Abstract 3230: Preclinical double humanized CD47/SIRPΑ mouse model and MC38 cell line expressing human CD47 for efficacy and safety assessment of anti-CD47/SIRPΑ-targeting therapies

Abstract 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). Herein, we describe a double humanized CD47/SIRPα model for efficacy and safety assessment of human CD47/SIRPα-targeting therapies in immunocompetent mice. The double humanized CD47 and SIRPα mouse model (hCD47/hSIRPα) was generated by intercrossing hCD47 and hSIRPα mice. Both hCD47 and hSIRPα are humanized and their model design enables expression of all human isoforms. hCD47 and hSIRPα are expressed at physiological levels, which enabled the biodistribution assessment of anti-SIRPα nanobodies, used as tracers in non-invasive in vivo imaging of tumors (T.R. Wagner et al., Front.Immunol. 2023). Activity of anti-CD47-targeting compounds were investigated in the model and a MC38 tumor cell line expressing hCD47 was developed to reproduce as much as possible the interactions between hCD47 and hSIRPα upon tumor engraftment in the mouse model. Tumor growth inhibition studies in the hCD47/hSIRPα model with the corresponding cell line have shown significant reduction of tumor growth in mice treated with Magrolimab (Hu5F9-G4). Furthermore, safety assessment of Magrolimab in MC38-hCD47-bearing hCD47/hSIRPα mice in tumor context recapitulates the clinical findings (C.K. Brierley et al., Transfusion. 2019), with a decline in hemoglobin and red blood cells post treatment. Altogether, these data suggest that the 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 FcγR to enable assessment of Fc-mediated function of human antibodies targeting human CD47 and/or SIRPα. Citation Format: Philippe De La Rochère, Angela Pappalardo, Gaëlle Martin, Yacine Cherifi, Patricia Isnard-Petit, Fabiane Sonego, Kader Thiam. Preclinical double humanized CD47/SIRPΑ mouse model and MC38 cell line expressing human CD47 for efficacy and safety assessment of anti-CD47/SIRPΑ-targeting therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3230.