CD38 Inhibitors: A Breakthrough for Age-Related Diseases

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- Updated by Jody Mullis
Medically reviewed by Dr. Sidra Samad

Learn how CD38 inhibitors target the root cause of age-related diseases like multiple myeloma, offering a promising breakthrough in treatment.

CD38 Inhibitors: A Promising Therapeutic Approach for Age-Related Diseases

Are you ready to discover how CD38 inhibitors might transform the treatment of age-related diseases? This article dives into the promising world of CD38 inhibitors, explaining how they work, their impact on NAD+ levels, and their role in various therapies. By targeting the enzymatic activity of the CD38 protein, these inhibitors help maintain cellular NAD levels, crucial for energy production and overall health. You’ll learn about their potential in treating multiple myeloma, autoimmune diseases, and metabolic disorders.

We’ll explore how CD38 inhibitors interact with natural compounds like flavonoid apigenin, a potent CD38 inhibitor, and their effects on immune cells such as natural killer cells. The research demonstrates that CD38 inhibitors can increase NAD levels, which is vital for cellular health, and how they affect the enzymatic activity of CD38 in multiple myeloma cells.

This article covers the clinical trials and efficacy of CD38 inhibitors, highlighting their role in combination therapies and monotherapy in multiple myeloma. You'll read about various studies and findings, including those by Shapiro and the National Institutes of Health, showing the broad impact of CD38 inhibitors on NAD metabolism and immune modulation.

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Mechanism of Action of CD38 Inhibitors

CD38 inhibitors work by targeting the enzymatic activity of the CD38 molecule. CD38 is a multifunctional enzyme found on the surface of many immune cells. It plays a key role in NAD+ metabolism, which is critical for cellular energy production.

Inhibitors like 78c act by specifically binding to CD38, thus preventing it from decreasing NAD+ levels. This binding is reversible and uncompetitive, meaning it interferes with the enzyme's function without permanently attaching to it. This unique interaction reduces NADase activity and stabilises NAD+ levels.

In enzymatic terms:

  • V_max: the maximum rate of reaction
  • K_m: the substrate concentration at which the reaction rate is half of V_max

By reducing both apparent V_max and K_m, CD38 inhibitors improve metabolic conditions, especially in age-related metabolic dysfunctions.

From a structural perspective, molecules like isatuximab bind to non-overlapping epitopes on the CD38 molecule. Unlike other antibodies, isatuximab specifically targets parts of CD38 without blocking the active site entirely, thus modulating rather than completely inhibiting its activities.

Additionally, CD38 inhibitors demonstrate varying efficacies across different species. Research indicates that inhibitors like 78c show potent effects in both human (recombinant rhCD38) and murine CD38 models.

Understanding the nuances of CD38 interactions helps in developing targeted therapies for autoimmune diseases, cancers, and metabolic disorders. For instance, anti-CD38 antibodies are proving effective in treatments for multiple myeloma due to their multifaceted targeting approach.

In essence, CD38 inhibitors such as 78c and isatuximab represent promising therapeutic avenues by preserving NAD+ levels, modulating immune responses, and providing a targeted approach to treating complex diseases.

Clinical Trials and Efficacy of CD38 Inhibitors

Clinical trials for CD38 inhibitors have shown promising results across various medical conditions. These inhibitors target the CD38 molecule, which is prevalent on the surface of certain cancer cells and immune cells. By focusing on CD38, these treatments aim to disrupt the growth and survival mechanisms of malignant cells.

Multiple Myeloma Treatment

Multiple Myeloma Treatment CD38 inhibitors are particularly notable in the treatment of multiple myeloma. Anti-CD38 monoclonal antibodies, such as daratumumab, have transformed therapeutic approaches. Clinical trials have shown significant improvements when combined with other agents like proteasome inhibitors and immunomodulatory drugs, enhancing overall survival rates.

Combination Therapies

Combining CD38 inhibitors with other immune checkpoint inhibitors, such as PD-1 inhibitors, is a growing research area. Studies, including those on isatuximab and cemiplimab, are currently assessing the enhanced efficacy of dual-target approaches in patients with certain B-cell malignancies and NK cell lymphomas. 

Lupus Management

Beyond cancer, CD38 inhibitors are being explored for autoimmune diseases. For instance, daratumumab's application in refractory systemic lupus erythematosus shows early promise. Targeting plasma cells with these inhibitors has produced credible results in preliminary trials.

