CD47 is a ubiquitously expressed immune checkpoint receptor playing a major role in recognition of self by phagocytes. CD47 interacts with SIRPα to generate an inhibitory signal blocking phagocytosis. Tumor cells have hijacked this immunosuppressive mechanism by overexpressing CD47, which efficiently protects them against attack by the body's immune system. Targeting CD47, with a blocking monoclonal antibody (mAb), promotes tumor elimination via antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC). In several in vivo models, blocking CD47 leads to tumor elimination, inhibits the development of metastasis and promotes the development of an antitumor immunological memory. Several anti-CD47 mAb are under clinical investigation for cancer treatment. However, the development of these antibodies is confronted with several hurdles. Due to the expression of CD47 also on healthy cells, mAb based therapies lead to toxicity, including severe anemia and thrombocytopenia, as well as rapid drug elimination. As a solution, we hypothesized that using not a mAb but a bispecific Ab format (biAb) pairing a high affinity tumor associated antigen (TAA) arm with a CD47 targeting arm of lower affinity could avoid these unwanted characteristics. Such a biAb with unbalanced affinities would allow to selectively target CD47 to the tumor cells. Both anti-human and anti-mouse CD47/TAA biAb were generated using the κλ body format, a fully human biAb composed of a common IgG heavy chain and two different light chains (i.e., kappa and lambda). We exploited light chain diversity to identify the TAA and CD47 targeting arms composing the biAbs. The resulting biAbs efficiently neutralized CD47 on TAA positive tumor cells, but interacted only weakly with healthy cells. Accordingly, the biAbs were not subject to CD47- mediated drug disposition and were well tolerated in vivo. The selection of a low affinity anti- CD47 arm was also primordial for biAb anti-tumor activity in a context of CD47 ubiquitous expression. The combination of targeted CD47 neutralization and Fc effector functions afforded by the biAb format resulted in potent killing by ADCP and ADCC in vitro, and translated into a potent anti-tumor activity in both xenograft and syngeneic in vivo models. In immunocompetent mouse models, biAb-mediated blockade of CD47 lead to tumor cell phagocytosis and the development of a long term immunological memory in vivo as mice were protected from tumor rechallenge. In vitro, we demonstrated that indeed cross-priming of anti-tumor CD8+ T cells had occurred. Taken together, my work confirmed that targeting CD47 is a powerful way to engage the innate and adaptive immune system to kill cancer. Thus, dual-targeting biAbs with unbalanced affinities are an elegant means to employ this strategy effectively yet safely in patients. With a better risk to benefit ratios, the biAb approach to CD47 targeting can be envisioned as part of combination therapies, for example synergizing with cyclophosphamide or anti-PD-L1 therapies. These studies also suggest that a similar bispecific design could be exploited for the targeting of other widely expressed receptors.