The Human CD38 Monoclonal Antibody Daratumumab Shows Antitumor Activity and Hampers Leukemia–Microenvironment Interactions in Chronic Lymphocytic Leukemia

Abstract

Purpose To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38+ CLL subtype. Experimental design The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blood mononuclear cells to analyze antibody-dependent cell cytotoxicity (ADCC), murine and human macrophages to study antibody-dependent cell phagocytosis (ADCP) or human serum to analyze complement-dependent cytotoxicity (CDC). The effect of daratumumab on CLL cell migration and adhesion to extracellular matrix was characterized. Daratumumab activity was validated in two in vivo models. Results Daratumumab demonstrated efficient lysis of patient-derived CLL cells and cell lines by ADCC in vitro and ADCP both in vitro and in vivo, while exhibited negligible CDC in these cells. To demonstrate the therapeutic effect of daratumumab in CLL, we generated a disseminated CLL mouse model with the CD38+ MEC2 cell line and CLL patient derived xenografts (CLL-PDX). Daratumumab significantly prolonged overall survival of MEC2 mice, completely eliminated cells from the infiltrated organs and significantly reduced disease burden in the spleen of CLL-PDX. The effect of daratumumab on patient-derived CLL cell dissemination was demonstrated in vitro by its effect on CXCL12-induced migration and in vivo by interfering with CLL cell homing to spleen in NSG mice. Daratumumab also reduced adhesion of CLL cells to VCAM-1, accompanied by down-regulation of the matrix metalloproteinase MMP9. Conclusions These unique and substantial effects of daratumumab on CLL viability and dissemination support the investigation of its use in a clinical setting of CLL.

Monoclonal antibodies targeting CD38 in hematological malignancies and beyond

“…Similarly, isatuximab kills lymphoma cells via ADCC and ADCP, and also has strong proapoptotic activity in lymphoma in the absence of cross‐linking agents . Daratumumab also shows preclinical anti‐tumor activity against CD38‐expressing CLL tumor cells and inhibits adhesion and migration of CLL tumor cells in the tumor microenvironment , indicating that CD38‐targeting antibodies may also be of value in the treatment of CD38‐positive CLL. Due to relatively high expression of the complement inhibitors and lower CD38 expression levels compared to MM cells, daratumumab failed to effectively induce CDC in most patient‐derived NHL and CLL cells .…”

“…The CD38 antibodies daratumumab and MOR202 induced potent killing of CD38‐expressing lymphoma cells primarily via ADCC and ADCP . Similarly, isatuximab kills lymphoma cells via ADCC and ADCP, and also has strong proapoptotic activity in lymphoma in the absence of cross‐linking agents .…”

“…Daratumumab also shows preclinical anti‐tumor activity against CD38‐expressing CLL tumor cells and inhibits adhesion and migration of CLL tumor cells in the tumor microenvironment , indicating that CD38‐targeting antibodies may also be of value in the treatment of CD38‐positive CLL. Due to relatively high expression of the complement inhibitors and lower CD38 expression levels compared to MM cells, daratumumab failed to effectively induce CDC in most patient‐derived NHL and CLL cells . Nevertheless, daratumumab and isatuximab showed a marked anti‐tumor activity in mouse xenograft models of NHL in vivo .…”

Anatomical Society Summer Meeting in Galway

“…However, recent evidence indicates that they can modulate CD38 enzymatic activity by decreasing cADPR production, which may in turn lead to decreased Ca 21 mobilization and signaling. 18,60 Further characterization of CD38-dependent signaling, including the RasGRP2/Rap1 axis, is therefore important for the design of novel treatments for CD38 1 hematological diseases.…”

Emerging immunological drugs for chronic lymphocytic leukemia

“…However, daratumumab also offers potential in other hematological neoplasms with CD38 expression, including CLL, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, follicular lymphoma and mantle cell lymphoma. In preclinical studies, daratumumab expressed Fc-mediated cell killing activity via CDC, ADCC and ADCP in primary CLL cells and leukemic cells from CLL patients [127]. In addition, daratumumab significantly prolonged overall survival of animals in a CLL mouse model [128].…”