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CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering
Simone C. Oostindie, Hilma J. van der Horst, Margaret A. Lindorfer, Erika M. Cook, Jillian C. Tupitza, Clive S. Zent, Richard Burack, Karl R. VanDerMeid, Kristin Strumane, Martine E.D. Chamuleau, Tuna Mutis, Rob N. de Jong, Janine Schuurman, Esther C.W. Breij, Frank J. Beurskens, Paul W.H.I. Parren, Ronald P. Taylor
Haematologica February 2019 : haematol.2018.207266; doi:10.3324/haematol.2018.207266
Simone C. Oostindie
Genmab, Utrecht, The Netherlands;
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Hilma J. van der Horst
Dept of Hematology, Amsterdam University Medical Center, Amsterdam, The Netherlands;
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Margaret A. Lindorfer
University of Virginia School of Medicine, Charlottesville, Virginia, USA;
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Erika M. Cook
University of Virginia School of Medicine, Charlottesville, Virginia, USA;
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Jillian C. Tupitza
University of Virginia School of Medicine, Charlottesville, Virginia, USA;
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Clive S. Zent
Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA;
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Richard Burack
Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA;
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Karl R. VanDerMeid
Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA;
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Kristin Strumane
Genmab, Utrecht, The Netherlands;
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Martine E.D. Chamuleau
Dept of Hematology, Amsterdam University Medical Center, Amsterdam, The Netherlands;
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Tuna Mutis
Dept of Hematology, Amsterdam University Medical Center, Amsterdam, The Netherlands;
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Rob N. de Jong
Genmab, Utrecht, The Netherlands;
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Janine Schuurman
Genmab, Utrecht, The Netherlands;
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Esther C.W. Breij
Genmab, Utrecht, The Netherlands;
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Frank J. Beurskens
Genmab, Utrecht, The Netherlands;
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Paul W.H.I. Parren
Lava Therapeutics
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Ronald P. Taylor
University of Virginia School of Medicine, Charlottesville, Virginia, USA;
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Author Affiliations

  1. Simone C. Oostindie1,*,
  2. Hilma J. van der Horst2,
  3. Margaret A. Lindorfer3,
  4. Erika M. Cook3,
  5. Jillian C. Tupitza3,
  6. Clive S. Zent4,
  7. Richard Burack4,
  8. Karl R. VanDerMeid4,
  9. Kristin Strumane1,
  10. Martine E.D. Chamuleau2,
  11. Tuna Mutis2,
  12. Rob N. de Jong1,
  13. Janine Schuurman1,
  14. Esther C.W. Breij1,
  15. Frank J. Beurskens1,
  16. Paul W.H.I. Parren5 and
  17. Ronald P. Taylor3
  1. 1 Genmab, Utrecht, The Netherlands;
  2. 2 Dept of Hematology, Amsterdam University Medical Center, Amsterdam, The Netherlands;
  3. 3 University of Virginia School of Medicine, Charlottesville, Virginia, USA;
  4. 4 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA;
  5. 5 Lava Therapeutics
  1. ↵* Corresponding author; email: sio{at}genmab.com
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Abstract

CD20 monoclonal antibody therapies have significantly improved the outlook for patients with B-cell malignancies. However many patients acquire resistance, demonstrating the need for new and improved drugs. We previously demonstrated that the natural process of antibody hexamer formation on targeted cells allows for optimal induction of complement-dependent cytotoxicity. Complement-dependent cytotoxicity can be potentiated by introducing a single point mutation such as E430G in the IgG Fc domain that enhances intermolecular Fc-Fc interactions between cell-bound IgG molecules, thereby facilitating IgG hexamer formation. Antibodies specific for CD37, a target that is abundantly expressed on healthy and malignant B cells, are generally poor inducers of complement-dependent cytotoxicity. Here we demonstrate that introduction of the hexamerization-enhancing mutation E430G in CD37-specific antibodies facilitates highly potent complement-dependent cytotoxicity in chronic lymphocytic leukemia cells ex vivo. Strikingly, we observed that combinations of hexamerization-enhanced CD20 and CD37 antibodies cooperated in C1q binding and induced superior and synergistic complement-dependent cytotoxicity in patient-derived cancer cells compared to the single agents. Furthermore, CD20 and CD37 antibodies colocalized on the cell membrane, an effect that was potentiated by the hexamerization-enhancing mutation. Moreover, upon cell surface binding, CD20 and CD37 antibodies were shown to form mixed hexameric antibody complexes consisting of both antibodies each bound to their own cognate target, so-called hetero-hexamers. These findings give novel insights into the mechanisms of synergy in antibody-mediated complement-dependent cytotoxicity and provide a rationale to explore Fc-engineering and antibody hetero-hexamerization as a tool to enhance the cooperativity and therapeutic efficacy of antibody combinations.

  • Received October 2, 2018.
  • Accepted February 19, 2019.
  • Copyright © 2019, Ferrata Storti Foundation
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Keywords

Indolent Non-Hodgkin's Lymphoma
Aggressive Non-Hodgkin's Lymphoma
chronic lymphocytic leukemia
Lymphoproliferative Disorders
cell therapy and immunotherapy

Vol 104 Issue 12

Haematologica: 104 (12)
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CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering
Simone C. Oostindie, Hilma J. van der Horst, Margaret A. Lindorfer, Erika M. Cook, Jillian C. Tupitza, Clive S. Zent, Richard Burack, Karl R. VanDerMeid, Kristin Strumane, Martine E.D. Chamuleau, Tuna Mutis, Rob N. de Jong, Janine Schuurman, Esther C.W. Breij, Frank J. Beurskens, Paul W.H.I. Parren, Ronald P. Taylor
Haematologica Feb 2019, haematol.2018.207266; DOI: 10.3324/haematol.2018.207266

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Simone C. Oostindie, Hilma J. van der Horst, Margaret A. Lindorfer, Erika M. Cook, Jillian C. Tupitza, Clive S. Zent, Richard Burack, Karl R. VanDerMeid, Kristin Strumane, Martine E.D. Chamuleau, Tuna Mutis, Rob N. de Jong, Janine Schuurman, Esther C.W. Breij, Frank J. Beurskens, Paul W.H.I. Parren, Ronald P. Taylor
Haematologica Feb 2019, haematol.2018.207266; DOI: 10.3324/haematol.2018.207266
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