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 common FcR gamma chain that is required for activity of FcγRI, III and IV types, along with the high affinity FcεRI receptor. The low affinity FcεRII receptor remains present. The FcγRIIb has been separately knocked out, as it lacks this common subunit.

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.

FcResolv huNOG and FcResolv huNOG-EXL demonstrate slightly decreased survival upon treatment with Pembrolizumab when compared to their base models with intact murine Fc gamma receptors (FcgRs).

Survival curve of FcResolv huNOG & FcResolv huNOG-EXL compared to their base models huNOG & huNOG-EXL, which have intact murine Fc gamma receptors (FcgRs).  Survival curves generated by combining data from two independent studies (n=47 huNOG + huNOG-EXL, n=40 FcResolv huNOG & FcResolv huNOG-EXL) illustrate a potential trend (weak significance of 0.03), likely due to the absence of murine FcgRs and subsequent Pembro binding, leading to slightly decreased survival. Results will vary based on dosing, tumors, etc.