Universität zu Köln

Lilienthal, Nils, Lohmann, Gregor, Crispatzu, Giuliano, Vasyutina, Elena ORCID: 0000-0001-9722-3419, Zittrich, Stefan, Mayer, Petra, Herling, Carmen Diana, Tur, Mehmet Kemal ORCID: 0000-0002-9259-6723, Hallek, Michael, Pfitzer, Gabriele, Barth, Stefan ORCID: 0000-0001-9589-653X and Herling, Marco (2016). A Novel Recombinant Anti-CD22 Immunokinase Delivers Proapoptotic Activity of Death-Associated Protein Kinase (DAPK) and Mediates Cytotoxicity in Neoplastic B Cells. Mol. Cancer Ther., 15 (5). S. 971 - 985. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-8514

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Abstract

The serine/threonine death-associated protein kinases (DAPK) provide pro-death signals in response to (oncogenic) cellular stresses. Lost DAPK expression due to (epi) genetic silencing is found in a broad spectrum of cancers. Within B-cell lymphomas, deficiency of the prototypic family member DAPK1 represents a predisposing or early tumorigenic lesion and high-frequency promoter methylation marks more aggressive diseases. On the basis of protein studies and meta-analyzed gene expression profiling data, we show here that within the low-level context of B-lymphocytic DAPK, particularly CLL cells have lost DAPK1 expression. To target this potential vulnerability, we conceptualized B-cell-specific cytotoxic reconstitution of the DAPK1 tumor suppressor in the format of an immunokinase. After rounds of selections for its most potent cytolytic moiety and optimal ligand part, a DK1KD-SGIII fusion protein containing a constitutive DAPK1 mutant, DK1KD, linked to the scFv SGIII against the B-cell-exclusive endocytic glyco-receptor CD22 was created. Its high purity and large-scale recombinant production provided a stable, selectively binding, and efficiently internalizing construct with preserved robust catalytic activity. DK1KD-SGIII specifically and efficiently killed CD22-positive cells of lymphoma lines and primary CLL samples, sparing healthy donor-or CLL patient-derived non-B cells. The mode of cell death was predominantly PARP-mediated and caspase-dependent conventional apoptosis as well as triggering of an autophagic program. The notoriously high apoptotic threshold of CLL could be overcome by DK1KD-SGIII in vitro also in cases with poor prognostic features, such as therapy resistance. The manufacturing feasibility of the novel CD22-targetingDAPK immunokinase and its selective antileukemic efficiency encourage intensified studies towards specific clinical application. (C) 2016 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lilienthal, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Lohmann, Gregor UNSPECIFIED UNSPECIFIED UNSPECIFIED Crispatzu, Giuliano UNSPECIFIED UNSPECIFIED UNSPECIFIED Vasyutina, Elena UNSPECIFIED orcid.org/0000-0001-9722-3419 UNSPECIFIED Zittrich, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, Carmen Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Tur, Mehmet Kemal UNSPECIFIED orcid.org/0000-0002-9259-6723 UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfitzer, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Barth, Stefan UNSPECIFIED orcid.org/0000-0001-9589-653X UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-276849
DOI:	10.1158/1535-7163.MCT-15-0685
Journal or Publication Title:	Mol. Cancer Ther.
Volume:	15
Number:	5
Page Range:	S. 971 - 985
Date:	2016
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-8514
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; SERINE/THREONINE KINASE; PROMOTER METHYLATION; CANCER; IMMUNOTOXINS; GENE; HYPERMETHYLATION; APOPTOSIS; ESTABLISHMENT; INHIBITORS Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27684