Daratumumab treatment leads to loss of CD38 on red blood cells

The success of daratumumab in several clinical trials has led to an extension of its licensing indication, for the treatment of relapsed and refractory Multiple Myeloma patients across the US and EU. Therefore, understanding the precise mechanism of action is of increasing importance. In a recent short communication, Harold C. Sullivan from The Center for Diffusion Medicine and Cellular Therapies, Department of Pathology and Laboratory of Medicine, Emory School of Medicine, Atlanta, USA and colleagues, reported that daratumumab treatment leads to the down-regulation of CD38 on red blood cells (RBCs). The study was published in April 2017 in Blood.

Key Findings:

• MM cells expressing CD38 are effectively targeted by daratumumab but RBCs, that also express CD38, do not appear to be affected
• Patients (pts) receiving daratumumab have negative direct antiglobulin tests (DAT) - suggesting a lack of antibodies attached to RBCs and positive indirect antibody tests (IAT) - suggesting antibodies against RBCs in the patient serum; RBC hydrolysis was also undetected
• Using 24 samples from daratumumab-treated patients and non-treated controls, the authors observed:
  • Antibody and CD38 antigen levels are decreased on RBCs isolated from daratumumab treated patients
  • RBC antigens (KELL and DUFFY) showed no difference between the two groups
  • Both CD38 antigen and bound antibody decline following daratumumab treatment
  • Daratumumab infusion led to complete saturation of CD38 on RBCs in-vivo
  • Complement activation was not detected on RBCs from daratumumab treated pts
  • CD38 protein on RBCs was detected pre-infusion, but was undetectable one week after treatment

In conclusion, daratumumab appears to remove CD38 from the surface of RBCs without inducing hemolysis, and this removal prevents further engagement of daratumumab by RBCs. This seems to protect RBCs from continual removal during daratumumab treatment, and the effect is reversed following treatment withdrawal.