Simple SummaryCancer treatments are increasingly based on therapeutic antibodies to clear tumors. While in vivo mouse models are useful to predict effectiveness of human antibodies it is not... Show moreSimple SummaryCancer treatments are increasingly based on therapeutic antibodies to clear tumors. While in vivo mouse models are useful to predict effectiveness of human antibodies it is not completely clear how useful these models are to test antibodies engineered with enhanced effector functions designed for humans. One of the changes considered for many new antibody-based drugs is the removal of fucose (resulting in afucosylated IgG) which enhances IgG-Fc receptor (Fc gamma R) mediated effector functions in humans through Fc gamma RIIIa. Here we show that afucosylated human IgG1 also have enhanced effector functions against peritoneal metastasis of melanoma cells in mice through the evolutionary related mouse Fc gamma RIV. This shows that afucosylated human IgG is functionally recognized across species and shows that mouse tumor models can be used to assess the therapeutic potential of afucosylated IgG1.Promising strategies for maximizing IgG effector functions rely on the introduction of natural and non-immunogenic modifications. The Fc domain of IgG antibodies contains an N-linked oligosaccharide at position 297. Human IgG antibodies lacking the core fucose in this glycan have enhanced binding to human (Fc gamma R) IIIa/b, resulting in enhanced antibody dependent cell cytotoxicity and phagocytosis through these receptors. However, it is not yet clear if glycan-enhancing modifications of human IgG translate into more effective treatment in mouse models. We generated humanized hIgG1-TA99 antibodies with and without core-fucose. C57Bl/6 mice that were injected intraperitoneally with B16F10-gp75 mouse melanoma developed significantly less metastasis outgrowth after treatment with afucosylated hIgG1-TA99 compared to mice treated with wildtype hhIgG1-TA99. Afucosylated human IgG1 showed stronger interaction with the murine Fc gamma RIV, the mouse orthologue of human Fc gamma RIIIa, indicating that this glycan change is functionally conserved between the species. In agreement with this, no significant differences were observed in tumor outgrowth in Fc gamma RIV-/- mice treated with human hIgG1-TA99 with or without the core fucose. These results confirm the potential of using afucosylated therapeutic IgG to increase their efficacy. Moreover, we show that afucosylated human IgG1 antibodies act across species, supporting that mouse models can be suitable to test afucosylated antibodies. Show less
Overdijk, M.B.; Verploegen, S.; Bogels, M.; Egmond, M. van; Bueren, J.J.L. van; Mutis, T.; ... ; Parren, P.W.H.I. 2015
Background 82 Aims: Development of liver metastases is a frequent complication in patients with colorectal cancer (CRC), even after successful resection of the primary tumor. As such, postoperative... Show moreBackground 82 Aims: Development of liver metastases is a frequent complication in patients with colorectal cancer (CRC), even after successful resection of the primary tumor. As such, postoperative adjuvant therapies that aim to eliminate residual disease after surgery may improve patient outcome. Methods: We used a colon carcinoma liver metastases model, in which CC531s colon carcinoma cells are injected into the portal circulation by a surgical procedure. As injected tumor cells are arrested in the liver, this model is suitable for investigating the interaction of tumor cells with the liver microenvironment. By administering tumor specific monoclonal antibodies (mAb) directly post-operatively, we were able to determine the effect of antibody therapy on eradication of arrested tumor cells and subsequent liver metastases outgrowth. Results: We showed that post-operative treatment with tumor specific monoclonal antibodies (mAb) prevents liver metastases outgrowth. Antibody-dependent phagocytosis (ADPh) was the main mechanism involved, as enhanced uptake of tumor cells by innate mononuclear phagocytes in the liver was observed after mAb therapy. Furthermore, Kupffer cells (KC) were identified as the most prominent effector cells, as depletion of KC abolished therapeutic efficacy. This was partly compensated by monocytes when animals were treated with a high mAb dose, but monocytes were unable to phagocytose tumor cells when rats were treated with low mAb doses. Conclusions: The finding that KC and monocytes can eliminate tumor cells through ADPh has important and promising clinical implications for designing new adjuvant therapies for patients undergoing CRC resection. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Show less
