What Is Daratumumab and CD38 Expression?

Daratumumab (marketed as Darzalex) is a human IgG1κ monoclonal antibody specifically designed to bind to CD38, a transmembrane glycoprotein highly expressed on multiple myeloma cells. CD38 is a multifunctional protein that acts as both a receptor and an enzyme, involved in calcium signaling and cell adhesion processes.

CD38 expression varies across different cell types, but it is particularly abundant on plasma cells, including malignant myeloma cells. This differential expression makes CD38 an ideal target for therapeutic intervention, as it allows for selective targeting of cancerous cells while minimizing effects on healthy tissues with lower CD38 expression levels.

How Daratumumab Works Through CD38 Targeting

The mechanism of action for daratumumab involves multiple immune-mediated effects. When the antibody binds to CD38 on myeloma cells, it initiates several processes that lead to cell death:

First, it activates complement-dependent cytotoxicity (CDC), where the complement system creates pores in the cancer cell membrane. Second, it triggers antibody-dependent cellular cytotoxicity (ADCC), recruiting natural killer cells to destroy the antibody-tagged cancer cells. Third, it induces antibody-dependent cellular phagocytosis (ADCP), where macrophages engulf and eliminate the tagged cancer cells. Additionally, daratumumab causes direct apoptosis (programmed cell death) and has immunomodulatory effects that reduce immunosuppressive cells in the tumor microenvironment.

CD38 Expression Levels and Treatment Response

The efficacy of daratumumab therapy correlates strongly with CD38 expression levels on target cells. Patients with higher CD38 expression on their myeloma cells typically show better responses to daratumumab treatment. This relationship has led to the development of CD38 expression testing as a potential biomarker for predicting treatment outcomes.

Research has shown that CD38 expression can decrease following daratumumab treatment, potentially leading to drug resistance. This phenomenon has prompted investigations into combination therapies and strategies to upregulate CD38 expression. For instance, all-trans retinoic acid (ATRA) has been shown to increase CD38 expression and may enhance daratumumab efficacy when used in combination.

Provider Comparison for Daratumumab Therapies

Several pharmaceutical companies are involved in developing CD38-targeting therapies:

  • Janssen Pharmaceuticals (Johnson & Johnson): Manufacturer of Darzalex (daratumumab), the first FDA-approved CD38-targeting monoclonal antibody.
  • Sanofi: Developer of Sarclisa (isatuximab), another CD38-targeting antibody approved for multiple myeloma treatment.
  • Takeda Pharmaceutical: Conducting clinical trials on combination therapies including daratumumab.
  • MorphoSys: Involved in CD38 antibody development and research.

The subcutaneous formulation of daratumumab (Darzalex Faspro) has significantly reduced administration time from several hours to just minutes, improving patient convenience and reducing infusion-related reactions compared to the intravenous formulation.

Benefits and Limitations of CD38-Targeted Therapy

Daratumumab offers several advantages in multiple myeloma treatment, including improved overall response rates and prolonged progression-free survival. When combined with standard treatment regimens, it has shown remarkable efficacy in both newly diagnosed and relapsed/refractory multiple myeloma cases.

However, there are limitations to consider. CD38 is expressed on normal lymphoid and myeloid cells, though at lower levels, which can lead to side effects including infusion reactions, cytopenias, and increased infection risk. Additionally, Celgene and other researchers have documented cases of reduced efficacy over time due to decreased CD38 expression on myeloma cells after prolonged treatment. The high cost of therapy remains a significant barrier for many patients, with annual treatment costs potentially exceeding $100,000 depending on dosing schedule and insurance coverage. Researchers at Dana-Farber Cancer Institute continue to investigate methods to overcome these limitations through novel combination approaches.

Conclusion

Daratumumab's targeting of CD38 expression represents a significant advancement in multiple myeloma treatment. As research continues, understanding the relationship between CD38 expression patterns and treatment response will likely lead to more personalized and effective therapeutic approaches. The development of companion diagnostics to measure CD38 expression levels may further refine patient selection and treatment strategies. While challenges remain, including managing resistance mechanisms and optimizing combination regimens, the success of daratumumab has validated CD38 as an important therapeutic target and paved the way for next-generation antibodies and novel approaches to enhance anti-myeloma immunity.

Citations

This content was written by AI and reviewed by a human for quality and compliance.