靶向 CD47 的肿瘤免疫基因治疗：分泌型 SIRPα-Fc 融合蛋白通过巨噬细胞和 NK 细胞活化消除肿瘤

CD47 protects healthy cells from macrophage attack by binding to signal regulatory protein (SIRP ), while its upregulation in cancer prevents immune clearance. Systemic treatment with CD47 antibodies requires a weakened Fc-mediated effector function or lower CD47-binding affinity to prevent side effects.

Our approach combines "the best of both worlds," i. e. , maximized CD47 binding and full Fc-mediated immune activity, by exploiting gene therapy for paracrine release.

We developed a plasmid vector encoding for the secreted fusion protein sCV1-hIgG1, comprising highly efficient CD47-blocking moiety CV1 and Fc domain of human immunoglobulin G1 (IgG1) with maximized immune activation. sCV1-hIgG1 exhibited a potent bystander effect, blocking CD47 on all cells via fusion protein secreted from only a fraction of cells or when transferring transfection supernatant to untransfected cells. The CpG-free plasmid ensured sustained secretion of sCV1-hIgG1.

In orthotopic human triple-negative breast cancer in CB17-severe combined immunodeficiency (SCID) mice, ex vivo transfection significantly delayed tumor growth and eradicated one-third of tumors. In intratumoral transfection experiments, CD47 blockage and increased migration of macrophages into the tumor were observed within 17 h of a single injection. Natural killer (NK) cell-mediated lysis of sCV1-hIgG1-expressing cells was demonstrated in vitro . Taken together, this approach also opens the opportunity to block, in principle, any immune checkpoints.