Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Artikel
Titel:
Novel conjugates of single‐chain Fv antibody fragments specific for stem cell antigen CD123 mediate potent death of acute myeloid leukaemia cells
Beteiligte:
Stein, Christoph;
Kellner, Christian;
Kügler, Markus;
Reiff, Nina;
Mentz, Kristin;
Schwenkert, Michael;
Stockmeyer, Bernhard;
Mackensen, Andreas;
Fey, Georg H.
Erschienen:
Wiley, 2010
Erschienen in:
British Journal of Haematology, 148 (2010) 6, Seite 879-889
Sprache:
Englisch
DOI:
10.1111/j.1365-2141.2009.08033.x
ISSN:
0007-1048;
1365-2141
Entstehung:
Anmerkungen:
Beschreibung:
SummaryFour new single‐chain Fv antibody fragments (scFvs) specific for the human leucocyte surface antigen CD123 (interleukin‐3 receptor α) were generated to achieve preferential targeting of leukaemia stem cells (LSCs) in acute myeloid leukaemia (AML). The scFvs were isolated from a phage display library generated with spleen RNA from mice, immunized with a fusion protein consisting of the extracellular domain of CD123 and the Fc domain of a human immunoglobulin G1. The scFvs displayed CD123‐specific binding on tumour cells (binding constants (KD) 4·5–101 nmol/l). The scFv with the highest affinity was used to design two cell death‐inducing molecules. First, an immunotoxin, a fusion protein with truncated Pseudomonas Exotoxin A, induced potent apoptosis of AML‐derived MOLM‐13 and SKNO‐1 cells at nanomolar concentrations. Second, the fusion to another scFv, specific for the low affinity Fcγ‐receptor III (CD16), created a bispecific single chain Fv (bsscFv). This bsscFv [123 × ds16] mediated potent lysis of AML‐derived MOLM‐13, THP‐1 and SKNO‐1 cells in antibody‐dependent cellular cytotoxicity (ADCC) reactions at picomolar concentrations. The recruitment of CD16‐positive effector cells for the lysis of AML cells via CD123 represents a novel combination with attractive prospects for future clinical testing.