Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies

摘要

CD47 is a ubiquitously expressed immune checkpoint receptor that is often upregulated in cancer. CD47 interacts with its counter- receptor SIRP alpha on macrophages and other myeloid cells to inhibit cancer cell phagocytosis and drive immune evasion. To overcome tolerability and "antigen sink" issues arising from widespread CD47 expression, we generated dual-targeting bispecific antibodies that selectively block the CD47-SIRP alpha interaction on malignant cells expressing a specific tumor- associated antigen; e.g., CD19 or mesothelin. These bispecific k lambda bodies are fully human, native IgGI molecules, combining tumor targeting and selective CD47 blockade with immune activating mechanisms mediated by the Fc portion of the antibody. CD47-neutralizing k lambda bodies efficiently kill cancer cells in vitro and in vivo but interact only weakly with healthy cells expressing physiological levels of CD47. Accordingly, a k lambda body administered to non-human primates showed a typical IgG pharmacokinetic profile and was well tolerated. Importantly, k lambda bodies preserve their tumoricidal capabilities in the presence of a CD47 antigen sink. Thus, dual-targeting kl bodies allow for efficacious yet safe targeting of CD47 in cancer. Such a bispecific design could be applied to limit the extent of neutralization of other ubiquitously expressed therapeutic targets.