The Multifunctional Enzyme CD38: A Target for Immunotherapeutic Approaches in Cancer

1. CD38 Structure and Enzymatic Functions

2. CD38 in Non-Solid Tumors

3. CD38 in Solid Tumors

4. CD38 in the Age-Related NAD Decline

5. CD38-Targeting Antibody for Clinical Uses

6. CD38 Potential Perspectives

1. CD38 Structure and Enzymatic Functions

CD38 is a type II transmembrane glycoprotein with a molecular weight of 46 kDa. CD38 was first identified in the early 1980s by E. L. Reinherz and S. F. Schlossman. CD38 has a short amino-terminal cytoplasmic tail, a single membrane-spanning region, and a long extracel-lular carboxy-terminal domain (Figure 1) ^[3]. CD38 is a bifunctional ectoenzyme that uses nicotinamide adenine dinucleotide (NAD) as a substrate to generate second messengers like cyclic ADP ribose (cADPR) ^{[4, 5]}, which contribute to the Ca²⁺ mobilization. The Ca²⁺ mobilization further activates the signaling pathways that control various biological processes such as insulin secretion and pancreatic β-cell proliferation ^[6].

Meanwhile, CD38 plays important roles in maintaining the dynamic balance of NAD and its metabolites levels. It has also been found that CD38, together with CD39, CD73, CD203a, etc., induces a suppressive immune microenvironment by degrading adenosine triphosphate/ATP, NAD+, cADPR, and adenosine monophosphate/AMP, which leads to the production of adenosine/ADO ^[7].

Figure 1. Schematic representation of CD38 structure

*This figure is derived from the publication on FASEB Journal ^[3]

CD38 is expressed in a variety of human tissues, including lymphocytes, natural killer cells, T cells, B-cell monocytes/macrophages pancreas, brain, spleen, and liver cells, etc ^{[8, 9]}. Interestingly, the levels of CD38 expression have been correlated with a variety of diseases, including acquired immunodeficiency syndrome/AIDS, autoimmune diseases (e.g., systemic lupus erythematosus, SLE), type 2 diabetes, osteoporosis, and cancer ^[10-12].

2. CD38 in Non-Solid Tumors

In non-solid tumors, CD38 is considered as a predictor of B-cell chronic lymphocytic leukemia (B-CLL) given its overexpression. B-CLL patients who suggested high expression of CD38 in the B lymphocytes of peripheral blood is strongly associated with poor prognosis ^[13]. Others, include Waldenström's macroglobulinemia ^[14], systemic light-chain (AL) amyloidosis ^[15], mantle cell lymphoma/MCL ^[16], acute myeloid leukemia/AML ^[17], acute lymphoblastic leukemia/ALL ^[18], and NK cell leukemia ^[19]. Among these non-solid tumors, high expression of CD38 is identified.

Figure 2. Mechanism of CD38 monoclonal antibody in multiple myeloma

*This figure is derived from the publication on Frontiers in immunology ^[20]

Notably, CD38 on multiple myeloma (MM) cells, its expression is very high, which suppresses immunity through its enzymatic activity ^[20]. In contrast, in normal lymphocytes and myeloid cells, CD38 expression is low. As described in Figure 2, monoclonal antibodies targeting the CD38 in MM cells can trigger a variety of different mechanisms to promote apoptosis and modulate the immune response ^[20].

3. CD38 in Solid Tumors

In some solid tumors, high levels of CD38 expression is associated with the increased adenosine ^[21]. It is well-recognized that adenosine has a marked dampening effect on the immune response. As represented in Figure 3, CD38 overexpression contributes to the production of adenosine in the tumor microenvironment. Then adenosine recruits immunosuppressive cells such as Treg cells, myeloid-derived suppressor cell/MDSC cells, cancer-associated fibroblast/CAF cells, etc., which results in disorders of the immune system. Further, adenosine binds to its receptor A2AR on the surface of immune cells to activate inhibitory signaling pathways ^[22]. All in all, CD38 might suppress immune response such as CD8+T cells via adenosine receptor signaling.

Figure 3. CD38 signaling pathway in the solid tumors

*This figure is derived from the publication on Cells ^[22]

Although the specified mechanisms of CD38 in solid tumors remain to be further explored, several studies have shed some light on the roles of CD38 in melanoma, glioma, esophageal, cervical, and lung cancers. In these diseases, CD38 appears to function as a tumor-promoting factor ^[23].

4. CD38 in the Age-Related NAD Decline

The aforementioned studies published in Nature Metabolism found that mice lacking CD38 were protected from age-related NAD decline and had enhanced metabolic health ^[2]. The findings raised the possibility that with an increasing burden of senescent cells, which is also implicated in the aging process, cause the degradation of NAD via the activation of CD38 (Figure 4) ^[1].

Figure 4. CD38 in the age-related NAD decline

*This figure is derived from the publication on Nature Metabolism ^[21]

NAD+ is a cellular coenzyme that's found in every cell of our bodies. Maintenance of NAD+ levels is important for anti-aging. Preliminary data suggest that blocking the activity of CD38 in aged animals can restore NAD+ levels in specific tissues ^[2]. Therefore, targeting CD38 may provide scientists with another way to address the decline in NAD+ against aging.

5. CD38-Targeting Antibody for Clinical Uses

In recent years, several novel immunotherapies targeting CD38 have been validated in preclinical models and clinical trials. In 2015, Daratumumab (Darzalex), a fully human anti-CD38 antibody developed by Johnson & Johnson, was approved for the treatment of patients with relapsed, drug-resistant MM. Daratumumab became the first CD38 antibody on the market.

On March 2, 2020, Sanofi received FDA approval for its oncology drug Isatuximab, the second CD38 antibody drug after Daratumumab, also for the treatment of MM treatment. Currently, both Daratumumab and Isatuximab show significant efficacy in MM therapy.

It is worth mentioning that several pharmaceutical companies, including China's Sumgen and YZY Biopharma, have also started the development of antibodies targeting CD38. Recently, CASI Pharmaceutical submitted an Investigational New Drug application (IND) for CD38 antibody. More pharmaceutical companies are in a highly competitive race, as shown in the table below.

*This data derives from pharmacodia.

6. CD38 Potential Perspectives

Apparently, antibody drugs have a wide application in cancer and autoimmune diseases. The development history of CD38 antibody drugs can be traced back to the 1990s, but currently only two CD38 monoclonal antibodies have been approved for marketing. According to Johnson & Johnson's latest earnings report, global sales of Darzalex reached $2.9 billion in 2019. It is said that global sales of Darzalex are expected to reach $6 billion in 2024, analysis on Pharma.

The expression of CD38 in immune cells suggests important roles in immune response, which provides a powerful weapon for the MM treatment. MM, a disease that affects more than 130,000 patients worldwide each year, antibodies targeting CD38 will not only fight tumors but also have potential value in the treatment of aging-related conditions such as fibrosis and metabolic disorders. Therefore, the development of CD38-targeted drugs is becoming more attractive for big pharmaceutical companies.