Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

Antibody modulation: Limiting the efficacy of therapeutic antibodies

“…Recently, Stachowiak et al demonstrated that steric confinement of highly crowded protein within regions of artificial lipid membranes is enough to drive membrane puckering and lipid tubule formation in the membrane [37], observing that puckering increases with protein concentration. We have observed punctate staining of CD20 that colocalises with FcγRIIB upon ligation with type I anti-CD20 mAb, in contrast to diffuse staining observed with the non-redistributing type II mAb [18][19][20]29]. The high density redistribution of CD20 and FcγRIIB induced by type I anti-CD20 mAb-ligation resembles the high density staining observed in the artificial membranes generated by Stachowiak et al [37] and may therefore be sufficient to trigger membrane puckering and subsequent endocytosis.…”

“…Both the extent and duration of depletion was greater in animals treated with the type II mAb and was independent of differential complement activation [23] and programmed cell death [18] mediated by type I and II mAb. Instead, type I anti-CD20 mAb were internalised and degraded in transgenic mouse B cells in vivo as well as primary and malignant human B cells treated in vitro, in contrast to the type II mAb [18].…”

“…Both the extent and duration of depletion was greater in animals treated with the type II mAb and was independent of differential complement activation [23] and programmed cell death [18] mediated by type I and II mAb. Instead, type I anti-CD20 mAb were internalised and degraded in transgenic mouse B cells in vivo as well as primary and malignant human B cells treated in vitro, in contrast to the type II mAb [18]. Internalisation was associated with a reduction in both antibody half-life [23] and phagocytosis of opsonised cells [24] by effectors (Figure 1), suggesting that internalisation of type I anti-CD20 mAb-ligated CD20 leads to reduced therapeutic efficacy and increased consumption of mAb from the serum.…”

“…Despite this similar propensity to shave, type II mAb outperform type I in mediating cellular clearance in vitro and in mouse models in a manner that can instead be explained by their lack of propensity to internalise [18,24]. Further to this the type II mAb obinituzumab has recently been trialled head to head with rituximab in CLL patients in combination with chlorambucil (CLL11, [61]) and found to nearly double progression free survival (albeit with a higher dosing schedule for obinituzumab).…”

“…In contrast, type II anti-CD20 mAb do not display either of these properties but instead evoke strong homotypic adhesion [14] and a non-apoptotic form of lysosomal cell death [14][15][16][17]. In addition, we observed that type I anti-CD20 mAb undergo more rapid internalization from the cell surface, in contrast to type II mAb [18][19][20]. Below we discuss the various ways in which the study of these two different types of mAb have elucidated a number of mechanisms of mAb resistance, before discussing how they may be overcome.…”