IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα, exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement by simultaneously binding to CD47 and CD20 of B cells
Jifeng Yu 1,3, Song Li2,3, 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 Tian 2✉
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To the Editor:
CD47, as the “don’t eat me” signal, interacts with the inhibitory signal-regulatory protein alpha (SIRPα) receptor expressed by myeloid cells and activated NK cells  and is overexpressed in different malignancies, causing tumors to escape the phagocytosis of macrophages . CD47 was identified as the main macrophage checkpoint, and blocking CD47 can make macrophages phagocytize tumor cells and produce therapeutic clearance. Recent progress has been made in targeting CD47 for cancer immunotherapy , and several CD47/SIRPα axis inhibitors have been developed for clinical trials with a favorable antitumor response in solid tumors and hematological malignancies [1, 3, 4]. However, the clinical development of Fc-active anti-CD47 antibodies is hindered by the potential adverse events of hematological dose-limiting toxicity due to the broad expression of CD47 on blood cells, including erythrocytes and platelets [5, 6]. The improved priming administration scheme of anti-CD47 molecules in combination with other agents promoting the expression of the prophagocytic signal on tumor cells has been used to avoid this adverse effect and demonstrated effective results [3, 7, 8].
Different bispecific antibodies (BsAb) or fusion proteins targeting both CD47 and B cell antigens, such as CD20 and CD19, were generated to target and deplete B cells via multiple antibody-mediated mechanisms [5, 9]. CD20-CD47SL, a CD47xCD20 BsAb, was observed to selectively bind to dual antigen-expressing lymphoma cells in the presence of an “antigen sink” of RBCs and recapitulated the synergistic effects of anti-CD47 antibody and rituximab combinations in mouse models of NHL . Another anti-CD47/CD20 BsAb showed potent antagonism of the CD47/SIRPα pathway . RTX-CD47, a CD20-targeting scFv antibody fragment derived from rituximab fused in tandem with a CD47-blocking scFv, demonstrated therapeutic anticancer activity in the mouse model of B-cell tumors . Meanwhile, a fully human BsAb targeting CD19 and CD47, NI-1701, demonstrated therapeutic effect in patients with B cell malignancies refractory/resistant to anti-CD20 targeted therapy . Another CD47xCD19 BsAb triggers recruitment and activation of innate immune effector cells in a B-cell lymphoma xenograft model . The role of CD47xCD19 co-ligation in inhibiting B cell proliferation illuminates a novel approach that may provide a therapeutic benefit in settings of autoimmunity and B cell malignancies. Here, we describe the anti-tumor mechanism of IMM0306, a fusion protein of CD20 monoclonal antibody (mAb) with the CD47 binding domain of SIRPα, by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement by simultaneously binding to CD47 and CD20 of B cells in different mouse xenograft tumor models.
IMM0306 is a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα on both heavy chains (Fig. 1A). IMM0306 was constructed and produced using an in-house developed CHO-K1 cell expression system. The binding activity of IMM0306 was analyzed by flow cytometry. The phagocytosis and in vitro anti-tumor activity of IMM0306 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.