SIRPα‑Fc fusion protein IMM01 exhibits dual anti‑tumor activities by targeting CD47/SIRPα signal pathway via blocking the “don’t eat me” signal and activating the “eat me” signal
Jifeng Yu1†, Song Li2†, Dianze Chen2, Dandan Liu2, Huiqin Guo2, Chunmei Yang2, Wei Zhang2, Li Zhang2,Gui Zhao2, Xiaoping Tu2, Liang Peng2, Sijin Liu2, Xing Bai2, Yongping Song1, Zhongxing Jiang1,Ruliang Zhang2 and Wenzhi Tian2*
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A novel recombinant SIRPα-Fc fusion protein, IMM01, was constructed and produced using an in-house developed CHO-K1 cell expression system, and the anti-tumor mechanism of IMM01 targeting the CD47-SIRPα pathway was explored. The phagocytosis and in vitro anti-tumor activity of IMM01 were evaluated by antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) assays. In vivo mouse tumor model studies were used to explore therapeutic efficacy as well as the mechanism of action. An in vitro binding assay revealed that IMM01 has a strong binding affinity to CD47 with an EC50 of 0.4967 nM. IMM01 can induce strong ADCP and moderate ADCC, but not CDC. IMM01-induced strong phagocytosis against tumor cells was attributed to dual activities of blocking the "don’t eat me" signal and activating the "eat me" signal, and IMM01 exhibits strong and robust in vivo anti-tumor activities either as monotherapy on hematological malignancies, or in combination therapy with PD-L1 monoclonal antibody (mAb), PD-1 mAb, and HER-2 mAb on solid tumors. Finally, IMM01 demonstrated a favorable safety profile with no human RBC binding activity or hemagglutination induction. IMM01 inhibits the growth of tumor cells by the following three possible mechanisms: (1) directly activating macrophages to phagocytize tumor cells; (2) activated macrophages degrade phagocytized tumor cells and present tumor antigens to T cells through MHC molecules to activate T cells; (3) activated macrophages can convert "cold tumors" into "hot tumors" and increase the infiltration of immune cells through chemotaxis by secreting some cytokines and chemokines.
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