Phase I and II Trials

Ongoing investigations in Phase I and II trials focus on the safety and preliminary efficacy across different patient cohorts. Early-stage studies often assess dosing, tolerability, and potential side effects, laying the groundwork for broader application. 

Current Challenges

Despite advancements, some challenges remain. The efficacy can vary based on the patient's disease stage and previous treatments. Moreover, accessibility and cost continue to be constraints in widespread clinical applications.

As we continue to explore the capabilities of CD38 inhibitors, these trials serve as a beacon of hope for patients seeking new, effective treatments.

Role of CD38 Inhibitors in Natural Killer Cells and Immune Modulation

We’ve all been there, grappling with complex terms like 'CD38 inhibitors' and wondering how they impact our immune system. Let’s break it down together.

Natural killer (NK) cells are a key component in our body's defence system. They play a crucial role in recognizing and destroying compromised cells. CD38, found on the surface of NK cells, helps modulate their activity. Interestingly, CD38 can either enhance or suppress NK cell action depending on the context.

When we think about inhibiting CD38, the goal is often to enhance the function of NK cells. This is crucial for conditions where a robust immune response is necessary, like fighting certain cancers or infections. Treatment with CD38 inhibitors can help reactivate NK cells, making them more effective at targeting harmful cells.

Research has shown that targeting CD38 can significantly impact immune modulation. For instance, the use of EZH2 inhibitors can lead to the upregulation of CD38 and CD48, enhancing sensitivity to treatments like Daratumumab. This offers a promising avenue for therapies that rely on the activation of the immune system.

Moreover, CD38’s role isn't limited to NK cells. It also affects other immune cells, such as T cells and B cells, implicating a broader aspect of immune modulation. For those of us looking into the potential of CD38 inhibitors, it’s fascinating to see how they can help in fine-tuning the immune response across different types of cells.

Imagine you’re steering a ship—sometimes you need to adjust the sails to catch more wind; similarly, CD38 inhibitors help adjust the 'sails' of our immune system to navigate through challenges more effectively.

It’s clear that CD38 inhibitors hold potential in various therapeutic contexts. By enabling better control over NK cell function, these inhibitors represent a significant advancement in immunotherapy. This opens up new possibilities for treating diseases that previously had few effective options.

Exploring the Role of Apigenin and CD38 Regulation

Recent studies have revealed intriguing connections between natural compounds and CD38 activity. Understanding these relationships provides valuable insights into how we can manage CD38 levels and their impact on health.

One such compound is apigenin, a flavonoid found in many fruits and vegetables. Researchers have been investigating its effects on CD38 and other aspects of cellular function. Let’s delve into some key questions to uncover these insights.

Does Apigenin Reduce CD38?

Research indicates that the flavonoid apigenin acts as an inhibitor of CD38.. By reducing CD38 expression, apigenin helps preserve higher levels of nicotinamide adenine dinucleotide (NAD+), which is crucial for cellular energy production and overall metabolic health. This inhibition of CD38 is particularly beneficial for maintaining muscle function and combating metabolic diseases.

Does Apigenin Increase GABA?

In addition to its impact on apigenin has also been shown to enhance the activity of GABA (gamma-aminobutyric acid) in the brain. GABA is a neurotransmitter that plays a key role in reducing neuronal excitability and promoting relaxation. The ability of apigenin to increase GABA activity contributes to its anxiolytic (anxiety-reducing) effects, making it valuable for both metabolic and neurological health.

Why Does CD38 Increase?

The reasons behind elevated CD38 expression are multifaceted. CD38 levels can rise due to factors such as inflammation, oxidative stress, and certain diseases. Chronic inflammation, often associated with conditions like obesity and diabetes, significantly contributes to higher CD38 levels. This increase leads to reduced NAD+ levels, exacerbating metabolic dysfunctions and other age-related issues.

By identifying the underlying causes of increased CD38 expression, researchers can develop targeted therapies to better manage its levels. This understanding is crucial for improving health outcomes and developing effective treatments.

By delving into these aspects, we gain a clearer picture of how natural compounds like apigenin can influence CD38 activity and overall health. These insights further underscore the importance of ongoing research into CD38 inhibitors and their potential therapeutic applications.

Understanding the Increase in CD38 Levels

Why does CD38 increase?
CD38 expression can rise due to several factors, including inflammation, oxidative stress, and certain diseases. Chronic inflammation, common in conditions like obesity and diabetes, significantly contributes to elevated CD38 levels. This increase leads to lower NAD+ levels, which can worsen metabolic dysfunctions and other age-related issues. Identifying the reasons behind CD38 upregulation is essential for developing targeted therapies to manage its levels effectively.

