Antibody-Dependent Cellular Cytotoxicity in Patients on Chronic Hemodialysis

Abstract

Background: Antibody (Ab)-dependent cellular cytotoxicity (ADCC) is considered to be a relevant mechanism of action of Ab-based tumor therapies. However, knowledge about ADCC capacity of dialysis patients (DP) is limited. The aim of our study was to investigate if ADCC capacity of effector cells obtained from DP differed from those of healthy individuals (HI). Methods: First, we performed ADCC assays with isolated polymorphonuclear cells (PMN) and peripheral blood mononuclear cells (PBMC), mediated by the epidermal growth factor receptor Ab cetuximab or panitumumab. As cetuximab is of human IgG1 and panitumumab of human IgG2 isotype, both Abs differ in their affinity to Fcγ receptors and effector cell recruitment. Results: Using PMN as effectors, ADCC levels via panitumumab proved to be higher than via cetuximab, but did not differ between DP and HI. In contrast, IgG2-mediated ADCC with PBMC from DP was significantly enhanced compared to HI. IgG2 Abs predominantly bind to FcγRIIa. Within the PBMC, monocytes are the only cytotoxic cells physiologically expressing this receptor. ADCC experiments with isolated monocytes confirmed them to be the pivotal cells for the observed effect. Analysis of monocytes' Fc receptor expression demonstrated no difference between DP and HI, but monocytes of DP proved to be numerically increased and appeared preactivated. Conclusion: Our studies implicate that ADCC capacity is not impaired in DP and that it might particularly be reasonable to apply human IgG2 Abs as therapeutics for these patients.

Development of a novel, fully human, anti-PCSK9 antibody with potent hypolipidemic activity by utilizing phage display-based strategy

“…Although IgG2 Fc and IgG4 Fc fragments can be used for constructing the full-length antibody when Fc effector function is undesirable for therapeutic activity, they show decreased conformational stability relative to that of IgG1 because of their higher propensity to aggregate [74,75]. It has been observed that IgG2 Fc is not completely devoid of ADCC activity under certain conditions [76,77]. Besides, disulfide-bond reshuffling and Fab-arm exchange occurring in IgG2 and IgG4 subclasses lead to multiple heterogeneous isoforms with altered activities [78,79].…”

Antibodies directed against receptor tyrosine kinases

“…44,45 Notably, panitumumab is not effective at recruiting NK cells and inducing NK cell-mediated ADCC but is effective at recruiting ADCC by myeloid effector cells (i.e., neutrophils and monocytes). 46,47 Based on the importance of RAS status for stratifying patients for treatment with cetuximab, several studies have demonstrated that the specific RAS mutation also determines the responsiveness to panitumumab treatment. 48,49 Further data are still needed to clarify the role of each specific RAS mutation for anti-EGFR-based treatments in mCRC and other types of cancers and this information should be considered for further clinical uses.…”