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.

Keywords: CD38; anticancer therapy; cancer; multiple myeloma.

Figure 1

Schematic representation of the role of CD38 in NAD+ metabolism. CD38 depletes NAD+ cellular level, generating cyclic ADP-ribose (cADPR). The process leads to the inflow of Ca²⁺ stimulates T cell activation and proliferation. Depletion of NAD+ level affects the activity of Sirt1, ART2.2, and PARP1, which are NAD+ consuming enzymes that play significant roles in T cell fate determination.

Figure 2

(A) Schematic representation of the factors that regulate the expression of the CD38 gene. It is worth noting that CD38 is localized both on the cell membrane and endoplasmic membranous system; (B) Schematic representation of the variety of CD38 types with their localization; STAT—signal transducer and activator of transcription, NF-κB—Nuclear factor kappa B, RxR—retinoid X receptor, LxR—Liver X receptor, NAD—Nicotinamide adenine dinucleotide, NMN—Nicotinamide mononucleotide, NR—nicotinamide riboside, ecCD38—extracellular CD38, iCD38—intracellular CD38.

Figure 3

Cytotoxic anti-CD38 antibodies can induce apoptosis of CD38-positive cancer cells through direct or indirect effects. As the level of cellular NAD+ plays a significant role in immune system modulation, small molecule CD38 inhibitors (smCD38i) or monoclonal antibodies that inhibit CD38 activity (CD38imAB) can promote an increase in tissue NAD+ levels and induce positive anti-tumor immune response [18,70,73,74]. There are also several novel anti-CD38 targeting antibodies with the enhanced activity.

Figure 4

Scheme depicting the therapeutic strategies for patients with primary and metastatic multiple myeloma. Primary neoplasm is divided into transplant eligible and ineligible patients.