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Immunology

T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct

Leukemia volume 27, pages 1107–1115 (2013)Cite this article

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Abstract

Patients with acute myelogenous leukemia (AML) are in high need of novel targeted therapies. Here we explored the ex vivo activity of AMG330, a novel T-cell-engaging BiTE (bi-specific T-cell engagers) antibody (Ab) construct, that is bispecific for the myeloid differentiation antigen, CD33 and CD3, in primary samples from AML patients (N=23) and AML cell lines. KG-1 and U937 cells were lysed in co-culture with healthy donor T-cells at AMG330 concentrations as low as 0.1 ng/ml (1.8 pM). T-cells derived from AML patient samples were found to be as active in redirected lysis by AMG330 as T-cells from healthy donors. In an autologous setting, AMG330 could activate and expand T-cells in primary AML patient samples, and effectively mediated the redirected lysis of AML blasts and normal myeloid cells. A deficiency in target-cell lysis was only observed in samples with very low initial effector-to-target (E:T) ratio. However, this could be overcome if previously stimulated autologous T-cells were tested in patient samples at a higher E:T ratio. In vivo experiments in immunodeficient mice demonstrated significant inhibition of tumor growth by AMG330 and an inducible infiltration of human T-cells into subcutaneous HL60 tumors. The activities of the CD33/CD3-bispecific BiTE Ab construct AMG330 warrant further development for the treatment of AML.

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Acknowledgements

JF was supported by GRK643 (SFB643), awarded by the Deutsche Forschungs Gemeinschaft (DFG).

Author contributions

MA and SWK developed the flow cytometric evaluation strategy. MA analyzed the data from primary cell cultures. JF performed and analyzed the experiments on primary AML cells. SS analyzed the T-cell activation data. SWK analyzed patient-related data. RK produced and characterized AMG330. PK spearheaded development of AMG330 for treatment of AML. KS, AH, BR and MF performed and analyzed the mouse experiments. PAB initiated the study and revised the paper. MA, AM and SWK designed the study and wrote the paper.

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  1. M Aigner and J Feulner: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Internal Medicine 5—Hematology/Oncology, University of Erlangen-Nuernberg, Erlangen, Germany

    M Aigner, J Feulner, S Schaffer, A Mackensen & S W Krause

  2. Amgen Research (Munich) GmbH, Munich, Germany

    R Kischel, P Kufer, K Schneider, A Henn, B Rattel, M Friedrich & P A Baeuerle

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  1. M Aigner
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Correspondence to S W Krause.

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Competing interests

MA, JF, AM, SWK: research funding from Amgen Research (Munich) GmbH. RK, PK, PAB, KS, AH, BR and MF are employed by Amgen Research (Munich) GmbH and have an ownership interest in Amgen, Inc.

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Aigner, M., Feulner, J., Schaffer, S. et al. T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct. Leukemia 27, 1107–1115 (2013). https://doi.org/10.1038/leu.2012.341

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