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A recombinant trispecific single‐chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting
Author(s) -
Kügler Markus,
Stein Christoph,
Kellner Christian,
Mentz Kristin,
Saul Domenica,
Schwenkert Michael,
Schubert Ingo,
Singer Heiko,
Oduncu Fuat,
Stockmeyer Bernhard,
Mackensen Andreas,
Fey Georg H.
Publication year - 2010
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2010.08300.x
Subject(s) - cd33 , antibody dependent cell mediated cytotoxicity , cancer research , peripheral blood mononuclear cell , antibody , chemistry , antigen , immunology , myeloid , microbiology and biotechnology , in vitro , biology , monoclonal antibody , cd34 , stem cell , biochemistry
Summary Two trivalent constructs consisting of single‐chain Fv antibody fragments (scFvs) specific for the interleukin‐3 receptor α chain (CD123), CD33 and the Fcγ‐receptor III (CD16) were designed and characterized for the elimination of acute myeloid leukaemia (AML) cells. The dual targeting single‐chain Fv triplebody (sctb) [123 × ds16 × 33] and the mono targeting sctb [123 × ds16 × 123] both specifically bound their respective target antigens and were stable in human serum at 37°C for at least 5 d. Both constructs induced potent antibody‐dependent cellular cytotoxicity (ADCC) of two different AML‐derived CD33‐ and CD123 double‐positive cell lines in the low picomolar range using isolated mononuclear cells (MNCs) as effector cells. In these experiments the dual targeting molecule produced significantly stronger lysis than the mono targeting agent. In addition, the sctbs showed a high potency in mediating ADCC of primary leukaemia cells isolated from peripheral blood or bone marrow of seven AML patients. Hence, these novel molecules displayed potent anti‐leukaemic effects against AML cells in vitro and represent attractive candidates for further preclinical development.