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

Willem Daneels (UGent) , Alexander Van Parys (UGent) , Leander Huyghe (UGent) , Elke Rogge (UGent) , Steffi De Rouck (UGent) , Ruben Christiaen, Lennart Zabeau (UGent) , Sylvie Taveirne (UGent) , Jo Van Dorpe (UGent) , Niko Kley, et al.
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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 (TM) were developed. In syngeneic murine models, the CD20-targeted murine IFN alpha 2-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 huIFN alpha 2 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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MLA
Daneels, Willem, et al. “High Efficacy of HuCD20-Targeted AcTaferon in Humanized Patient Derived Xenograft Models of Aggressive B Cell Lymphoma.” EXPERIMENTAL HEMATOLOGY & ONCOLOGY, vol. 13, no. 1, 2024, doi:10.1186/s40164-024-00524-4.
APA
Daneels, W., Van Parys, A., Huyghe, L., Rogge, E., De Rouck, S., Christiaen, R., … Offner, F. (2024). High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma. EXPERIMENTAL HEMATOLOGY & ONCOLOGY, 13(1). https://doi.org/10.1186/s40164-024-00524-4
Chicago author-date
Daneels, Willem, Alexander Van Parys, Leander Huyghe, Elke Rogge, Steffi De Rouck, Ruben Christiaen, Lennart Zabeau, et al. 2024. “High Efficacy of HuCD20-Targeted AcTaferon in Humanized Patient Derived Xenograft Models of Aggressive B Cell Lymphoma.” EXPERIMENTAL HEMATOLOGY & ONCOLOGY 13 (1). https://doi.org/10.1186/s40164-024-00524-4.
Chicago author-date (all authors)
Daneels, Willem, Alexander Van Parys, Leander Huyghe, Elke Rogge, Steffi De Rouck, Ruben Christiaen, Lennart Zabeau, Sylvie Taveirne, Jo Van Dorpe, Niko Kley, Anje Cauwels, Erik Depla, Jan Tavernier, and Fritz Offner. 2024. “High Efficacy of HuCD20-Targeted AcTaferon in Humanized Patient Derived Xenograft Models of Aggressive B Cell Lymphoma.” EXPERIMENTAL HEMATOLOGY & ONCOLOGY 13 (1). doi:10.1186/s40164-024-00524-4.
Vancouver
1.
Daneels W, Van Parys A, Huyghe L, Rogge E, De Rouck S, Christiaen R, et al. High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma. EXPERIMENTAL HEMATOLOGY & ONCOLOGY. 2024;13(1).
IEEE
[1]
W. Daneels et al., “High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma,” EXPERIMENTAL HEMATOLOGY & ONCOLOGY, vol. 13, no. 1, 2024.
@article{01HZJAFJSYGAMCF47VQPNFX5S8,
  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 (TM) were developed. In syngeneic murine models, the CD20-targeted murine IFN alpha 2-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 huIFN alpha 2 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.}},
  articleno    = {{59}},
  author       = {{Daneels, Willem and Van Parys, Alexander and Huyghe, Leander and Rogge, Elke and De Rouck, Steffi and Christiaen, Ruben and Zabeau, Lennart and Taveirne, Sylvie and Van Dorpe, Jo and Kley, Niko and Cauwels, Anje and Depla, Erik and Tavernier, Jan and Offner, Fritz}},
  issn         = {{2162-3619}},
  journal      = {{EXPERIMENTAL HEMATOLOGY & ONCOLOGY}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{20}},
  title        = {{High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma}},
  url          = {{http://doi.org/10.1186/s40164-024-00524-4}},
  volume       = {{13}},
  year         = {{2024}},
}

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