By delving into these aspects, we gain a clearer picture of how natural compounds like apigenin can influence CD38 activity and overall health. These insights further underscore the importance of ongoing research into CD38 inhibitors and their potential therapeutic applications.


Small Molecule Inhibitors and Antibody-Based CD38 Inhibitors

Small molecule inhibitors targeting CD38 have gained attention due to their potential therapeutic benefits. These inhibitors primarily block the enzyme's activity by interfering at the molecular level, which impacts NAD+ metabolism and immunity. One example is N1-Inosine 5′-monophosphate, a fragment relevant to the cyclic adenosine diphosphoribose (cADPR) pathway, which plays a crucial role in calcium signalling.

Monoclonal antibodies are another class of CD38 inhibitors. Unlike small molecules, these antibodies target CD38 with high specificity, reducing the enzyme's activity and altering the NAD+ landscape within tissues. This approach has shown promise in oncology, particularly in enhancing anti-tumour immune responses.

Interestingly, some small molecule CD38 inhibitors and monoclonal antibodies work synergistically. For instance, anti-CD38 antibodies can increase tissue NAD+ levels and promote T cell fitness, which is crucial for an effective immune response.

Another point to consider is the variety of inhibitors. Flavonoids are commonly researched small molecule inhibitors, many of which are non-covalent and competitive. Rhein is unique among these, acting as an uncompetitive inhibitor in the flavonoid class, offering a different mechanism of CD38 inhibition.

Despite their differences, both small molecule inhibitors and monoclonal antibodies hold potential in treating various diseases. The ongoing scientific efforts to develop more specific inhibitors could lead to more targeted and effective treatments.

For more information, you can read about the synthesis of 8-Amino-N1-Inosine 5′-monophosphate and its relevance to CD38 inhibitors at MDPI Molecules

This combination of small molecule and antibody-based inhibitors represents a promising frontier in medical research, with the potential to revolutionise how we approach treatment for various conditions, including cancer and immune system disorders.

The potential of CD38 Inhibitors for Age-Related Diseases and Memory B Cells

The potential of CD38 inhibitors in addressing age-related diseases is quite significant. As we age, NAD+ levels decline, impacting metabolic functions and accelerating the ageing process. Research indicates that CD38 inhibitors might effectively target and mitigate this decline. For example, research found that the small molecule 78c, a CD38 inhibitor, improved the metabolic health of aged mice by increasing NAD+ levels. This suggests that CD38 inhibitors could be harnessed to treat common age-related conditions, such as diabetes and insulin resistance.

Memory B cells, known for their role in the immune response, also express CD38. These cells are essential for long-term immunity as they remember past infections and enable a quicker response upon re-exposure. The expression of CD38 on memory B cells indicates a potential dual benefit of CD38 inhibitors, not only in metabolic health but also in modulating immune functions.

The therapeutic potential of CD38 inhibitors spans a broad spectrum, impacting both metabolism and immune functions. Continued research is crucial to fully understand their capabilities and limitations, but the initial findings are undeniably promising.


In conclusion, CD38 inhibitors present a significant breakthrough in the treatment of age-related diseases and multiple myeloma. By targeting the enzyme CD38, these inhibitors can help maintain cellular NAD levels, which are crucial for energy production and overall health. Research shows that flavonoid apigenin is an inhibitor that can effectively reduce the enzymatic activity of CD38, potentially benefiting patients with various conditions.

CD38 knockout studies and myeloma research have demonstrated that CD38 monoclonal antibodies can improve outcomes for multiple myeloma patients. These antibodies target CD38-positive cells, reducing the levels of CD38 and its NADase activity. The catalytic activity of CD38 is essential in regulating cellular functions, and inhibiting it can lead to significant therapeutic benefits.

Studies have also found that CD38 is expressed in multiple tissues and its enzymatic activity is crucial in the regulation of NAD+ metabolism. The enzyme CD38 may play a role in mitochondrial dysfunction and its inhibition could lead to improved cellular health. Novel CD38 inhibitors are being explored for their potential in treating autoimmune diseases and cancers.

The effect of CD38 on immune cells like natural killer cells and the role of anti-human CD38 antibodies in therapy highlights the broad potential of these inhibitors. Research continues to explore the relationships between CD38 and its impact on health, revealing new therapeutic avenues.

Understanding the intricate roles of CD38 and its inhibitors opens new avenues for treating complex diseases. As we continue to explore these promising therapies, the potential to improve health outcomes and extend longevity becomes ever more attainable.

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