Immune checkpoints such as PD-1, PD-L1, and CTLA-4 are breakthrough in human cancer treatment. However, response rates are still non-ideal in a portion of cancer patients. Blocking a single target may not effectively inhibit immunosuppression because of multiple signal pathways involving in complicated oncogenesis mechanisms. The SIRPα/CD47 is one of the inhibitory signal pathways preventing tumor cells from phagocytic clearance and they both have been taken as potential targets in cancer treatment. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hSIRPα/hCD47 dual humanized mice for our clients all over the world.

hSIRPα/hCD47 Molecule

Human signal regulatory protein alpha (hSIRPα), also termed CD172a or SHPS-1, is an inhibitory immunoreceptor belonging to the SIRP family. In the extracellular domain, hSIRPα contains three Ig-like domains, including two C1-set domains and an NH2-terminal V-set domain which interacts with CD47. In the cytoplasmic domain, hSIRPα possesses four Tyr residues. The expression of hSIRPα is found on monocytes, macrophages, granulocytes, dendritic cells (DCs), some bone marrow progenitor cells, and neurons. hSIRPα has a stable expression level on phagocytes.

Human CD47(hCD47), also termed integrin-associated protein (IAP) as it is connected with integrins. hCD47 is composed of five transmembrane regions but only with a single Ig-like domain residing on the cell surface. hCD47 is broadly expressed on all normal cells and its expression level fluctuates due to the immune state. It is recognized as a molecular switch regulating homeostatic clearance of host cells. Recent studies claimed that high hCD47 levels have been found on cancer cells, such as ovarian cancer, bladder cancer, multiple myeloma, non-Hodgkin’s lymphoma, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, etc.

hSIRPα/hCD47 Signal Pathway

The most important physiological function of hSIRPα-hCD47 interactions is their role in the homeostasis of host cells. The interaction of hCD47 and hSIRPα emits a downregulatory signal-regulating phagocytosis, thus preventing healthy autologous cells from phagocytic clearance. Accordingly, hCD47 functions as a “don’t eat me” signal. However, tumor cells with abundant expression of hCD47 could rely on this inhibitory signal pathway to evade macrophage phagocytosis. Specifically, hSIRPα-hCD47 interactions between tumor cells and macrophages inhibit macrophage phagocytosis, prevent clearance of tumor cells, and therefore enhance survival of tumor cells. It has been evidenced that the hSIRPα-hCD47 interactions restrict the efficacy of cancer therapeutic antibodies. The interaction of hSIRPα and hCD47 could be blocked by anti-hSIRPα or anti-hCD47 antibodies.

Interaction of SIRPα and CD47. Fig.1 Interaction of SIRPα and CD47. (Barclay, 2014)

Targets of the SIRPα-CD47 pathway in cancer. Fig.2 Targets of the SIRPα-CD47 pathway in cancer. (Chao, 2012)

Development of hSIRPα/hCD47 Dual Humanized Mice

Anti-hSIRPα or anti-hCD47 antibodies could interrupt the interactions of hSIRPα and hCD47 and then prompt the exposure of tumor cells under immune surveillance. Under this circumstance, phagocytosis of macrophages would be activated and tumor cells could be eliminated by the host immune system. Accumulating evidences have demonstrated the anti-hCD47 antibodies or in combination with other therapeutics reduced tumor burden in various cancer types. The hSIRPα/hCD47 pathway reveals its significance as therapeutic targets in cancer treatment. With advanced technology, Creative Biolabs has assisted our clients in their study projects with our well-established hSIRPα/hCD47 dual humanized mice. If you have any questions about this model, please feel free to contact us for further discussions.

Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:

References

  1. Barclay, A. N.; et al. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu Rev Immunol. 2014.32: 25-50.
  2. Chao, M. P.; et al. The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol. 2012. 24(2): 225-232.

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