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Lymphoma

The novel tribody [(CD20)2xCD16] efficiently triggers effector cell-mediated lysis of malignant B cells

Leukemia volume 27, pages 190–201 (2013)Cite this article

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Abstract

Bispecific antibodies (bsab) offer a promising approach for optimizing antibody-based therapies. In the present study, [(CD20)2xCD16], a recombinant CD20- and CD16-directed bsab in the tribody format, was designed to optimize recruitment of FcγRIII (CD16)-positive effector cells. [(CD20)2xCD16] retained the antigen specificities of the parental monoclonal antibodies and binding to FcγRIIIa was not compromised by the F/V polymorphism at amino-acid position 158. [(CD20)2xCD16] mediated potent lysis of lymphoma cell lines and freshly isolated tumor cells from patients, even at low picomolar concentrations (∼10 pM). Irrespective of the CD16a allotype, potency as well as efficacy of lysis obtained with the tribody was significantly higher than lysis triggered by rituximab. Tumor cell killing also occurred when autologous NK cells were used as effector cells. Compared with rituximab, the tribody demonstrated depletion of autologous B cells in ex vivo whole blood assays at 100-fold lower antibody concentration. In mice with a reconstituted humanized hematopoietic system, established by transplantation of human CD34-positive cord blood cells, this novel tribody significantly depleted autologous human B cells. Thus, tribodies such as [(CD20)2xCD16], recruiting CD16-positive effector cells, may represent promising candidates for clinical development.

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Acknowledgements

Anja Muskulus, Heidi Bosse and Britta von Below are kindly acknowledged for expert technical assistance. This study was supported by research grant 2007.065.1 and 2007.065.2 from the Wilhelm Sander-Stiftung (Munich, Germany), as well as intramural funding from the Christian-Albrechts University Kiel.

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  1. P Glorius and A Baerenwaldt: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts University, Kiel, Germany

    P Glorius, C Kellner, M Staudinger, T Valerius, A Humpe, R Repp, M Gramatzki & M Peipp

  2. Department of Biology, Chair of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

    A Baerenwaldt & F Nimmerjahn

  3. Department of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany

    M Dechant

  4. Oncologic Medical Office Kronach, Kronach, Germany

    M Stauch

  5. Genmab, Utrecht, The Netherlands

    F J Beurskens, P W H I Parren & J G J van de Winkel

  6. Department of Immunology, Immunotherapy Laboratory, University Medical Center Utrecht, The Netherlands

    J G J van de Winkel

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Competing interests

FJB, PWHIP, JGJvdW are employees of Genmab, a biotech company that develops therapeutic human monoclonal antibodies, including the CD20 antibody ofatumumab. MP serves as consultant for Genmab. The remaining authors declare no conflicts of interest.

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Glorius, P., Baerenwaldt, A., Kellner, C. et al. The novel tribody [(CD20)2xCD16] efficiently triggers effector cell-mediated lysis of malignant B cells. Leukemia 27, 190–201 (2013). https://doi.org/10.1038/leu.2012.150

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