Display options
Cite
Kellner C, Günther A, Humpe A, et al. Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30. Oncoimmunology. 2015;5(1):e1058459doi: 10.1080/2162402X.2015.1058459.
Kellner, C., Günther, A., Humpe, A., Repp, R., Klausz, K., Derer, S., Valerius, T., Ritgen, M., Brüggemann, M., van de Winkel, J. G., Parren, P. W., Kneba, M., Gramatzki, M., & Peipp, M. (2016). Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30. Oncoimmunology, 5(1), e1058459. https://doi.org/10.1080/2162402X.2015.1058459
Kellner, Christian, et al. "Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30." Oncoimmunology vol. 5,1 (2016): e1058459. doi: https://doi.org/10.1080/2162402X.2015.1058459
Kellner C, Günther A, Humpe A, Repp R, Klausz K, Derer S, Valerius T, Ritgen M, Brüggemann M, van de Winkel JG, Parren PW, Kneba M, Gramatzki M, Peipp M. Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30. Oncoimmunology. 2015 Jun 05;5(1):e1058459. doi: 10.1080/2162402X.2015.1058459. eCollection 2016. PMID: 26942070; PMCID: PMC4760288.
Copy Download .nbib Format: NLM
Share it on

Oncoimmunology. 2015 Jun 05;5(1):e1058459. doi: 10.1080/2162402X.2015.1058459. eCollection 2016.

Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30.

Oncoimmunology

Christian Kellner, Andreas Günther, Andreas Humpe, Roland Repp, Katja Klausz, Stefanie Derer, Thomas Valerius, Matthias Ritgen, Monika Brüggemann, Jan Gj van de Winkel, Paul Whi Parren, Michael Kneba, Martin Gramatzki, Matthias Peipp

Affiliations

  1. Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
  2. 2nd Department of Medicine; Christian-Albrechts-University Kiel ; Kiel, Germany.
  3. Genmab; Utrecht, the Netherlands; Department of Immunology; University Medical Center Utrecht; Utrecht, the Netherlands.
  4. Genmab; Utrecht, the Netherlands; Department of Cancer and Inflammation Research; Institute of Molecular Medicine; University of Southern Denmark; Odense, Denmark; Department of Immunohematology and Blood Transfusion; Leiden University Medical Center; Leiden, the Netherlands.

PMID: 26942070 PMCID: PMC4760288 DOI: 10.1080/2162402X.2015.1058459

Abstract

Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated through the IgG Fc receptor FcγRIIIa represents a major effector function of many therapeutic antibodies. In an attempt to further enhance natural killer (NK) cell-mediated ADCC, we combined therapeutic antibodies against CD20 and CD38 with recombinant immunoligands against the stimulatory NK cell receptors NKG2D or NKp30. These immunoligands, respectively designated as ULBP2:7D8 and B7-H6:7D8, contained the CD20 scFv 7D8 as a targeting moiety and a cognate ligand for either NKG2D or NKp30 (i.e. ULBP2 and B7-H6, respectively). Both the immunoligands synergistically augmented ADCC in combination with the CD20 antibody rituximab and the CD38 antibody daratumumab. Combinations with ULBP2:7D8 resulted in higher cytotoxicity compared to combinations with B7-H6:7D8, suggesting that coligation of FcγRIIIa with NKG2D triggered NK cells more efficiently than with NKp30. Addition of B7-H6:7D8 to ULBP2:7D8 and rituximab in a triple combination did not further increase the extent of tumor cell lysis. Importantly, immunoligand-mediated enhancement of ADCC was also observed for tumor cells and autologous NK cells from patients with hematologic malignancies, in which, again, ULBP2:7D8 was particularly active. In summary, co-targeting of NKG2D was more effective in promoting rituximab or daratumumab-mediated ADCC by NK cells than co-ligation of NKp30. The observed increase in the ADCC activity of these therapeutic antibodies suggests promise for a 'dual-dual-targeting' approach in which tumor cell surface antigens are targeted in concert with two distinct activating NK cell receptors (i.e. FcγRIIIa and NKG2D or B7-H6).

Keywords: ADCC; CD20; NK cells; NKG2D; NKp30; antibody

References

  1. Blood. 2006 Mar 1;107(5):1955-62 - PubMed
  2. Blood. 2002 Feb 1;99(3):754-8 - PubMed
  3. Science. 2005 Dec 2;310(5753):1510-2 - PubMed
  4. Science. 2004 Nov 26;306(5701):1517-9 - PubMed
  5. J Exp Med. 2009 Jul 6;206(7):1495-503 - PubMed
  6. J Clin Oncol. 2008 Apr 10;26(11):1774-7 - PubMed
  7. Leukemia. 2012 Apr;26(4):830-4 - PubMed
  8. MAbs. 2014 Mar-Apr;6(2):409-21 - PubMed
  9. J Immunol. 2012 Dec 15;189(12):5493-7 - PubMed
  10. J Immunol Methods. 2011 Oct 28;373(1-2):67-78 - PubMed
  11. J Immunol. 2011 Feb 1;186(3):1840-8 - PubMed
  12. Oncoimmunology. 2013 Jun 1;2(6):e24481 - PubMed
  13. Cancer Res. 2011 Aug 1;71(15):5134-43 - PubMed
  14. Science. 1999 Jul 30;285(5428):730-2 - PubMed
  15. J Immunol. 2012 Nov 15;189(10):5037-46 - PubMed
  16. Blood. 2009 Sep 24;114(13):2657-66 - PubMed
  17. Adv Enzyme Regul. 1984;22:27-55 - PubMed
  18. Blood. 2008 Sep 15;112(6):2390-9 - PubMed
  19. Cancer Res. 2010 Apr 15;70(8):3209-17 - PubMed
  20. Leukemia. 2011 Jun;25(6):1053-6 - PubMed
  21. J Immunol. 2008 May 1;180(9):6392-401 - PubMed
  22. Nat Med. 2000 Apr;6(4):443-6 - PubMed
  23. Br J Haematol. 2013 Oct;163(2):182-93 - PubMed
  24. Neoplasia. 2012 Feb;14(2):121-30 - PubMed
  25. Science. 2011 Jan 7;331(6013):44-9 - PubMed
  26. Blood. 2006 Oct 15;108(8):2648-54 - PubMed
  27. Clin Cancer Res. 2011 Nov 1;17 (21):6742-53 - PubMed
  28. Clin Dev Immunol. 2012;2012:421702 - PubMed
  29. Blood. 2011 Feb 24;117(8):2423-32 - PubMed
  30. Blood. 2006 Jan 1;107(1):159-66 - PubMed
  31. Nat Rev Cancer. 2012 Mar 22;12(4):278-87 - PubMed
  32. Immunotherapy. 2012 May;4(5):511-27 - PubMed
  33. Immunity. 2001 Feb;14(2):123-33 - PubMed
  34. J Clin Invest. 2012 Sep;122(9):3260-70 - PubMed
  35. Methods. 2014 Jan 1;65(1):105-13 - PubMed
  36. Clin Cancer Res. 2012 Jan 15;18(2):499-509 - PubMed
  37. J Clin Oncol. 2008 Apr 10;26(11):1789-96 - PubMed
  38. Drug Discov Today. 2007 Nov;12(21-22):898-910 - PubMed
  39. Nat Med. 2011 Jun;17(6):700-7 - PubMed
  40. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4285-9 - PubMed
  41. J Exp Med. 1999 Nov 15;190(10):1505-16 - PubMed
  42. Blood. 2014 Jan 30;123(5):678-86 - PubMed
  43. Haematologica. 2012 Jun;97(6):937-42 - PubMed
  44. Trends Mol Med. 2014 Feb;20(2):72-82 - PubMed
  45. J Clin Invest. 2012 Mar;122(3):1066-75 - PubMed
  46. J Clin Oncol. 2003 Nov 1;21(21):3940-7 - PubMed
  47. Front Immunol. 2013 Mar 27;4:76 - PubMed

Publication Types