Monoclonal antibodies targeting CD38 in hematological malignancies and beyond

Abstract

CD38 is a multifunctional cell surface protein that has receptor as well as enzyme functions. The protein is generally expressed at low levels on various hematological and solid tissues, while plasma cells express particularly high levels of CD38. The protein is also expressed in a subset of hematological tumors, and shows especially broad and high expression levels in plasma cell tumors such as multiple myeloma (MM). Together, this triggered the development of various therapeutic CD38 antibodies, including daratumumab, isatuximab, and MOR202. Daratumumab binds a unique CD38 epitope and showed strong anti-tumor activity in preclinical models. The antibody engages diverse mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, programmed cell death, modulation of enzymatic activity, and immunomodulatory activity. CD38-targeting antibodies have a favorable toxicity profile in patients, and early clinical data show a marked activity in MM, while studies in other hematological malignancies are ongoing. Daratumumab has single agent activity and a limited toxicity profile, allowing favorable combination therapies with existing as well as emerging therapies, which are currently evaluated in the clinic. Finally, CD38 antibodies may have a role in the treatment of diseases beyond hematological malignancies, including solid tumors and antibody-mediated autoimmune diseases.

Keywords: CD38; cancer; daratumumab; isatuximab; multiple myeloma; therapeutic antibody.

Figure 1

Mechanisms of action of daratumumab.

Figure 2

Daratumumab modulates the enzymatic activity of CD 38. (A, B) Concentration‐dependent inhibition of CD38 cyclase activity by daratumumab tested on recombinant CD38 protein (A) or CHO cells stably transfected with human CD38 (B). Therefore, recombinant CD38 protein or CHO‐CD38 cells were incubated with daratumumab and NGD, and the presence of fluorescent cGDPR in supernatant was measured. The graphs show the % inhibition in cGDPR production compared to the untreated controls. (C) Enzymatic processing of NAD and NADP by CD38 and modulation of this activity by daratumumab.

Figure 3

Resolving interference of daratumumab in the indirect antiglobulin test ( IAT ). (A, B) Daratumumab in the patient's serum binds to the test RBCs. After adding the anti‐IgG reagent, RBC agglutination is observed, thereby generating a false‐positive result (A) or masking the presence of irregular antibodies (B). (C, D) Daratumumab‐specific anti‐idiotype antibodies are added to the patient's serum and bind to daratumumab (1). Alternatively, test RBCs are treated with DTT, resulting in denaturation of CD38 and loss of daratumumab binding (2). If the patient has no irregular antibodies, binding of daratumumab to RBCs is blocked generating a negative IAT test result. However, if the serum contains irregular antibodies, binding of these antibodies to RBC will result in a true positive IAT test result.