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Background CD47, a ubiquitously expressed ‘don’t eat me’ signal, enables tumor cells to evade phagocytic clearance by interacting with Signal Regulatory Protein α (SIRPα) expressed on macrophages and dendritic cells. Therapeutics targeting the CD47-SIRPα pathway promote the elimination of tumor cells via two primary mechanisms: 1. Blocking antibodies (either monoclonal or bispecific antibodies) that interrupt CD47-SIRPα interaction to facilitate macrophage-mediated phagocytosis of tumor cells, and 2. Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).These processes further enhance dendritic cell-mediated antigen presentation, activating anti-tumor adaptive immunity. As such, the CD47-SIRPα axis has emerged as a high priority immune-oncology target.Methods To support translational evaluation of CD47-targeted therapies, GemPharmatech generated a double knock-in hCD47/hSIRPα mouse model with human CD47/SIRPα extracellular domains in BALB/c mice, named BALB/c-hCD47/hSIRPα. hCD47 and hSIRPα protein expression levels of BALB/c-hCD47/hSIRPα were detected to confirm the successful construction. This model was used to assess anti-tumor efficacy of anti-hCD47 antibody (Magrolimab (5F9)) in a CT26-hCD47 (CT26 cells overexpressing human CD47) colorectal tumor model engrafted onto BALB/c-hCD47/hSIRPα mice. In addition, anti-SIRPα antibodies were tested to evaluate an alternative targeting strategy, given the known toxicity associated with CD47 blockade. Anti-tumor efficacy study of hSIRPα×hClaudin18.2 bispecific antibody (BsAb) was performed on BALB/c-hCD47/hSIRPα mice bearing EMT6-hCD47-hClaudin18.2 (EMT6 cells overexpressing human CD47 and human Claudin18.2) triple-negative breast tumor model.Results hCD47 and hSIRPα expression were verified on BALB/c-hCD47/hSIRPα mice. Treatment with anti-hCD47 antibody led to tumor regression in a dose dependent manner. hSIRPα×hClaudin18.2 BsAb also demonstrated significant anti-tumor effect when administered to CD47/SIRPα knockin mice bearing EMT6-hCD47hClaudin18.2 tumor cells.Conclusions The BALB/c-hCD47/hSIRPα mice provides a clinically relevant immunocompetent mouse model for evaluating CD47/hSIRPα targeted therapies. This model is particularly valuable for overcoming limitations in traditional murine models and offers insight into the mechanisms of CD47 pathway mediated tumor clearance, toxicity management and immune activation.