Abstract 2836: Assessment of therapeutic antibody efficacy without the interference of murine Fc receptors allows for investigation of human antibody-dependent cellular cytotoxicity mediated by NK cells in the FcResolv™ hIL-15 NOG mouse model
Authors: Rhein Simone , Stecklum Maria , Buczek Monika , Richardson Janell , Hoffmann Jens 
Published: March 2024

Abstract
Targeted antibody therapy is applied to treat various cancer types. In addition to the primary mode of action (MOA), which involves direct binding to the tumor antigen, indirect MOA acting through the constant region (Fc) of the antibody can enhance anti-tumor efficacy. Indirect mechanisms engage the innate immune system, mediated by both the complement system (complement-dependent cytotoxicity (CDC)) and immune cells (antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC)). These indirect mechanisms can complicate the evaluation and accurate assessment of antibody-induced ADCC by human NK cells in current mouse models. In immune-deficient mouse strains (e.g. NOG), false positives and/or negatives may occur due to interactions with murine Fc receptors. These can either result in anti-tumor responses via activation of the murine innate immune system or can interfere with the human-targeted therapy's primary MOA. To study the response to anti-cancer antibodies without the interference of these murine Fc receptor interactions and to investigate ADCC mediated by human NK cells, a novel mouse model deficient in Fc receptors and expressing human IL-15 (FcResolv™ hIL-15 NOG) was employed for testing antibody therapies. Methods: Patient-derived xenograft (PDX) tumor models were transplanted into hIL-15 NOG and FcResolv™ hIL-15 NOG mice. A human head and neck squamous cell carcinoma and a lung adenocarcinoma PDX model were both treated with cetuximab. Treatment with pertuzumab and trastuzumab was applied in a breast ductal carcinoma PDX model. Rituximab treatment was tested in two diffuse large B cell lymphoma PDX models. Based on growth kinetics, the lung cancer PDX model was chosen for further testing of ADCC in the NK cell-humanized FcResolv™ hIL-15 NOG mouse. Results and Conclusion: There was no difference in percent tumor growth inhibition between the FcResolv™ hIL-15 NOG and hIL-15 NOG mice with regards to cetuximab treatment in the lung and head and neck cancer or for trastuzumab treatment of breast ductal carcinoma. However, pertuzumab treatment revealed a false positive efficacy, with the false positive effect more pronounced in hIL-15 NOG mice than in FcResolv™ hIL-15 NOG mice. In one of the lymphoma models, a false negative result was observed. Here, rituximab did not show notable tumor inhibition in the hIL-15 NOG mice but did in the FcResolv™ hIL-15 NOG mice. These results demonstrate that FcResolv™ hIL-15 NOG mice serve as a suitable mouse model for a more accurate assessment of the therapeutic efficacy of anti-tumor antibodies. Additionally, evaluation of human-mediated ADCC of therapeutic antibodies in NK cell-humanized FcResolv™ hIL-15 NOG allows detection of effects specifically mediated by human NK cells.
Citation Format: Simone Rhein, Maria Stecklum, Monika Buczek, Janell Richardson, Jens Hoffmann. Assessment of therapeutic antibody efficacy without the interference of murine Fc receptors allows for investigation of human antibody-dependent cellular cytotoxicity mediated by NK cells in the FcResolv™ hIL-15 NOG mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2836.