog expressed in moss – will therefore allow the treatment of complement-associated human diseases by rebalancing instead of inhibiting the complement cascade.

Authors 13

1. Todor Tschongov

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

2. Swagata Konwar

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

3. Andreas E Busch
   Affiliation as printed

   Eleva GmbH, Freiburg, Germany

4. Christian Sievert
   Affiliation as printed

   Eleva GmbH, Freiburg, Germany

5. Andrea Hartmann

   Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

   Affiliation as printed

   Department of Infection Biology, Leibniz Insitute for Natural Product Research and Infection Biology, Jena, Germany

6. Marina Noris

   Mario Negri Institute for Pharmacological Research

   Affiliation as printed

   Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Dacco", Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

7. Sara Gastoldi

   Mario Negri Institute for Pharmacological Research

   Affiliation as printed

   Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Dacco", Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

8. Sistiana Aiello

   Mario Negri Institute for Pharmacological Research

   Affiliation as printed

   Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Dacco", Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

9. Andreas Schaaf
   Affiliation as printed

   Eleva GmbH, Freiburg, Germany

10. Jens Panse Aachen Department of Oncology, Hematology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Center for Integrated Oncology (CIO), Aachen, Bonn, Cologne, Düsseldorf (ABCD) Germany Pauwelsstrasse 30, Aachen, Germany

    Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany

11. Peter F. Zipfel

    Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) · Friedrich Schiller University Jena

    Affiliation as printed

    Department of Infection Biology, Leibniz Insitute for Natural Product Research and Infection Biology, Jena, Germany

    Institute of Microbiology, Friedrich-Schiller-University, Jena, Germany

12. Paulina Dabrowska‐Schlepp
    Affiliation as printed

    Eleva GmbH, Freiburg, Germany

13. Karsten Häffner corresponding

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany