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The Fc-engineered CD19 antibody MOR208 (XmAb5574) induces natural killer cell-mediated lysis of acute lymphoblastic leukemia cells from pediatric and adult patients

Leukemia volume 27, pages 1595–1598 (2013)Cite this article

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The introduction of therapeutic antibodies such as the CD20 antibody rituximab has improved the treatment options of patients with B-cell lymphomas. However, B-lineage acute lymphoblastic leukemia (ALL) patients often do not benefit from this therapeutic option, because CD20 is not expressed in the majority of cases, especially when the disease originated from more immature B-precursor cells. Hence, both monoclonal and bispecific antibodies were developed against other target antigens expressed by B-ALL blasts.1 CD19 is a promising candidate, because it is expressed very early during B-cell development and thus is highly displayed by the majority of both precursor and mature B-ALL cells.2 Several CD19-targeting molecules are in different phases of preclinical and clinical development,3, 4, 5, 6, 7, 8 but to date no CD19 antibodies have been approved for clinical application. Recently, convincing results have been obtained in a phase II clinical study in adult ALL patients with blinatumomab, a bispecific (CD19 × CD3) single-chain fragment variable engaging T cells.8

NK cell cytotoxicity is impaired against autologous cells due to interactions between KIR on NK cells and HLA class I molecules on the target cells. To determine whether MOR208 was able to overcome KIR-mediated inhibition, ADCC reactions were performed in an autologous setting (Figure 2e). NK cells were prepared from the peripheral blood of an ALL patient on day 20 after the first course of consolidation chemotherapy. At that time point considerable amounts of malignant blasts were still detectable, and accounted for 40% of peripheral leukocytes (data not shown). It is impressive that MOR208 induced ADCC with NK cells derived from the patient, and mediated lysis of primary autologous ALL blasts with high HLA class I expression. This indicated that the activating signals of the Fc-engineered antibody were strong enough to overcome HLA class I-mediated NK cell inhibition.

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References

  1. Hoelzer D, Gökbuget N . Chemoimmunotherapy in acute lymphoblastic leukemia. Blood Rev 2012; 26: 25–32.

    Article  CAS  PubMed  Google Scholar 

  2. Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM . Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation. Blood 1984; 63: 1424–1433.

    CAS  PubMed  Google Scholar 

  3. Kellner C, Bruenke J, Stieglmaier J, Schwemmlein M, Schwenkert M, Singer H et al. A novel CD19-directed recombinant bispecific antibody derivative with enhanced immune effector functions for human leukemic cells. J Immunother 2008; 31: 871–884.

    Article  CAS  PubMed  Google Scholar 

  4. Lang P, Barbin K, Feuchtinger T, Greil J, Peipp M, Zunino SJ et al. Chimeric CD19 antibody mediates cytotoxic activity against leukemic blasts with effector cells from pediatric patients who received T-cell-depleted allografts. Blood 2004; 103: 3982–3985.

    Article  CAS  PubMed  Google Scholar 

  5. Ward E, Mittereder N, Kuta E, Sims GP, Bowen MA, Dall'Acqua W et al. A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo. Br J Haematol 2011; 155: 426–437.

    Article  CAS  PubMed  Google Scholar 

  6. Cochlovius B, Kipriyanov SM, Stassar MJ, Schuhmacher J, Benner A, Moldenhauer G et al. Cure of Burkitt's lymphoma in severe combined immunodeficiency mice by T cells, tetravalent CD3 x CD19 tandem diabody, and CD28 costimulation. Cancer Res 2000; 60: 4336–4341.

    CAS  PubMed  Google Scholar 

  7. Horton HM, Bernett MJ, Pong E, Peipp M, Karki S, Chu SY et al. Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res 2008; 68: 8049–8057.

    Article  CAS  PubMed  Google Scholar 

  8. Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 2011; 29: 2493–2498.

    Article  CAS  PubMed  Google Scholar 

  9. Nimmerjahn F, Ravetch JV . Antibodies, Fc receptors and cancer. Curr Opin Immunol 2007; 19: 239–245.

    Article  CAS  PubMed  Google Scholar 

  10. de Haij S, Jansen JH, Boross P, Beurskens FJ, Bakema JE, Bos DL et al. In vivo cytotoxicity of type I CD20 antibodies critically depends on Fc receptor ITAM signaling. Cancer Res 2010; 70: 3209–3217.

    Article  CAS  PubMed  Google Scholar 

  11. Weng WK, Levy R . Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003; 21: 3940–3947.

    Article  CAS  PubMed  Google Scholar 

  12. Desjarlais JR, Lazar GA, Zhukovsky EA, Chu SY . Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective. Drug Discov Today 2007; 12: 898–910.

    Article  CAS  PubMed  Google Scholar 

  13. Zalevsky J, Leung IW, Karki S, Chu SY, Zhukovsky EA, Desjarlais JR et al. The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates. Blood 2009; 113: 3735–3743.

    Article  CAS  PubMed  Google Scholar 

  14. Awan FT, Lapalombella R, Trotta R, Butchar JP, Yu B, Benson DM et al. CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody. Blood 2010; 115: 1204–1213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rafiq S, Cheney C, Mo X, Jarjoura D, Muthusamy N, Byrd JC . XmAb-5574 antibody demonstrates superior antibody-dependent cellular cytotoxicity as compared with CD52- and CD20-targeted antibodies in adult acute lymphoblastic leukemia cells. Leukemia 2012; 26: 1720–1722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Daniela Hallack, Anja Muskulus, Britta von Below and Heidi Bosse for expert technical assistance, and Kirsten Bleckmann for collecting clinical information. Xencor Inc. is kindly acknowledged for providing MOR208 (XmAb5574) and the respective control molecules.

Author contributions

CK and MP designed and performed experiments, analyzed data and wrote the manuscript; AP performed experiments; EAZ provided vital new reagents and edited the manuscript; AH, MG and RR planned experiments, provided well-characterized samples and wrote the manuscript. AS, MB and MK provided well-characterized samples and edited the manuscript.

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Author notes

  1. E A Zhukovsky: Current affiliation: Affimed Therapeutics AG, Heidelberg, Germany.

Authors and Affiliations

  1. Division of Stem Cell Transplantation and Immunotherapy, Second Department of Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany,

    C Kellner, A Pötzke, R Repp, A Humpe, M Gramatzki & M Peipp

  2. Xencor, Inc., Monrovia, CA, USA

    E A Zhukovsky

  3. Second Department of Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany

    M Brüggemann & M Kneba

  4. Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Germany

    A Schrauder & M Schrappe

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Corresponding author

Correspondence to M Peipp.

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Competing interests

EAZ is a former employee of Xencor Inc. This research was completed by EAZ while he was employed at Xencor Inc. The remaining authors declare no conflict of interests.

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Kellner, C., Zhukovsky, E., Pötzke, A. et al. The Fc-engineered CD19 antibody MOR208 (XmAb5574) induces natural killer cell-mediated lysis of acute lymphoblastic leukemia cells from pediatric and adult patients. Leukemia 27, 1595–1598 (2013). https://doi.org/10.1038/leu.2012.373

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