Anti-Human CD38 (Daratumumab) (LT2500-GRP)

CD38 is a type II transmembrane glycoprotein that functions as an adhesion molecule with ectoenzymatic activities that contribute to intracellular calcium mobilization1, 2. Dysregulation is associated with a number of diseases, including HIV, autoimmune, type II diabetes mellitus, osteoporosis, and hematological malignancies such as multiple myeloma (MM)1, a neoplasm characterized by clonal expansion of malignant plasma cells2. CD38 is a target of MM immunotherapy, and, in 2015, the US Food and Drug Administration approved the use of daratumumab for MM treatment3. Daratumumab kills CD38-expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking3, 4 as well as by immune-mediated tumor cell lysis via complement dependent cytotoxicity (CDC)5, antibody dependent cell mediated cytotoxicity (ADCC)5, and antibody dependent cellular phagocytosis (ADCP)3, 4, 6. Daratumumab also modulates CD38 enzymatic activities, blunting cyclase activity and enhancing hydrolase activity, resulting in decreased Ca2+ mobilization and reduced downstream signaling1. Furthermore, subsets of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs), and B cells (CD38+Bregs) are decreased by daratumumab3, and CD38 is uniformly removed from the surface of red blood cells without inducing detectable hemolysis7. Daratumumab was generated by immunizing HuMAb-mice with purified HA-CD38 recombinant protein alone or alternating with CD38-transfected NIH-3T3 cells5. Mouse splenocytes and lymph node cells were isolated, fused with SP2/0 myeloma cells, and tested for binding to CHO-CD38 cells. The daratumumab epitope maps to two β-strands containing amino acids 233–246 and 267–280 of CD38. Binding to CD38 is completely abolished when the serine at position 274 is replaced with phenylalanine. Daratumumab does not bind to cynomolgus CD38. Daratumumab clone AL9, a non-therapeutic biosimilar antibody for research use only was developed recombinantly and has the same variable regions as the original therapeutic.