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

Abstract

Background: CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.

Aim: Among the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38-mediated T-cell activation. Patients who respond to anti-CD38 targeting treatment experience more marked changes in T-cell expansion, activity, and clonality than nonresponders.

Implications: Resistance mechanisms that undermine the immunomodulatory effects of CD38-targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment-related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T-cell engagers.

Keywords: CD38 antibodies; adenosine; bone marrow niche; daratumumab; immunomodulation; isatuximab; multiple myeloma.

FIGURE 1

CD38 on the cell surface and in intracellular compartments, including endoplasmic reticulum. ADPR, adenosine diphosphate ribose; Ca, calcium; cADPR, cyclic adenosine diphosphate ribose; ER, endoplasmic reticulum; NAADP, nicotinic acid adenine dinucleotide phosphate; NAD, nicotinamide adenine dinucleotide; TCR, T‐cell receptor. Reprinted from Cell Calcium, Vol 101, Lee HC, Deng QW, Zhao YJ, The calcium signaling enzyme CD38—a paradigm for membrane topology defining distinct protein functions, 102514, Copyright (2022), with permission from Elsevier.

FIGURE 2

Canonical and noncanonical pathways of adenosine production in normal conditions and in the hypoxic MM BM niche. This figure shows the shift to noncanonical pathway of ADO production in the presence of a low pH environment, such as in the BM niche. An excess of NAD⁺ due to the shift from oxidative phosphorylation to aerobic glycolysis activates the CD38/CD203a/TRACP pathway, while the low pH also causes the inhibition of CD73. Additionally, ATP can be directly converted to AMP by CD203a. ADO, adenosine; ADP, adenosine diphosphate; ADPR, adenosine diphosphate ribose; AMP, adenosine monophosphate; ATP, adenosine triphosphate; CD203a, ectonucleotide pyrophosphatase/phosphodiesterase‐1; CD38, cyclic ADP‐ribose hydrolase; CD39, ectonucleoside triphosphate diphosphohydrolase‐1; CD73, 5′ nucleotidase; TRACP, tartrate‐resistant acid phosphatase.

FIGURE 3

Different mechanisms of action of anti‐CD38 antibodies. ADCC, antibody‐dependent cellular cytotoxicity; ADCP, antibody‐dependent cellular phagocytosis; Breg, regulatory B cell; CDC, complement‐dependent cytotoxicity; Dara, daratumumab; Isa, isatuximab; MDSC, myeloid‐derived suppressor cell; NK, natural killer; Treg, regulatory T‐cell.

FIGURE 4

Summary of resistance mechanisms and strategies to overcome resistance. ADO, adenosine; BCMA, B‐cell maturation antigen; FcRn, neonatal Fc receptor; IgG, immunoglobulin G; NK, natural killer.