以表达抗 CD47 抗体的溶瘤病毒靶向 Fc 受体介导效应和“别吃我”信号治疗转移性卵巢癌

mAbs blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the "don't eat me" pathway. However, this strategy is associated with severe toxicity. EXPERIMENTAL DESIGN: To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV- CD47-G1) or IgG4 scaffold (OV- CD47-G4).

Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47-SIRP signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV- CD47-G1, but not OV- CD47-G4, activated human NK-cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. In vivo , these multifaceted functions of OV- CD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared with OV- CD47-G4 and a parental oHSV. The murine counterpart of OV- CD47-G1, OV- mCD47-G2b, also enhanced mouse NK-cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared with OV- mCD47-G3. OV- mCD47-G2b was also superior to mCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection.

Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.