FcResolv® NOG Portfolio

A flexible NOG-based foundation with reduced functional murine Fc-receptor activity for studies across therapeutic modalities. 
FcResolv® NOG extends the established engraftment utility of the NOG background by reducing functional murine Fc-receptor activity. This provides a consistent host foundation for studies involving diverse therapeutic candidates and modalities while limiting a cross-species pathway that can affect the interpretation of human IgG therapeutics.

The FcResolv® NOG background also provides flexibility for programs comparing different modalities, benchmarking candidates against approved therapies, or evaluating combinations that include antibodies or other Fc-containing biologics. When used for human immune system engraftment, reduced Fc-dependent contributions from residual murine cells can additionally support clearer attribution of responses to the engrafted human immune system.

Research Applications Across Therapeutic Modalities

FcResolv® NOG models support xenograft, human cell and tissue engraftment, and human immune system applications across a range of therapeutic modalities.

  • Oncology and Immuno-Oncology: Support CDX and PDX studies involving Fc-independent therapies, antibodies, Fc-containing biologics, immune-cell therapies, approved-drug comparators, and combinations.
  • Human Immune System Studies: Use model-specific humanization strategies to evaluate selected human immune responses with reduced Fc-dependent contributions from residual murine host cells.
  • Human Cell and Tissue Engraftment: Engraft normal or pathological human cells and tissues on a permissive NOG-based background with reduced functional murine Fc-receptor activity.
  • Cross-Modality and Combination Studies: Maintain a consistent host foundation as programs compare therapeutic modalities or introduce antibodies and other Fc-containing components.

Key Ways FcResolv® NOG Can Strengthen Study Continuity and Interpretation 

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Reduce Murine Fc-Receptor Interference

Human IgG Fc domains can interact with Fc receptors on residual murine innate cells. FcResolv® NOG reduces this cross-species pathway at the host-model level, limiting a potential source of mouse-derived Fc-dependent activity. For antibody-based therapeutics, this can reduce the risk of false-positive or false-negative interpretation attributable to murine Fc-receptor interactions.

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Maintain Continuity Across Therapeutic Modalities

Use a consistent NOG-based host across studies involving Fc-independent treatments, antibodies, Fc-containing biologics, cell therapies, approved-drug comparators, and combination regimens—without changing the background strain solely because Fc biology enters the study.

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Support Clearer Attribution in Humanized Studies 

When FcResolv® NOG is used for human immune system engraftment, reduced murine Fc-receptor activity can help distinguish responses mediated by the engrafted human immune system from Fc-dependent activity contributed by residual murine host cells. The humanization strategy must still provide the human immune populations and functions required for the therapeutic mechanism being evaluated.

Learn more about the FcResolv® NOG Portfolio:

One Foundation Across Changing Study Needs

Therapeutic research programs may evaluate multiple candidates, compare therapeutic modalities, benchmark a new intervention against an approved drug, revisit earlier approaches, or combine treatments with different mechanisms.

Changing the host strain when the therapeutic format changes introduces another biological variable that can complicate interpretation across studies. FcResolv® NOG provides a consistent foundational background across these different study needs.

When an antibody or another Fc-containing therapeutic is included, reduced murine Fc-receptor activity is already built into the host. This preserves flexibility for cross-modality comparisons and combination studies without requiring a change in background strain solely to manage murine Fc interactions.

Potential applications include studies involving small molecules, cell therapies, therapeutic antibodies, Fc fusions, antibody–drug conjugates, Fc-retaining bispecifics, approved therapeutic comparators, and combination regimens.

Additional Value for Human Immune System Engraftment

Humanized immune system mice contain an introduced human immune compartment while retaining residual murine innate cells. In conventional triple-immunodeficient hosts, human IgG therapeutics may interact with human Fc receptors on graft-derived cells and murine Fc receptors on residual host cells.

Using FcResolv® NOG as the host reduces the murine Fc-receptor contribution. When the relevant human effector populations are represented and functional, this can support clearer attribution of Fc-dependent responses to the engrafted human immune system.

The same foundational background can be used across humanized studies involving Fc-independent treatments, antibody therapeutics, approved-drug comparators, Fc-containing biologics, cell-based approaches, and combination regimens.

Fc Biology May Enter Through More Than the Test Article

Human IgG may enter a study through an administered therapeutic, an Fc-containing combination partner, the human immune graft, or an immunoglobulin-producing xenograft. FcResolv® NOG reduces the potential for these sources of human IgG to engage residual murine Fcγ-receptor pathways.

