CD19-specific triplebody SPM-1 engages NK and γδ T cells for rapid and efficient lysis of malignant B-lymphoid cells
| Autor: | Karl-Peter Hopfner, Alexandra Schele, Ursula J.E. Seidel, Nadja C. Fenn, Annemarie Honegger, Christian B. Schiller, Todd A. Braciak, Sarah Wildenhain, Fuat Oduncu, Ingo Schubert, Kerstin Lämmermann, Peter Lang, Georg H. Fey, Claudia C. Roskopf, Uwe Jacob |
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| Přispěvatelé: | University of Zurich, Roskopf, Claudia C |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cytotoxicity Immunologic medicine.medical_treatment Lymphocyte Activation 0302 clinical medicine Antineoplastic Agents Immunological Tumor Cells Cultured Gamma delta T cell Intraepithelial Lymphocytes Antibody-dependent cell-mediated cytotoxicity Hematology biology leukemia Killer Cells Natural Leukemia medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis 2730 Oncology immunotherapy Rituximab Research Paper antibody-dependent cellular cytotoxicity medicine.medical_specialty Lymphoma B-Cell gamma delta T cell Antigens CD19 610 Medicine & health single chain triplebody CD19 03 medical and health sciences Lymphocytes Tumor-Infiltrating Internal medicine Cell Line Tumor medicine 10019 Department of Biochemistry Humans B cell Cell Proliferation Dose-Response Relationship Drug business.industry Immunotherapy medicine.disease Molecular biology Cytolysis Kinetics 030104 developmental biology Immunology biology.protein 570 Life sciences business |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Christian B. Schiller 1, * , Todd A. Braciak 2, * , Nadja C. Fenn 1, * , Ursula J. E. Seidel 3, * , Claudia C. Roskopf 2, * , Sarah Wildenhain 1, * , Annemarie Honegger * , Ingo A. Schubert 5 , Alexandra Schele 1 , Kerstin Lammermann 2 , Georg H. Fey 6 , Uwe Jacob 6 , Peter Lang 3 , Karl-Peter Hopfner 1, # , Fuat S. Oduncu 2, # 1 Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, Munich, Germany 2 Division of Hematology and Oncology, Medizinische Klinik und Poliklinik IV, Klinikum der Universitat Munchen, Munich, Germany 3 Department of General Paediatrics, Oncology/Haematology, University Children’s Hospital Tubingen, Tubingen, Germany 4 Department of Biochemistry, University of Zurich, Zurich, Switzerland 5 Department of Biology, University of Erlangen-Nuremberg, Erlangen, Germany 6 Westend-Innovation, Munich, Germany * CBS, TAB, NCF, UJES, CCR and SW are co-first authors in this study # KPH and FSO are co-senior authors in this study Correspondence to: Claudia C. Roskopf, email: Claudia.Roskopf@med.uni-muenchen.de Keywords: single chain triplebody, antibody-dependent cellular cytotoxicity, gamma delta T cell, leukemia, immunotherapy Received: June 30, 2016 Accepted: October 03, 2016 Published: November 04, 2016 ABSTRACT Triplebodies are antibody-derived recombinant proteins carrying 3 antigen-binding domains in a single polypeptide chain. Triplebody SPM-1 was designed for lysis of CD19-bearing malignant B-lymphoid cells through the engagement of CD16-expressing cytolytic effectors, including NK and γδ T cells. SPM-1 is an optimized version of triplebody ds(19-16-19) and includes humanization, disulfide stabilization and the removal of potentially immunogenic sequences. A three-step chromatographic procedure yielded 1.7 - 5.5 mg of purified, monomeric protein per liter of culture medium. In cytolysis assays with NK cell effectors, SPM-1 mediated potent lysis of cancer-derived B cell lines and primary cells from patients with various B-lymphoid malignancies, which surpassed the ADCC activity of the therapeutic antibody Rituximab. EC 50 -values ranged from 3 to 86 pM. Finally, in an impedance-based assay, SPM-1 mediated a particularly rapid lysis of CD19-bearing target cells by engaging and activating both primary and expanded human γδ T cells from healthy donors as effectors. These data establish SPM-1 as a useful tool for a kinetic analysis of the cytolytic reactions mediated by γδ T and NK cells and as an agent deserving further development towards clinical use for the treatment of B-lymphoid malignancies. |
| Databáze: | OpenAIRE |
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