Targeting CD38 with Daratumumab: A Promising Approach for Multiple Myeloma Therapy

A type II transmembrane glycoprotein, CD38, is prevalent in various blood-related cancers, such as multiple myeloma (MM), and is a potential target for monoclonal antibody (mAb) therapies. The study explored the anti-MM properties of daratumumab, a new mAb under clinical trial for treating MM. Originating from HuMab-mice, daratumumab was selected for its strong binding affinity. It showed a robust response against a range of CD38-expressing MM cell lines, whether sensitive or resistant to existing MM treatments, with a median fluorescence intensity (MFI) significantly higher than that of the isotype control. Cells lacking CD38 mRNA did not bind to daratumumab. The mAb induced natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against CD38-positive MM cells, but not against CD38-negative cells, indicating its selective targeting. The cytotoxic effect was dose-dependent, with maximum efficacy at concentrations of 0.01-0.1μg/ml. The study also examined the impact of daratumumab on NK and peripheral blood mononuclear cells (PBMCs), which express CD38 at lower levels than MM cells. Pretreatment of PBMCs or NK cells with daratumumab did not significantly affect ADCC against MM1S cells. The bone marrow (BM) microenvironment's role in protecting MM cells was considered, and daratumumab was found to induce ADCC against MM cells in the presence of BM stromal cells (BMSCs), suggesting its efficacy in the BM environment. The findings were consistent with patient cell responses, with daratumumab inducing ADCC in both allogeneic and autologous patient MM cells. The study also investigated complement-mediated cytotoxicity (CDC) and found that daratumumab induced CDC in MM cells expressing low levels of CD59 and CD55, regardless of BMSC presence. CDC was effective in purified MM cells from six out of nine patients, and was not influenced by the presence of complement inhibitor proteins. Additionally, daratumumab induced apoptosis in certain cell lines and cell death in purified patient MM cells, as determined by annexin V/PI staining. The results suggest that daratumumab can effectively eliminate MM tumor cells through multiple cytotoxic mechanisms, supporting its clinical development to enhance MM patient outcomes.