NKG-hSIRPα Mouse

NKG mice are a type of severe immunodeficient mouse developed by Cyagen by deleting the Il2rg gene from the NOD-Scid strain. This strain lacks mature T, B, and NK cells, exhibits reduced complement activity, and weak macrophage phagocytosis of human cells. As a result, NKG mice can efficiently engraft human hematopoietic stem cells (HSC), peripheral blood mononuclear cells (PBMC), patient-derived xenografts (PDX), or adult stem cells and tissues.

SIRPα (Signal Regulatory Protein alpha), encoded by the SIRPα gene, is a transmembrane glycoprotein of the immunoglobulin superfamily critically involved in regulating myeloid cell activity ^[1]. Expressed on a variety of immune cells, including macrophages, dendritic cells, neutrophils, and a subset of T cells, SIRPα primarily functions as an inhibitory receptor through its interaction with CD47, a broadly expressed cell surface protein ^[2]. Engagement of SIRPα by CD47 triggers intracellular signaling via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within its cytoplasmic domain, leading to the suppression of phagocytosis and playing a vital role in self-recognition and the maintenance of tissue homeostasis ^[3]. However, CD47 is usually upregulated on the surface of malignant cells. Therefore, antibodies that block the interaction between CD47 and SIRPα should be able to enhance the phagocytosis of macrophages in the tumor microenvironment, inhibit tumor growth, making anti-SIRPα antibodies an ideal tool for cancer immunotherapy. Aberrant SIRPα signaling or its dysregulation has been implicated in the pathogenesis of several diseases, including cancer, where it contributes to immune evasion, as well as autoimmune and neurodegenerative disorders, highlighting its significance as a potential therapeutic target ^[4].

The NKG-hSIRPα mouse is a humanized model constructed by replacing the exon 2 coding region plus partial intron 2 of the mouse Sirpa gene in situ with the "Human SIRPA CDS-3'UTR of Mouse Sirpa-WPRE-BGH pA" cassette. The homozygous NKG-hSIRPα mice are viable and fertile. Compared with NKG mice, NKG-hSIRPα mice further inhibit the phagocytosis of transplanted tumors by host macrophages through enhancing the function of the CD47-SIRPα signaling pathway, thus accelerating tumor growth [5]. This model provides a crucial experimental platform for studying the ability of CAR-M therapy to overcome the immunosuppressive microenvironment, as well as for developing anti-tumor drugs targeting the CD47/SIRPα pathway.