Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Abstract

CD38 is a transmembrane glycoprotein with ectoenzymatic activity involved in regulation of migration, signal transduction, and receptor-mediated adhesion. CD38 is highly expressed on various malignant cells, including multiple myeloma (MM), and at relatively low levels in other tissues, making it a suitable target for therapeutic antibodies. Several anti-CD38 therapies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab (SAR650984), respectively. Studies have shown that anti-CD38 therapies are effective in the treatment of relapsed/refractory MM and are well tolerated, with infusion reactions being the most common side effects. They can be used as monotherapy or in combination with immunomodulatory agents, such as pomalidomide, or proteasome inhibitors to potentiate their activity. Here we examine isatuximab and several anti-CD38 agents in development that were generated using new antibody engineering techniques and that may lead to more effective CD38 targeting. We also summarize trials assessing these antibodies in MM, other malignancies, and solid organ transplantation. Finally, we propose that further research on the mechanisms of resistance to anti-CD38 therapy and the development of biomarkers and new backbone regimens with CD38 antibodies will be important steps in building more personalized treatment for patients with MM.

Keywords: anti-CD38 therapy; isatuximab; multiple myeloma.

Figure 1

Schematic representation of huCD38/isatuximab-Fab complex (A). huCD38 is colored in gray, light chain and heavy chain of isatuximab in green and yellow, respectively. Schematic representation of the paratope of the complex huCD38/isatuximab-Fab (B). Light-chain and heavy-chain of isatuximab are colored in green and pale yellow, respectively. The residues part of the paratope are represented in sticks and colored in dark green if located on the light-chain or in orange if located on the heavy-chain of isatuximab. huCD38, human CD38.

Figure 1

Schematic representation of huCD38/isatuximab-Fab complex (A). huCD38 is colored in gray, light chain and heavy chain of isatuximab in green and yellow, respectively. Schematic representation of the paratope of the complex huCD38/isatuximab-Fab (B). Light-chain and heavy-chain of isatuximab are colored in green and pale yellow, respectively. The residues part of the paratope are represented in sticks and colored in dark green if located on the light-chain or in orange if located on the heavy-chain of isatuximab. huCD38, human CD38.

Figure 2

Comparison of isatuximab and daratumumab epitopes on huCD38. The gray shading denotes huCD38, the blue shading denotes the epitope of huCD38 for isatuximab, and the red shading denotes the epitope of huCD38 for daratumumab. Glu233 is highlighted in pink. huCD38, human CD38.

Figure 3

Isatuximab inhibits CD38-NADase activity. MM LP-1 cells cultivated in culture media were treated with the indicated concentrations of IgG1 (control), isatuximab, or daratumumab. Synthesis of cADPR was measured by mass spectrometry. AUC, area under the curve; cADPR, cyclic adenosine diphosphate-ribose; Ig, immunoglobulin; MM, multiple myeloma; NAD, nicotinamide adenine dinucleotide.

Figure 4

Pomalidomide enhances isatuximab activity in vivo. Female NSG mice (n = 8/group) with subcutaneously implanted MOLP-8 tumors (3 × 10⁶ cells in 50% matrigel) were treated with PBS, isatuximab (5 doses of 40 mg/kg IV), pomalidomide (10 mg/kg intraperitoneally, once daily for 14 days), or the combination of both isatuximab and pomalidomide. IV, intravenously; NSG, NOD scid gamma; PBS, phosphate-buffered saline; SEM, standard error of mean.