Skip to main content

ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1288597

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

Provisionally accepted
Fleur S. van de Bovenkamp Fleur S. van de Bovenkamp 1,2*Douwe J. Dijkstra Douwe J. Dijkstra 2Leoni Abendstein Leoni Abendstein 2Nicole V. Borggreven Nicole V. Borggreven 2Jos Pool Jos Pool 2Rob Zuijderduijn Rob Zuijderduijn 2Christoph Gstöttner Christoph Gstöttner 2Kyra A. Gelderman Kyra A. Gelderman 3Timon Damelang Timon Damelang 4,5Gestur Vidarsson Gestur Vidarsson 4,5Anna M. Blom Anna M. Blom 6Elena Dominguez Vega Elena Dominguez Vega 2Paul W. Parren Paul W. Parren 1,2Thomas Sharp Thomas Sharp 2Leendert Trouw Leendert Trouw 2
  • 1 Lava Therapeutics B.V., Den Bosch, Netherlands
  • 2 Leiden University Medical Center (LUMC), Leiden, Netherlands
  • 3 Sanquin Diagnostic Services, Amsterdam, Netherlands
  • 4 Sanquin Research, Amsterdam, Netherlands
  • 5 Utrecht University, Utrecht, Netherlands, Netherlands
  • 6 Lund University, Lund, Skane County, Sweden

The final, formatted version of the article will be published soon.

    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.

    Keywords: complement, Antibobies, inhibition, targeted, Autoimmunity

    Received: 04 Sep 2023; Accepted: 17 Apr 2024.

    Copyright: © 2024 van de Bovenkamp, Dijkstra, Abendstein, Borggreven, Pool, Zuijderduijn, Gstöttner, Gelderman, Damelang, Vidarsson, Blom, Dominguez Vega, Parren, Sharp and Trouw. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Fleur S. van de Bovenkamp, Lava Therapeutics B.V., Den Bosch, Netherlands

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.