Modulating CD38 enzymatic activity during antibody-based immunotherapy in multiple myeloma: a basic science perspective - PubMed
2 days ago
- #multiple myeloma resistance
- #adenosine immunosuppression
- #CD38 immunotherapy
- CD38 is a multifunctional ectoenzyme highly expressed on malignant plasma cells in multiple myeloma (MM), contributing to an immunosuppressive bone marrow microenvironment by degrading NAD+ into ADPR, fueling adenosine production.
- CD38-targeting monoclonal antibodies (e.g., daratumumab, isatuximab) exert antitumor activity but face resistance; their modulation of CD38 enzymatic activity and adenosinergic metabolism during therapy is key to improving efficacy.
- In vitro, both daratumumab and isatuximab promoted NAD+ degradation with ADPR accumulation; in vivo, adenosine levels in bone marrow plasma remained high during daratumumab therapy, while inosine increased, attenuating the bone marrow-peripheral blood gradient.
- Adenosinergic metabolism remains active during CD38-targeted therapy, likely due to reduced CD38 expression from antibody-driven internalization or microvesicle release, and adenosine deaminase-mediated degradation, sustaining immunosuppressive adenosine concentrations.
- Persistent adenosine production above purinergic receptor thresholds suggests ongoing adenosinergic immunosuppression, contributing to a tolerogenic niche that may drive immune evasion and resistance, supporting combination therapies targeting adenosinergic signaling.