Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells
| Autor: | Ingo Schubert, Christina Krupka, Andreas Mackensen, Karsten Spiekermann, Annemarie Honegger, Sarah Wildenhain, Todd A. Braciak, Stefan W. Krause, Marion Subklewe, Nadja C. Fenn, Uwe Jacob, Christian B. Schiller, Georg H. Fey, Michael Aigner, Claudia C. Roskopf, Fuat Oduncu, Karl-Peter Hopfner |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy medicine.medical_treatment Immunology CD33 therapeutic antibodies CD16 lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine Antigen redirected lysis hemic and lymphatic diseases medicine Immunology and Allergy cd33-cd16-cd123 nk cells Original Research business.industry dual targeting Myeloid leukemia Immunotherapy medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens single-chain triplebodies Leukemia 030104 developmental biology aml Oncology 030220 oncology & carcinogenesis Cancer research Interleukin-3 receptor immunotherapy Stem cell business lcsh:RC581-607 |
| Zdroj: | OncoImmunology, Vol 7, Iss 9 (2018) Oncoimmunology |
| Popis: | A number of agents designed for immunotherapy of Acute Myeloid Leukemia (AML) are in preclinical and early clinical development. Most of them target a single antigen on the surface of AML cells. Here we describe the development and key biological properties of a tri-specific agent, the dual-targeting triplebody SPM-2, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK cells as cytolytic effectors. Primary blasts of nearly all AML patients carry at least one of these target antigens and the pair is particularly promising for the elimination of blasts and leukemia stem cells (LSCs) from a majority of AML patients by dual-targeting agents. The cytolytic activity of NK cells mediated by SPM-2 was analyzed in vitro for primary leukemic cells from 29 patients with a broad range of AML-subtypes. Blasts from all 29 patients, including patients with genomic alterations associated with an unfavorable genetic subtype, were lysed at nanomolar concentrations of SPM-2. Maximum susceptibility was observed for cells with a combined density of CD33 and CD123 above 10,000 copies/cell. Cell populations enriched for AML-LSCs (CD34pos and CD34pos CD38neg cells) from 2 AML patients carried an increased combined antigen density and were lysed at correspondingly lower concentrations of SPM-2 than unsorted blasts. These initial findings raise the expectation that SPM-2 may also be capable of eliminating AML-LSCs and thus of prolonging survival. In the future, patients with a broad range of AML subtypes may benefit from treatment with SPM-2. |
| Databáze: | OpenAIRE |
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