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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1379023

Enhancement of complement-dependent cytotoxicity by linking factor-H derived short consensus repeats 19-20 to CD20 antibodies

Provisionally accepted
Lena Prantl Lena Prantl 1Philipp Heider Philipp Heider 1Lisa Bergmeister Lisa Bergmeister 1Jan-Paul Bohn Jan-Paul Bohn 1Dominik Wolf Dominik Wolf 1Zoltan Banki Zoltan Banki 1Andreas Bosch Andreas Bosch 2Maximilian Plach Maximilian Plach 2Georg Huber Georg Huber 3Silke Schrödl Silke Schrödl 3Christian Thirion Christian Thirion 3Heribert Stoiber Heribert Stoiber 1*
  • 1 Innsbruck Medical University, Innsbruck, Tyrol, Austria
  • 2 2bind, Regensburg, Germany
  • 3 SIRION Biotech GmbH, München, Bavaria, Germany

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

    Antibody-mediated complement-dependent cytotoxicity (CDC) on malignant cells is regulated by several complement control proteins, including the inhibitory complement factor H (fH). fH consists of 20 short consensus repeat elements (SCRs) with specific functional domains. Previous research revealed that the fH-derived SCRs 19-20 (SCR1920) can displace full-length fH on the surface of chronic lymphocytic leukemia (CLL) cells, which sensitizes CLL cells for e.g. CD20-targeting therapeutic monoclonal antibody (mAb) induced CDC. Therefore, we constructed lentiviral vectors for the generation of cell lines that stably produce mAb-SCR-fusion variants starting from the clinically approved parental mAbs rituximab, obinutuzumab and ofatumumab, respectively. Flow-cytometry revealed that the modification of the mAbs by the SCRs does not impair the binding to CD20. Increased in vitro lysis potency compared to their parental mAbs was corroborated by showing specific and dose dependent target cell elimination by CDC when compared to their parental mAbs. Lysis of CLL cells was not affected by the depletion of NK cells, suggesting that antibody-dependent cellular cytotoxicity plays a minor role in this context. Overall, this study emphasizes the crucial role of CDC in the elimination of CLL cells by mAbs and introduces a novel approach for enhancing CDC by directly fusing fH SCR1920 with mAbs.

    Keywords: CLL, B cell chronic lymphocytic leukemia, CDC, complement-dependent cytotoxicity, RCA, Regulator of complement activation, OFA, Ofatumumab, RTX, Rituximab, OBI, Obinutuzumab, hSCR, human recombinant factor H-derived short consensus repeat, fH human Factor H

    Received: 30 Jan 2024; Accepted: 01 Jul 2024.

    Copyright: © 2024 Prantl, Heider, Bergmeister, Bohn, Wolf, Banki, Bosch, Plach, Huber, Schrödl, Thirion and Stoiber. 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: Heribert Stoiber, Innsbruck Medical University, Innsbruck, 6020, Tyrol, Austria

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