Targeting CD38 in T-ALL using a novel Fc-engineered antibody

Introduction:

Antibody-based immunotherapy is increasingly used in B-cell precursor ALL (BCP-ALL). In BCP-ALL, we have shown that the efficacy of CD19 antibodies can be enhanced by improving the antibody's ability to recruit effector cells via Fc-engineering. Unlike BCP-ALL, immunotherapeutic interventions in T-ALL are practically non-existent, so that novel approaches are urgently required. Only recently, elevated CD38 expression levels have been described in a substantial number of T-ALL patients, making CD38 an attractive candidate for antibody therapy in that entity.

Methods:

The CD38 antibody daratumumab (Dara) was engineered by introducing amino acid substitutions in the Fc (Fragment, crystallizable) domain generating a novel antibody daratumumab-DE (Dara-DE). Antibody-dependent effector mechanisms were tested in vitro in the T-ALL cell line CEM and in primary patient cells amplified in xenografts. Furthermore, NSG mice injected with CEM cells and primary patient cells were treated with Dara with and without a chemotherapy (DEXA, VCR, and PEG-ASP) regimen mimicking ALL induction.

Results:

Dara-DE showed enhanced efficacy in antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells against ALL patient cells in vitro. In xenograft animals, Dara as a monotherapy was only marginally efficient in prolonging the survival. However, the combination of Dara and Chemo resulted in a remarkable increase in overall survival compared to conventional chemotherapy.

Conclusion:

Dara combined with chemotherapy may represent a promising novel approach in the treatment of T-ALL. The efficacy of Dara may further be enhanced by applying Fc-modifications. Experiments evaluating Dara-DE in vivo are currently in progress.