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Mol Ther. 2015 Apr;23(4):648-55. doi: 10.1038/mt.2015.2. Epub 2015 Jan 12.

Characterization of a bispecific FLT3 X CD3 antibody in an improved, recombinant format for the treatment of leukemia.

Author information

1
1] Department of Immunology, Eberhard Karls Universität Tübingen, Tübingen, Germany [2] Present address: Synimmune GmbH, Auf der Morgenstelle 15, Tübingen, Germany.
2
Department of Immunology, Eberhard Karls Universität Tübingen, Tübingen, Germany.
3
1] Department of Immunology, Eberhard Karls Universität Tübingen, Tübingen, Germany [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Department of Internal Medicine 2, Eberhard Karls Universität Tübingen, Tübingen, Germany.
5
1] Department of Internal Medicine 2, Eberhard Karls Universität Tübingen, Tübingen, Germany [2] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

FLT3 is a receptor-tyrosine-kinase that is expressed on leukemic cells of the myeloid and lymphoid lineage rather specifically. We here report on the construction and selection of bispecific FLT3 X CD3 antibodies in a new recombinant format, termed Fabsc, that resembles the normal antibody structure more closely than the well-established bispecific single chain (bssc)-format. Our preferred antibody, which emerged from an initial selection procedure utilizing different FLT3- and CD3-antibodies, contains the FLT3-antibody 4G8 and the CD3-antibody UCHT1. The 4G8 X UCHT1 Fabsc-antibody was found to be superior to a bssc-antibody with identical specificities with respect to (i) affinity to the target antigen FLT3, (ii) production yield by transfected cells, and (iii) the diminished formation of aggregates. T-cell activation in the presence and absence of cultured leukemic cells and killing of these cells was comparable for both molecules. In addition, the 4G8 X UCHT1 Fabsc-antibody was found to induce T-cell activation and efficient killing of leukemic blasts in primary peripheral blood mononuclear cell (PBMC) cultures of acute myeloid leukemia (AML) patients. In these experiments, the bispecific molecule was clearly superior to an Fc-optimized monospecific FLT3-antibody described previously, indicating that within PBMC of AML patients the recruitment of T cells is more effective than that of natural killer cells.

PMID:
25578618
PMCID:
PMC4395786
DOI:
10.1038/mt.2015.2
[Indexed for MEDLINE]
Free PMC Article

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