Several partners have extensively co-validated the hFcγR mouse model
Ex vivo ADCC induction by NK cells
- The humanized FcγR model is highly effective for evaluating human therapeutic antibodies, eliminating the need to test mouse-specific antibodies first. This is illustrated by the higher levels of NK cell-mediated ADCC observed in hFcγR NK cells compared to NK cells from WT mice after Rituximab treatment (graph A below). Rituximab is a monoclonal antibody with a regular hIgG1 Fc which targets CD20 on B cells, leading to their depletion.
- The hFcγR model also allows for the translational assessment and ranking of human antibodies that induce ADCC. This is shown by the increased cell lysis following treatment with Obitunuzumab, which has been engineered to display enhanced Fc binding, relative to Rituximab (graph B below). This data reproduces what is observed in the clinic and confirms the effective hFcγRIII-mediated cytotoxicity, as well as the relevance of the hFcγR model for immuno-oncology.
▶ Data on ADCC was presented at AACR 2024, courtesy of Ariane Morel, Caroline Denis and Rachel Courtois at Innate Pharma
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In vivo Fc-dependent B-cell depletion
- An anti-CD20 antibody depleted B cells in the humanized FcγR model, while its silenced Fc variant did not. Antibody-mediated B-cell depletion is a powerful tool for treating autoimmune diseases and certain types of cancer such as B-cell lymphomas and leukemias.
▶ Similar data was presented at different conferences by us and argenx
Fc-dependent effect of anti-influenza A therapeutic antibodies
- The hFcγR mice are susceptible to influenza A infection, as shown by the body weight loss in the absence of treatment (PBS). The anti-influenza antibody with enhanced Fc binding (anti-flu-GA) provides better prophylactic protection than the WT antibody or the Fc-null variant (anti-flu-GRLR) in hFcγR mice. This shows that this model is also useful for studying infectious diseases and their therapies.
▶ For more details, see our poster presented at AACR 2024
What sets the genO-hFcγR model apart?
Our model presents unique features:
- Fully functional humanized receptors (FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB) and downstream signaling
- Human-like expression pattern
- No expression of murine FcγR
- Fully immunocompetent
Intercrossings
In order to expand the range of applications of our genO-hFcγR mouse, we are intercrossing it with the following mouse models:
- genO-hFcRn (Viuff et al., 2016), which has shown to improve translatability of PK assessment of therapeutics with extended half-life via FcRn recycling
- genO-hIgG1 to assess tolerability to therapeutic human IgG1 antibodies
- Humanized immune checkpoint models to obtain flexibility of therapeutics assessment: bispecific or combination therapies targeting immune checkpoints
- genO-panhCD3 to assess anti-CD3 therapeutics with Fc-competent or Fc-engineered portions
Humanized FcγR mouse for outstanding translatability
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