Enhancing cytotoxicity of immunotoxins in AML: Focus on BI 836858 a Fc-engineered CD33 antibody

The treatment of Acute Myeloid Leukemia (AML) is evolving at a marked pace; resistance to intensive induction chemotherapy causing deaths in elderly patients has sparked these developments. At present, more targeted approaches are being developed where only the malignant cells are eliminated and will hopefully lead to better tolerability and increased efficacy.

Antibodies-based immunoconjugates have been employed to target cell-specific surface receptors. Interleukin-3, granulocyte-macrophage colony-stimulating factor and CD33 receptors have been used as therapeutic targets for AML cells.

In a recent publication in Blood, N. Daver and F. Ravandi from the MD Anderson Cancer Center comment on further advancements in AML treatment with reference to Natural Killer (NK) antibody dependent cellular toxic effects of Fc-engineered CD33 antibodies.

Their commentary is based on data published by Vasu et al. in Blood. Vasu et al. investigated the in vitro efficacy of BI 836858, a fully human, Fc-engineered, anti-CD33 antibody in AML cell lines and primary AML blasts. Vasu et al. reported that BI 836858 demonstrated an anti-leukemic effect through autologous and allogenic NK cell degranulation. It addition, BI 836858 caused NK cell-mediated Antibody-Dependent Cellular Cytotoxicity (ADCC).

In this same study, the authors also compared the difference in BI 836858-mediated ADCC in patients who had received a 10-day course of decitabine therapy (DAC); pre-DAC treatment versus post-DAC treatment. The results showed higher ADCC at day 28 post-DAC treatment compared to pre-DAC treatment. Vasu et al. postulate that this observation occurred as a result of decitabine increasing ligands which activate NK receptors and thus enhancing the ADCC effect of BI 836858 (see figure 1).

Figure 1: Decitabine may have immunomodulatory effects.

The commentary by N. Daver and F. Ravandi states that these results are of significance for AML as two novel antibody based treatment strategies have been identified:

• The first strategy employs the NK cell-mediated ADCC
• The second strategy relates to a synergistic immunomodulatory effect of DNA-methyltransferase inhibitors (DNMTi’s) in combination with anti-CD33 antibodies to potentiate NK cell-mediated activity on AML blasts

In summary, Vasu et al. conclude that these data provide the basis for a new combination therapy.

Please find the link to the commentary article in Blood.