Researchers who work with antibody-based therapies find that murine Fc gamma receptors (FcγRs) can confound preclinical study results, causing false positives or false negatives that lead to incorrect conclusions and derail drug discovery. By knocking out these receptors, FcResolv™ NOG models provide clarity in antibody-based drug studies, offering greater confidence and more translatable data while utilizing fewer resources.
These novel mouse models improve your antibody-based therapy assessment in three critical ways:
Eliminate the false positives and false negatives that occur when an antibody-based therapeutic's Fc domain interacts with murine FcγRs.
Distinguish true drug efficacy from off-target effects mediated through the mouse immune system and eliminate costly deconvolution steps.
Avoid wasteful investments based on false positives or missing out on a promising candidate due to false negatives. FcResolv NOG mouse models provides improved clarity for more reliable answers.
FcResolv NOG mouse models expand the utility of the powerful Taconic NOG platform and can be used in similar applications as the base models (CIEA NOG mouse® and hIL-15 NOG). FcResolv NOG mice are ideal for investigating any indication which utilizes a therapy incorporating an Fc domain, including immuno-oncology, autoimmune disease, and more.
The FcResolv NOG model portfolio is based on the super immunodeficient NOG mouse. This highly versatile strain lacks adaptive immune cells and has an attenuated innate immune response, yet still retains some residual mouse immune cells that can interact with therapeutic antibodies. FcResolv NOG models eliminate this interaction by knocking out the activity of all murine FcγRs, including the FcγRI, IIB, III and IV types, along with the high affinity FcεRI receptor. The low affinity FcεRII receptor remains present.
Table of all Fc receptors whose function is knocked out in the FcResolv NOG mouse models, including their expression patterns and binding affinity of various mouse and human immunoglobulin G and E (IgG and IgE) subclasses. Note that FcεRI also requires the FcRγ common subunit and is nonfunctional in the FcResolv NOG model. The low affinity FcεRII receptor remains present.
Functional knockout of murine FcγR activity enables accurate detection of immunotherapy efficacy in humanized mice engrafted with tumors. Nivolumab (anti-PD1) does not suppress tumor growth in HSC-engrafted NOG mice (bottom row) but displays anti-tumor efficacy in HSC-engrafted FcResolv NOG mice (top row) where there are no murine FcγRs to interact with the Fc domain of the therapeutic. From Katano et al. 2021.
Intact FcγRs are expressed on residual murine immune cells in super immunodeficient NOG mice. These murine FcγRs can interact with the Fc domain of an antibody-based therapeutic and trigger an effect (for example, tumor growth inhibition) that is mediated through mouse innate immune cells and is independent of the therapeutic's intended mode of action. In FcResolv NOG mice, these receptors are absent, so there is no mouse innate immune response to interfere with interpretation of an Fc-based antibody therapeutic's efficacy.
In super immunodeficient NOG mice, FcγRs are expressed on residual murine immune cells. Although the exact mechanisms are not yet well-understood, these innate mouse receptors can bind antibody-based therapeutics through recognition of the Fc domain and interfere with the therapeutic's intended activity. In FcResolv NOG mice these receptors are absent, so there is no opportunity for them to interfere with interpretation of an antibody therapeutic's efficacy.
The hIL-15 NOG mouse supports human NK cell engraftment through expression of the human IL-15 cytokine and can be used to study therapeutics which act through ADCC mediated by human NK cells. However, FcγRs expressed on residual murine immune cells in the hIL-15 NOG mouse can interact with the Fc domain of an antibody-based therapeutic and trigger off-target effects (for example, tumor growth inhibition) mediated through mouse innate immune cells which are independent of the therapeutic's intended mode of action. In FcResolv hIL-15 NOG mice these FcγRs are absent, so human NK cell-mediated ADCC can be specifically detected without having to deconvolute the contribution of off-target effects to observed efficacy.
Contact Taconic to learn how the FcResolv NOG or FcResolv hIL-15 NOG can help you obtain the right answers, faster and with greater confidence, when evaluating antibody-based therapies.
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