CD47 BLOCKING IMMUNOSTIMULATORY ANTIBODY CONJUGATES ELICIT ROBUST TUMOR-SPECIFIC IMMUNITY FROM PHAGOCYTIC CELLS

Cancer Immunotherapies targeting adaptive immune checkpoints have been substantially explored as they elicited durable clinical responses across multiple types of cancers. Asides from the success of anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors, more recent findings highlight the significance of checkpoints in the innate arm of immunity. As an innate immune checkpoint, CD47 has been shown to be highly expressed by various types of solid and hematologic tumors and to be correlated with aggressive disease and poor patient outcomes. CD47 delivers an inhibitory “don’t eat me” signal to macrophages through SIRP⍺, enabling the escape of cancer cells from macrophage-mediated phagocytosis. A growing number of studies have shown that interrupts the CD47-SIRP⍺ axis enhances the phagocytosis of tumor cells by macrophages and promotes the downstream activation of the adaptive immune system. However, in preclinical and early clinical stages, the blockade of CD47-SIRP⍺ still shows a relatively low response rate in the solid tumor. Solely blocking this phagocytosis checkpoint is not sufficient to engage macrophages, a pro-phagocytic cue as an “eat me” signal must also be present to activate the effector function of macrophages, which enhances the innate immune sensing and stimulates the essential immune surveillance process. Recent and ongoing clinical trials are demonstrating the therapeutic efficacy of CD47 blockade in combination with monoclonal antibodies, chemotherapy, or other checkpoint inhibitors for adult cancer. In this study, we propose an engineered CD47 antibody variant that exhibits strong immunostimulatory property while promoting tumor cell phagocytosis at the same time