FcResolv® NOG Portfolio

FcResolv® NOG models extend the utility of the NOG platform by combining established engraftment applications with reduced functional murine Fc-receptor activity across foundational, human cytokine-supported, and humanized immune system configurations.

This flexible architecture supports programs spanning Fc-independent and Fc-containing therapeutic modalities, including studies comparing novel candidates with approved drugs or evaluating combinations in which an Fc-bearing component may be introduced.

FcResolv® NOG Models

  • Combines the permissive NOG background with reduced functional murine Fc-receptor activity
  • Provides a consistent host foundation across the Fc-independent therapies, antibodies, Fc-containing biologics, cell therapies, approved-drug comparisons, and combination studies
  • Supports cell line and patient-derived tumor xenografts
  • Supports engraftment of normal or pathological human cells and tissues
  • Supports human immune system applications using model-specific humanization strategies
  • Reduces Fc-dependent contributions from residual murine host cells when human lgG enters the experimental system
  • Available in foundational, human cytokine-supported, and CD34+ HSC-humanized configurations

Supporting Data

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.

chart of absent receptors in nog models

Table of all murine Fc receptors, including their expression patterns and binding affinity of various mouse and human immunoglobulin G and E (IgG and IgE) subclasses. In FcResolv NOG mouse models, FcR expression is virtually eliminated by knockout of the FcRγ common subunit, along with the FcRIIb receptor which lacks this common subunit. Note that FcεRI also requires the FcRγ common subunit and is presumed to be nonfunctional in the FcResolv NOG model. The low-affinity FcεRII receptor remains present.

nog permits detection antibody based immunotherapy efficiency graphics

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.

alleviate false negatives diagram

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.

specifically detect diagram

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).

Pembro graph

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.

FcResolv NOG Model: FAQs

To prevent expression of several different Fc receptors, two genes are knocked out in the FcResolv NOG models: the Fcgr2b gene, which encodes for FcγRIIb, and the Fcer1g gene, which encodes for the common FcRγ subunit. This approach prevents cell surface expression of FcγRI, FcγRIII, FcγRIV, and FcεRI. See our Fc receptor data table for more details.

The most well-understood mechanism through which Fc receptors confound antibody-based therapy studies occurs when an Fc domain interacts with those receptors, which then activate murine innate cells to cause xenograft tumor killing via ADCC or antibody-dependent cellular phagocytosis (ADCP). This mechanism and other possible sources of confounding factors are illustrated above.

Any antibody-based therapy that includes an Fc domain may benefit from study in an FcResolv NOG mouse, as it reduces confounding effects introduced by the drug's interaction with mouse Fc receptors. Suitable applications for the FcResolv NOG model portfolio include studies on monoclonal antibodies (mAbs), bispecific and trispecific antibodies, bispecific T cell engagers (BiTEs), bispecific killer cell engagers (BiKEs), trispecific killer cell engagers (TriKEs), NK cell engagers (NKCEs) and dual affinity retargeting antibodies (DARTs), along with other forms of engineered antibody scaffolds.

FcResolv NOG mouse models are versatile, super immunodeficient models that lend themselves to a wide variety of therapeutic areas, including immuno-oncology, autoimmune disease, infectious disease, regenerative medicine, and more. The FcResolv hIL-15 NOG is most useful for studies involving human NK cells, primarily related to immuno-oncology. The FcResolv NOG-EXL is suited for studies requiring myeloid or lymphoid cell reconstitution, with particular utility for studying acute myelogenous leukemia (AML).

Human IgG Fc domains can interact with Fc receptors on residual murine innate cells. Depending on the antibody format, target, model, and study context, these interactions may affect antibody handling, the fate of antibody-coated human cells, or Fc-dependent biological responses.

FcResolv® NOG reduces this cross-species pathway, lowering the risk that murine Fc-receptor activity contributes to false-positive or false-negative interpretation of an antibody-based therapeutic.

A consistent host background reduces one source of experimental discontinuity when comparing candidates, modalities, approved therapies, and combinations. Direct comparison still requires alignment of the humanization method, donor, xenograft, study timing, dose, endpoints, and relevant human immune-cell composition.

The FcResolv® advantage is that researchers do not need to introduce a background-strain change solely because one study includes human IgG or another Fc-containing therapeutic.

Fcer1g encodes the common Fc-receptor γ-chain used by activating murine Fcγ receptors and selected additional innate receptor complexes. Its deletion therefore attenuates some residual murine innate functions beyond classical FcγR activity.

These additional effects are context-dependent and may represent either a benefit or a model-selection consideration depending on the tissue, biological challenge, and study objective. FcResolv® NOG should not be interpreted as lacking all residual murine innate activity.

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