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Leukemia. 2014 Jan;28(1):59-69. doi: 10.1038/leu.2013.243. Epub 2013 Aug 20.

Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system.

Author information

1
Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
2
1] Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany [2] Helmholtz-Zentrum Dresden-Rossendorf, Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
3
Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
4
1] Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany [2] Center for Regenerative Therapies Dresden, 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
5
1] Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany [2] Helmholtz-Zentrum Dresden-Rossendorf, Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany [3] Center for Regenerative Therapies Dresden, 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.

Abstract

Owing to their clinical success, there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia (AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform that consists of a universal effector module (EM) and individual target modules (TMs). Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (for example, the extracellular CD137 ligand domain) to the TM, the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector-to-target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.

PMID:
23958923
DOI:
10.1038/leu.2013.243
[Indexed for MEDLINE]

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