The use of monoclonal antibodies (mAbs) in treating cancer patients has become an important addition to chemo- and radiotherapy. Depending on the type of antibody, these mAbs induce a variety of different effector functions, including induction of apoptosis and growth inhibition that can lead to eradication of the tumor. Additionally, tumor targeting mAbs can activate the immune system resulting in induction of complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP) of tumor cells by natural killer cells or myeloid cells (monocyte/macrophages and neutrophils). Currently most clinically used mAbs are primarily chimeric or humanized Immunoglobulin G1 (IgG1) mAbs, which bind to IgG Fc receptors (FcγRs).
Efficient binding to FcγRs requires the IgG-Fc-glycan moieties at position 297. In humans, core-fucosylation of IgG is particularly important for binding to human FcγRIIIa and FcγRIIIb, resulting in enhanced uptake of opsonized particles and enhanced ADCC. These properties are increasingly exploited in the next generation of therapeutic anti-tumor IgG.
In this study we investigated whether removal of the core fucose also enhanced killing of tumor cells by mouse effector cells, and whether this prevented tumor outgrowth in vivo. Therefore a chimeric IgG1 (TA99), targeting gp75 on B16F10 mouse melanoma cells, was generated with- and without core-fucose, and their effect was assessed in both in vitro and in vivo models.
In vitro mouse immune cells were incubated with B16F10-gp75 cells in the presence or absence of wildtype or low fucose TA99 and tumor killing was analyzed. In vivo the effect of the TA99 IgG1 low fucose on tumor outgrowth was assessed by injecting both B16F10-gp75 cells and either TA99 IgG1 wt or low fucose in the peritoneal cavity of mice.
Fourteen days post injection tumor outgrowth was analyzed. Mice treated with TA99 low fucose had significantly less tumors in comparison to the wildtype TA99 IgG1, showing that changing the fucosylation of the Fc domain has a remarkable effect on the effectiveness of an antibody therapy.
These results emphasize that when the core fucose of therapeutic IgG antibodies is removed, efficacy of monoclonal antibody therapies will be enhanced significantly. Additionally, the effect works cross species, suggesting mouse models are also suitable to study this phenomenon and to screen antibodies in vivo for enhanced effector functions. Ultimately, this may lead to improved clinical outcome of cancer patients.
Citation Format: Rens Braster, Remco Visser, Gestur Vidarsson, Marjolein van Egmond. The art of omission: Low fucose antibodies enhance tumor cell clearance in vivo. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A02.
- ©2015 American Association for Cancer Research.