Variable Contribution of Monoclonal Antibodies to ADCC in patients with chronic lymphocytic leukemia

Abstract

Monoclonal antibodies (mAbs) are increasingly used in treatment protocols for chronic lymphocytic leukemia (CLL). Here we determined (i) the extent of antibody-dependent cellular cytotoxicity (ADCC) of four different mAbs against primary CLL cells, (ii) whether ADCC correlates with antigen density on CLL cells, and (iii) whether allogeneic natural killer (NK) cells display superior ADCC than autologous. Effector cells for ADCC were (i) NK-92 cells not expressing FcR, (ii) NK-92 cells transfected with a high-affinity Fc receptor, (iii) autologous NK cells from patients with CLL, (iv) allogeneic NK cells. Results suggest that ADCC contributes to killing of CLL cells by anti-CD20 antibodies (rituximab and veltuzumab), whereas mAbs against CD22 (epratuzumab) and CD23 (lumiliximab) showed minimal ADCC. The magnitude of anti-CD20 mediated ADCC did not correlate with antigen density of CD20. ADCC was not influenced by the FcR genotype expressed by autologous NK cells. Allogeneic NK cells were superior to autologous NK cells in killing primary CLL cells.

Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies

“…Previous studies have shown that the FcgRIIIA polymorphism is associated with differential affinity and binding to human IgG1 mAbs. However, in CLL, the FcgR polymorphism did not predict responses to low-fucosylated mAbs, 32,36,37 suggesting that this polymorphism does not explain the variability in degranulation responses. Instead, NK-cell degranulation might be affected by the effector/target ratio, in agreement with Fischer et al 38 Finally, the individual variability might be also attributed to intrinsic resistance of CLL cells to degranulation as observed in 1/21 patients.…”

“…Only two studies have investigated the ability of NK cells to mediate ADCC against primary CLL cells in the presence of anti-CD20 mAbs. 9,32 Weitzman et al 32 showed that rituximab and veltuzumab, another anti-CD20 mAb optimized for enhanced complement-dependent cytotoxicity, resulted in similar levels of ADCC in the presence of primary CLL cells and NK cell lines. Recently, we have shown that EMAB-6, an anti-CD20 optimized for FcgRIIIA engagement, induced greater ADCC against CLL cells than rituximab, in the presence of NK cells from healthy donors.…”

“…Consequently, these data strongly support the use of anti-CD20 mAbs optimized for FcgR engagement to induce efficient ADCC. Surprisingly, very few studies have evaluated anti-CD20 mAb-mediated ADCC in CLL, 9,32 with most anti-CD20 ADCC studies using non-Hodgkin's lymphoma cell lines. Only two studies have investigated the ability of NK cells to mediate ADCC against primary CLL cells in the presence of anti-CD20 mAbs.…”

Glycovariant anti-CD37 monospecific protein therapeutic exhibits enhanced effector cell-mediated cytotoxicity against chronic and acute B cell malignancies

“…8 Given the enhanced ADCC by SMIP-016 GV , we hypothesized that this may maintain the enhanced ADCC at lower SMIP protein concentrations. It has been suggested that serum plasma and IgG can affect the concentrations of therapeutic monoclonal antibodies within the body, 12 and, therefore, efficacy at low concentrations is desirable for therapy. SMIP-016, SMIP-016 GV and rituximab were used at decreasing log concentrations in an ADCC assay using normal donor NK cells as effectors and CLL B cells as targets.…”

“…10 This glycoform engineering has been shown to enhance ADCC 11 through cells bearing FcγRIIIa, an important component in how monoclonal antibodies are clinically effective. 12 For example, afucosylated anti-CD20 antibodies show higher B cell depletion than their fucosylated counterpart by reaching saturated ADCC levels at lower concentrations and through improved FcγRIIIa binding. 13 In addition, it has been reported that antibodies lacking the core fucose in The Fc portion of SMIP-016 GV has enhanced affinity for low and high affinity soluble FcγRIII.…”