PuSH - Publication Server of Helmholtz Zentrum München: CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330.

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Krupka, C. ; Kufer, P.* ; Kischel, R.* ; Zugmaier, G.* ; Bögeholz, J. ; Köhnke, T. ; Lichtenegger, F.S. ; Schneider, S.* ; Metzeler, K.H.* ; Fiegl, M.* ; Spiekermann, K. ; Baeuerle, P.A.* ; Hiddemann, W. ; Riethmüller, G.* ; Subklewe, M.

CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330.

Blood 123, 356-365 (2014)

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Antibody-based immunotherapy represents a promising strategy to target and eliminate chemoresistant leukemic cells. Here, we evaluated the CD33/CD3-bispecific BiTE® antibody (AMG 330) for its suitability as therapeutic agent in AML. We first assessed CD33 expression levels by flow cytometry and found expression in >99% of patient samples (n=621). CD33 was highest expressed in AMLs with NPM1 mutations (p<0.001) and lower in AMLs with complex karyotypes and t(8;21) translocations (p<0.001). Furthermore, leukemic stem cells within the CD34(+)/CD38(-) compartment displayed CD33 at higher levels than healthy donor stem cells (p=0.047). In MS-5 feeder cell-based long-term cultures that supported the growth of primary AML blasts for up to 36 days, AMG 330 efficiently recruited and expanded residual CD3(+)/CD45RA(-)/CCR7(+) memory T-cells within the patient sample. Even at low effector to target ratios, the recruited T-cells lysed autologous blasts completely in the majority of samples and substantially in the remaining samples in a time- dependent manner. This study provides the first correlation of CD33 expression levels with AML genotype in a comprehensive analysis of adult patients. Targeting CD33 ex-vivo using AMG 330 in primary AML samples led to T-cell recruitment and expansion and remarkable antibody-mediated cytotoxicity suggesting efficient therapeutic potential in-vivo.

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