Targeting CD38 in Neoplasms and Non-Cancer Diseases

Abstract

CD38 is a myeloid antigen present both on the cell membrane and in the intracellular compartment of the cell. Its occurrence is often enhanced in cancer cells, thus making it a potential target in anticancer therapy. Daratumumab and isatuximab already received FDA approval, and novel agents such as MOR202, TAK079 and TNB-738 undergo clinical trials. Also, novel therapeutics such as SAR442085 aim to outrank the older antibodies against CD38. Multiple myeloma and immunoglobulin light-chain amyloidosis may be effectively treated with anti-CD38 immunotherapy. Its role in other hematological malignancies is also important concerning both diagnostic process and potential treatment in the future. Aside from the hematological malignancies, CD38 remains a potential target in gastrointestinal, neurological and pulmonary system disorders. Due to the strong interaction of CD38 with TCR and CD16 on T cells, it may also serve as the biomarker in transplant rejection in renal transplant patients. Besides, CD38 finds its role outside oncology in systemic lupus erythematosus and collagen-induced arthritis. CD38 plays an important role in viral infections, including AIDS and COVID-19. Most of the undergoing clinical trials focus on the use of anti-CD38 antibodies in the therapy of multiple myeloma, CD19- B-cell malignancies, and NK cell lymphomas. This review focuses on targeting CD38 in cancer and non-cancerous diseases using antibodies, cell-based therapies and CD38 inhibitors. We also provide a summary of current clinical trials targeting CD38.

Astatine-211 based radionuclide therapy: Current clinical trial landscape

“…Thus, the treatment aim is to achieve eradication of multiple myeloma minimal residual disease (MRD). The CD38 antigen is a good target expressed on malignant plasma cells, regardless of mutational status (39,40). Cell binding and cytotoxicity from in vitro studies, favorable biodistribution, and in vivo data on efficacy using mouse models of both bulky disease and low disease burdens have been reported (41).…”

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

“…3,40 CD38 is present on both the cell membrane and in intracellular compartments, including the mitochondria and endoplasmic reticulum (Figure 1). 43 Depending on its orientation, the C-terminal catalytic site may face the extracellular environment or be directed toward the cytosol, and the change in catalytic site from external to internal may be a mechanism to regulate its signaling activity. [43][44][45] Activation of CD38 results in Ca 2+ mobilization from the endoplasmic reticulum via ryanodine receptors, leading to an increase of intracellular Ca 2+ concentration.…”

“…43 Depending on its orientation, the C-terminal catalytic site may face the extracellular environment or be directed toward the cytosol, and the change in catalytic site from external to internal may be a mechanism to regulate its signaling activity. [43][44][45] Activation of CD38 results in Ca 2+ mobilization from the endoplasmic reticulum via ryanodine receptors, leading to an increase of intracellular Ca 2+ concentration. 46 Importantly, the majority of the CD38 enzyme exists as a Type II membrane protein with its catalytic site facing the outside of the cell, thus CD38 is mainly an ecto-NAD glycohydrolase.…”

Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma

“…In the MM niche, TNT-mediated transcellular transfer of mitochondria from neighboring BMSCs to MM cells supports OXPHOS in MM cells, and this process is dependent on CD38 expression [ 76 ]. CD38 is a transmembrane glycoprotein present both on the cell membrane and in the intracellular compartment [ 92 ]. MM cells express high levels of CD38.…”

“…MM cells express high levels of CD38. Therefore, monoclonal antibodies against CD38 (e.g., datatumumab and isatuximab) can be used to successfully treat MM [ 92 ]. Anti-CD38 monoclonal antibodies have several mechanisms of action, including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, direct cellular apoptosis, and modulation of extracellular ectoenzyme activity [ 93 ].…”