[ICKSH 2025] CD38 at a crossroads of immune modulation and therapeutic innovation

As CD38 emerges as a central immuno-oncology target, its multifunctional role in immune signaling, NAD metabolism, and tumor microenvironment modulation has attracted growing scientific and clinical attention.

In recent years, CD38-targeting monoclonal antibodies such as daratumumab (product name: Darzalex) and isatuximab (product name: Sarclisa) have reshaped the treatment landscape for multiple myeloma, offering new hope in both standard-risk and high-risk settings.

At the same time, efforts to decipher CD38’s role in inflammaging and metabolic regulation have opened additional avenues for therapeutic development beyond cancer.

At the 2025 International Congress of the Korean Society of Hematology (ICKSH 2025) held at Grand Walkerhill, Seoul, Dr. Fabio Malavasi, a pioneer in CD38 research from the University of Torino, Italy, offered unique insights into the evolving science of CD38-targeting agents and their implications in clinical practice.

Speaking with Korea Biomedical Review, Dr. Malavasi elaborated on the immunomodulatory functions of CD38 antibodies and discussed the potential divergence in mechanisms between daratumumab and isatuximab.

Microvesicles, monoclonal antibodies, and therapeutic divergence

Malavasi's research originally focused on daratumumab, the first anti-CD38 antibody approved for multiple myeloma.

His team discovered that the interaction between daratumumab and surface CD38 induces the release of microvesicles enriched with the target molecule and ectoenzymes. These vesicles, coated with the therapeutic antibody, circulate through the bloodstream and modulate immune responses by being internalized by effector cells such as NK cells and monocytes.

"These mini cells carry the antibody and get internalized through Fc receptors, likely delivering their cargo into recipient immune cells," Malavasi said. "We've observed that genes related to immune response are upregulated in these cells, suggesting a profound modulatory effect."

However, when asked whether a similar mechanism applies to isatuximab, another CD38-targeting antibody, Malavasi noted important distinctions.

"There is a tendency of isatuximab to be internalized on its own, but I don’t have direct experimental experience with it. It entered clinical use later than daratumumab, and to my knowledge, it does not induce the same vesicle-mediated effects," he said. “While both antibodies target CD38, their mechanisms differ in subtle but potentially significant ways.”

Isatuximab, which originated as a murine antibody and was later humanized, is known for its ability to trigger direct apoptosis and inhibit CD38’s enzymatic activity—two attributes believed to underlie its potential advantage in high-risk or extramedullary myeloma.

"Isatuximab was selected for its capacity to directly induce cell death and block the enzymatic functions of CD38, which plays multiple roles as a signaling transducer and ectoenzyme in NAD metabolism," Malavasi said.

While early clinical findings suggest isatuximab may offer superior efficacy in specific subsets like 1q-amplified myeloma or extramedullary disease, Malavasi cautioned that such differences appear modest so far.

"The data are promising, but the therapeutic advantages are not as strong as we had hoped,” he said.

Future perspectives beyond monotherapy

Malavasi also emphasized the importance of combination therapies, especially as CD38’s biological functions continue to be elucidated.

As a multifunctional molecule involved in NAD metabolism, calcium signaling, and immunomodulation, CD38 presents opportunities for synergistic combinations with immune checkpoint inhibitors or bispecific antibodies.

"My personal interest lies in bispecific or trispecific antibodies," Malavasi shared. "These constructs can bridge killer cells, such as T cells or NK cells, to tumor-specific targets. They are cheaper than CAR-T therapies and show great promise, especially in resource-limited settings."

Malavasi also acknowledged the economic hurdles associated with advanced biologics.

"Therapies like daratumumab have dramatically improved patient outcomes with few side effects, but their high cost poses challenges, particularly in Europe where the public healthcare system must cover these treatments,” he said.

Reflecting on the broader landscape, Malavasi noted that CD38’s versatility makes it a compelling target not only in oncology but also in age-related and metabolic diseases.

CD38 expression increases with age, contributing to NAD depletion and chronic inflammation—a process known as inflammaging.

Strategies that inhibit CD38 or restore NAD metabolism are now being explored in preclinical models of aging and inflammatory conditions.

“The story of CD38 started in 1978 as a T-cell activation marker, but today it represents a molecular node connecting immunology, metabolism, and oncology,” he said. “Its multifunctionality is what makes it so exciting as a therapeutic target.”