Introduction: Antibody dependent cellular cytotoxicity is a key mode of action of therapeutic antibodies. ADCC enhancement as well as a broader coverage of F/V allotypes leads to maximal utilization of the anti-tumor effect. Glycooptimization provides the best available opportunity to maximize ADCC activity of monoclonal antibodies. Utilizing the GEX™ platform allows the combination of minimizing fucosylation, maximizing galactosylation and branching, which maximally increases the ADCC activity. The GEX™ platform comprises a comprehensive portfolio of proprietary glycoengineered human suspension cell lines, which allow for the high yield production of proteins with tailored glycosylation patterns. Productivities of 22g/L perfusion bioreactor volume have been achieved for ADCC optimized monoclonal antibodies. Cancer therapies with monoclonal antibodies including CetuGEX™ are often accompanied by treatment with glucocorticoids in order to prevent or counteract side effects like infusion reactions. However, the immunosuppressive character of glucocorticoids may also have the potential to inhibit the ADCC effect and immune cells mediating ADCC, respectively. In this study, we analyzed the influence of different glucocorticoids on ADCC mediated by CetuGEX™.
Methods: By using a europium release assay with an EGFR-expressing cancer cell line and PBMCs as effector cells we tested the ability of hydrocortisone, prednisolone, methylprednisolone and dexamethasone to inhibit ADCC mediated by CetuGEX™. In addition, we analyzed the direct effect of glucocorticoids on effector and target cells using flow cytometry.
Results: All tested glucocorticoids inhibited the CetuGEX™-mediated ADCC. This effect was not caused by a decreased expression of EGFR on the target cells. NK cells which are key effector cells mediating ADCC were found to be less activated in presence of glucocorticoids and CetuGEX™ compared to CetuGEX™ alone.
Conclusions: Glucocorticoids have a negative influence on ADCC mediated by NK cells which is one of the key modes of actions of CetuGEX™ and other ADCC enhanced antibodies. Therefore, the use of glucocorticoids during may impair clinical the efficacy ADCC-enhanced antibodies and should be avoided or at least minimized.
Citation Format: Christoph Goletz, Johanna Rühmann, Beate Habel, Antje Danielczyk, Steffen Goletz. Hydrocortisone, prednisolone, methylprednisolone, and dexamethasone inhibit CetuGEX™-mediated ADCC in vitro [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B068.
- ©2016 American Association for Cancer Research.