Daratumumab is an anti-CD38 directed
monoclonal antibody approved for the treatment of
multiple myeloma (MM) and functions primarily via Fc-mediated effector mechanisms such as
complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and T-cell activation. However, not all patients respond to
daratumumab therapy and management of MM remains challenging.
Radioimmunotherapy with alpha particle-emitting
radionuclides represents a promising approach to significantly enhance the potency of therapeutic
antibodies in
cancer treatment. Here we report the results of mechanistic and feasibility studies using
daratumumab radiolabeled with an alpha-emitter 225Actinium for
therapy of MM. CD38-positivelymphoma Daudi cell line and MM cell lines KMS-28BM and KMS-28PE were treated in vitro with 225Ac-daratumumab. 225Ac-daratumumab Fc-functional properties were assessed with C1q binding and ADCC assays. The pharmacokinetics and
tumor uptake of 111In-daratumumab in Daudi
tumor-bearing
severe combined immunodeficiency (SCID) mice were measured with microSPECT/CT. The
therapeutic effects of 225Ac-daratumumab on Daudi and KSM28BM
tumors in mice and treatment side effects were evaluated for 50 days posttreatment. The safety of 225Ac-labeled antimurine CD38 mAb in immunocompetent mice was also evaluated. 225Ac-daratumumab efficiently and specifically killed CD38-positive
tumor cells in vitro, while its
complement binding and ADCC functions remained unaltered. MicroSPECT/CT imaging demonstrated fast clearance of the radiolabeled
daratumumab from the circulation and tissues, but prolonged retention in the
tumor up to 10 days.
Therapy and safety experiments with 225Ac-daratumumab showed a significant increase in the antitumor potency in comparison to naked antibody without any significant side effects. Our results highlight the potential of targeting alpha-emitters to
tumors as a therapeutic approach and suggest that 225Ac-daratumumab may be a promising therapeutic strategy for the treatment of
hematologic malignancies.