A dual-targeting triplebody mediates preferential redirected lysis of antigen double-positive over single-positive leukemic cells

Schubert I, Saul D, Nowecki S, Mackensen A, Fey G, Oduncu FS (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Publisher: Landes Bioscience

Book Volume: 6

Pages Range: 286-96

Journal Issue: 1

DOI: 10.4161/mabs.26768

Abstract

The single-chain triplebody HLA-ds16-hu19 consists of three single-chain Fv (scFv) antibody fragments connected in a single polypeptide chain. This protein with dual-targeting capacity mediated preferential lysis of antigen double-positive (dp) over single-positive (sp) leukemic cells by recruitment of natural killer (NK) cells as effectors. The two distal scFv modules were specific for the histocompatibility protein HLA-DR and the lymphoid antigen CD19, the central one for the Fc gamma receptor CD16. In antibody-dependent cellular cytotoxicity (ADCC) experiments with a mixture of leukemic target cells comprising both HLA-DR sp HuT-78 or Kasumi-1 cells and (HLA-DR plus CD19) dp SEM cells, the triplebody mediated preferential lysis of the dp cells even when the sp cells were present in <=20-fold numerical excess. The triplebody promoted equal lysis of SEM cells at 2.5-fold and 19.5-fold lower concentrations than the parental antibodies specific for HLA-DR and CD19, respectively. Finally, the triplebody also eliminated primary leukemic cells at lower concentrations than an equimolar mixture of bispecific single-chain Fv fragments (bsscFvs) separately addressing each target antigen (hu19-ds16 and HLA-ds16). The increased selectivity of targeting and the preferential lysis of dp over sp cells achieved by dual-targeting open attractive new perspectives for the use of dual-targeting agents in cancer therapy.

Authors with CRIS profile

Involved external institutions

Klinikum der Universität München (Großhadern und Innenstadt) Germany (DE)

How to cite

APA:

Schubert, I., Saul, D., Nowecki, S., Mackensen, A., Fey, G., & Oduncu, F.S. (2014). A dual-targeting triplebody mediates preferential redirected lysis of antigen double-positive over single-positive leukemic cells. Mabs, 6(1), 286-96. https://doi.org/10.4161/mabs.26768

MLA:

Schubert, Ingo, et al. "A dual-targeting triplebody mediates preferential redirected lysis of antigen double-positive over single-positive leukemic cells." Mabs 6.1 (2014): 286-96.

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