2. Academic Validation
  3. High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma

High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma

  • Exp Hematol Oncol. 2024 Jun 3;13(1):59. doi: 10.1186/s40164-024-00524-4.
Willem Daneels 1 2 3 4,  Alexander Van Parys 5 6 7,  Leander Huyghe 5 6 7,  Elke Rogge 5 6 7,  Steffi De Rouck 5 6 7,  Ruben Christiaen 7,  Lennart Zabeau 7,  Sylvie Taveirne 7,  Jo Van Dorpe 8 9 10,  Niko Kley 7,  Anje Cauwels 8 5 6 7,  Erik Depla 7,  Jan Tavernier # 8 5 6 7,  Fritz Offner # 11 12 8
Affiliations

Affiliations

  • 1 Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. willem.daneels@ugent.be.
  • 2 Department of Hematology, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium. willem.daneels@ugent.be.
  • 3 Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium. willem.daneels@ugent.be.
  • 4 VIB-UGent Center for Medical Biotechnology, Ghent, Belgium. willem.daneels@ugent.be.
  • 5 VIB-UGent Center for Medical Biotechnology, Ghent, Belgium.
  • 6 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • 7 Orionis Biosciences BV, Ghent, Belgium.
  • 8 Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
  • 9 Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
  • 10 Department of Pathology, Ghent University Hospital, Ghent, Belgium.
  • 11 Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
  • 12 Department of Hematology, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium.
  • # Contributed equally.
PMID: 38831452 DOI: 10.1186/s40164-024-00524-4
Abstract

Type I interferon (IFN) is a potent antitumoral drug, with an important history in the treatment of hematologic malignancies. However, its pleiotropic nature leads to severe dose-limiting toxicities that blunt its therapeutic potential. To achieve selective targeting of specific immune or tumor cells, AcTakines (Activity-on-Target Cytokines), i.e., immunocytokines utilizing attenuated cytokines, and clinically optimized A-Kines™ were developed. In syngeneic murine models, the CD20-targeted murine IFNα2-based AcTaferons (AFNs) have demonstrated clear antitumoral effects, with excellent tolerability. The current study explores the antitumoral potential of the humanized huCD20-Fc-AFN in 5 different humanized patient derived xenograft (PDX) models of huCD20+ aggressive B non-Hodgkin lymphomas (B-NHLs). The huCD20-Fc-AFN consists of a huCD20-specific single-domain antibody (VHH) linked through a heterodimeric 'knob-in-hole' human IgG1 Fc molecule to an attenuated huIFNα2 sequence. An in vitro targeting efficacy of up to 1.000-fold could be obtained, without detectable in vivo toxicities, except for selective (on-target) and reversible B cell depletion. Treatment with huCD20-Fc-AFN significantly increased the median overall survival (mOS) in both non-humanized (mOS 31 to 45 days; HR = 0.26; p = 0.001), and humanized NSG/NOG mice (mOS 34 to 80 days; HR = 0.37; p < 0.0001). In humanized mice, there was a trend for increased survival when compared to equimolar rituximab (mOS 49 to 80 days; HR = 0.73; p = 0.09). The antitumoral effects of huCD20-Fc-AFN were partly due to direct effects of type I IFN on the tumor cells, but additional effects via the human immune system are essential to obtain long-term remissions. To conclude, huCD20-Fc-AFN could provide a novel therapeutic strategy for huCD20-expressing aggressive B-NHLs.

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