What is CD38?

CD38: A Multifunctional Molecule in Health and Disease

CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of various hematopoietic cells, including plasma cells, B cells, T cells, and myeloid cells, that functions as both a receptor and an enzyme with critical roles in immune regulation, cell signaling, and calcium mobilization. 1

Structure and Expression

CD38 is a type II transmembrane glycoprotein with:

• Molecular weight of approximately 45 kDa
• Expression on multiple cell types, with particularly high expression on:
  • Plasma cells (co-expressed with CD138)
  • Activated B lymphocytes
  • Subsets of T lymphocytes
  • Myeloid cells

Biological Functions

Enzymatic Activity

• Functions as an ectoenzyme that can cleave NAD+ and NADP+ to generate:
  • Cyclic ADP-ribose (cADPR)
  • Nicotinic acid adenine dinucleotide phosphate (NAADP)
• These metabolites regulate autophagy by triggering lysosomal calcium release events that promote fusion of lysosomes with autophagosomes 2

Receptor Functions

• Acts as a receptor involved in:
  • Cell adhesion
  • Signal transduction
  • Modulation of cyclase and hydrolase activity 1

B Cell Regulation

• Closely associates with CD19 in resting B cells and with the IgM-BCR upon engagement
• Regulates B cell antigen receptor (BCR) organization and signaling
• Can induce B lymphocyte proliferation and apoptosis through cytokine crosslinking 3, 4

T Cell Regulation

• Expressed on a subset of activated T cells
• T cells expressing high CD38 show:
  • Reduced proliferative capacity
  • Improved potential to produce cytokines like IL-2 and IFN-γ 5

Clinical Significance

Diagnostic Marker

• Serves as a powerful disease marker for:
  • Multiple myeloma (MM) - core marker for plasma cell identification along with CD138 2, 6
  • Chronic lymphocytic leukemia (CLL) - negative prognostic marker 2, 7
  • Acute myeloid leukemia (AML)
  • T-cell acute lymphoblastic leukemia (T-ALL) 8

Prognostic Value

• In CLL:
  • Expression of CD38 (≥7% of B lymphocytes) correlates with unmutated IGHV status
  • Associated with shorter progression-free survival and overall survival 2
  • Functions as a component of a complex network delivering growth and survival signals to CLL cells 7

Therapeutic Target

• Daratumumab is an IgG1κ human monoclonal antibody that binds to CD38 and inhibits the growth of CD38-expressing tumor cells through multiple mechanisms:

  • Direct induction of apoptosis through Fc-mediated cross-linking
  • Complement-dependent cytotoxicity (CDC)
  • Antibody-dependent cell-mediated cytotoxicity (ADCC)
  • Antibody-dependent cellular phagocytosis (ADCP) 1

• Approved for treatment of multiple myeloma, with significant clinical activity as monotherapy (approximately 30% response rate) and higher activity when combined with proteasome inhibitors or immunomodulatory drugs 2

• Emerging target for chimeric antigen receptor (CAR) T-cell therapy in multiple hematologic malignancies including MM, T-ALL, and AML 8

Clinical Considerations When Targeting CD38

• CD38 is expressed on normal hematopoietic progenitors, which may lead to on-target, off-tumor effects requiring careful monitoring 8

• Daratumumab therapy can interfere with:

  • Serum protein electrophoresis and immunofixation (if the patient's myeloma cells also produce IgG kappa)
  • Monitoring of minimal residual disease by multicolor flow cytometry
  • Blood cross-matching techniques (due to CD38 expression on erythrocytes) 2

• To mitigate cross-matching interference, comprehensive red cell antigen screening before initiating therapy is recommended 2

In summary, CD38 is a multifunctional molecule with significant roles in cellular physiology and pathology, serving as both an important diagnostic/prognostic marker and a validated therapeutic target in multiple hematologic malignancies.