CD47 is overexpressed on many human tumor cells and interacts with its ligand, the signal-regulating protein alpha (SIRPα), a protein expressed on macrophages and dendritic cells, to induce a “don’t eat me” signal. CD47 and its interaction with phagocytes is therefore a promising therapeutic target to treat cancer (S.B. Willingham et al., Proc Natl Acad Sci U S A. 2012). Here, we describe a double humanized knock-in model, the genO-hCD47/hSIRPα model, designed for the efficacy and safety assessment of human CD47/SIRPα-targeting therapies in immunocompetent mice.

This model was generated by intercrossing genO-hCD47 and genO-hSIRPα mice, with both models designed to enable the expression of all human isoforms of hCD47 and hSIRPα.

hCD47 and hSIRPα are expressed at physiological levels, which enabled the assessment of biodistribution of anti-SIRPα nanobodies, used as tracers in non-invasive in vivo tumor imaging (T.R. Wagner et al., Front.Immunol. 2023). Activity of anti-CD47-targeting compounds were investigated in the model and a murine MC38 colon adenocarcinoma cell line expressing hCD47 was developed to reproduce as much as possible the interactions between hCD47 and hSIRPα upon tumor engraftment in this syngeneic mouse model. Magrolimab analog (Hu5F9-G4) induced tumor growth inhibition studies in the genO-hCD47/hSIRPα model inoculated with MC38 expressing hCD47. Furthermore, safety assessment of Magrolimab analog in naïve genO-hCD47/hSIRPα mice showed a drop on the number of red blood cells (RBCs) and hemoglobin 1 day post-treatment, with a recovery by 8 days post-treatment. Additionally, MC38-hCD47-bearing genO-hCD47/hSIRPα mice treated with Magrolimab also recapitulates the clinical findings, with a decline in RBCs and hemoglobin post treatment (C.K. Brierley et al., Transfusion. 2019).

Altogether, these data suggest that the genO-hCD47/hSIRPα model enables assessment of efficacy and safety of CD47 and/or SIRPα-targeting agents. The model is currently being upgraded to express humanized Fcγ receptors (FcR), which will facilitate the assessment of Fc-mediated functions of antibodies targeting human CD47 and/or SIRPα.