Dual-targeting triplebody 33-3-19 mediates selective lysis of biphenotypic CD19+ CD33+ leukemia cells
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Claudia C. Roskopf1, Todd A. Braciak1, Nadja C. Fenn2, Sebastian Kobold3, Georg H. Fey4, Karl-Peter Hopfner2, Fuat S. Oduncu1
1Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Hematology/Oncology, Munich, Germany
2Ludwig-Maximilians-Universität München, Department of Biochemistry and Gene Center, Munich, Germany
3Center for Integrated Protein Science (CIPSM) and Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Division of Clinical Pharmacology, Munich, Germany
4Friedrich-Alexander-University Erlangen-Nuremberg, Department of Biology, Erlangen, Germany
Claudia C. Roskopf, e-mail: [email protected]
Keywords: leukemia, mixed phenotype acute leukemia (MPAL), immunotherapy, dual-targeting triplebody, selectivity
Received: November 11, 2015 Accepted: February 23, 2016 Published: March 10, 2016
Simultaneous targeting of multiple tumor-associated antigens (TAAs) in cancer immunotherapy is presumed to enhance tumor cell selectivity and to reduce immune escape.
The combination of B lymphoid marker CD19 and myeloid marker CD33 is exclusively present on biphenotypic B/myeloid leukemia cells. Triplebody 33-3-19 binds specifically to both of these TAAs and activates T cells as immune effectors. Thereby it induces specific lysis of established myeloid (MOLM13, THP-1) and B-lymphoid cell lines (BV173, SEM, Raji, ARH77) as well as of primary patient cells. EC50 values range from 3 pM to 2.4 nM. In accordance with our hypothesis, 33-3-19 is able to induce preferential lysis of double- rather than single-positive leukemia cells in a target cell mixture: CD19/CD33 double-positive BV173 cells were eliminated to a significantly greater extent than CD19 single-positive SEM cells (36.6% vs. 20.9% in 3 hours, p = 0.0048) in the presence of both cell lines. In contrast, equivalent elimination efficiencies were observed for both cell lines, when control triplebody 19-3-19 or a mixture of the bispecific single chain variable fragments 19-3 and 33-3 were used. This result highlights the potential of dual-targeting agents for efficient and selective immune-intervention in leukemia patients.
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