PHST001，一种人源化抗CD24 hIgG4抗体，对转移性肿瘤有效，并在竞争性IgG存在下保留其抗肿瘤活性

Background: CD24 is a highly glycosylated tumor antigen with a restricted expression profile that acts as macrophage “don't eat me” signal. CD24 is highly expressed by many human cancers and interacts with the macrophage receptor Siglec-10 to protect cancer cells from phagocytosis. PHST001 is a clinical-stage humanized anti-CD24 monoclonal antibody of IgG4 isotype currently in clinical evaluation. In vivo, PHST001 shows significantly greater efficacy against solid tumors than the anti-CD47 antibody Magrolimab. We assessed PHST001's preclinical efficacy against metastatic tumors and the role of Fc receptor engagement in its anti-tumor activity. Results and Methods: BT474, a human Her2+ breast tumor cell line, metastasizes to the axillary lymph nodes when engrafted in the mammary fat pad of NSG mice. In contrast to control-treated mice, PHST001 treatment inhibited the formation of lymph node metastases in orthotopic xenograft models of BT474. To generate a disseminated metastatic model, BT474 cells were engrafted intracardially. A metastatic model was also generated in a syngeneic system by expressing human CD24 in MC38 cells (MC38-huCD24) and implanting tumor cells intracardially. PHST001 treatment significantly reduced the number and size of metastatic lesions in both xenograft BT474 and immune competent MC38-huCD24 models. To define PHST001's mechanism of action, a variant antibody bearing a LALAGANA mutation (Fc-inert) was generated. This variant induced phagocytosis of tumor cells to a lesser extent than PHST001 (human IgG4), demonstrating the contribution of Fc receptor engagement to PHST001 efficacy. When combined with a companion agent, such as the anti-Her2 ADC trastuzumab deruxtecan, the Fc-inert version of PHST001 dramatically increased phagocytosis, demonstrating the contribution of CD24 blockade to PHST001 efficacy in absence of direct Fc receptor engagement. In vitro, PHST001 induced phagocytosis of human neutrophils, however this effect was completely inhibited by the IgG present in serum at physiological concentrations (50%). PHST001 anti-tumor efficacy against BT474 in NSG mice was maintained even when mice were supplemented with polyclonal IgG to match levels found in immunocompetent mice. Conclusions: PHST001 prevents metastatic spread and demonstrates anti-tumor activity against established metastases. In vitro, peripheral blood cells expressing CD24 are protected from PHST001-mediated phagocytosis due to competition for Fc receptors by high levels of endogenous IgG, predicting protection in treated patients. PHST001 retains anti-tumor effects in vivo despite polyclonal IgG presence, indicating that competition for Fc receptors by endogenous IgG is not a barrier for efficacy in the tumor microenvironment.