The SIRPα and CD47 become high-profile targets in cancer therapeutics due to their roles in inhibiting the phagocytosis of tumor cells by macrophages. Combinational therapy has several advantages compared with monoclonal therapy. Thus, combining the anti-SIRPα and anti-CD47 antibodies with anti-PD-1 antibody might be an attractive option for refractory malignancies. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hSIRPα/hCD47/hPD-1 triple humanized mice for our clients all over the world.
Human programmed cell death protein-1 (hPD-1) is one of the immune checkpoints. Immune checkpoints are a series of molecules that play a protective role in the body's immune system. They act as brakes, preventing inflammatory damage caused by excessive activation of T cells. Overexpression of hPD-1 on T cells that infiltrate the tumor tissues can be detected.
Human signal-regulatory protein α (SIRPα) is also known as CD172a, SHPS-1, P84, and BIT. It is a plasma membrane glycoprotein with a glycosylation structure which has species and tissue specificity. hSIRPα can be detected on the surface of nerve cells and myeloid cells. In myeloid cells, hSIRPα often appears as an inhibitory receptor.
Human CD47 (hCD47), also known as integrin-related protein (IAP). It is composed of an extracellular N-terminal highly glycosylated IgV-like domain, five highly hydrophobic and highly transmembrane fragments, and a short selectively spliced cytoplasmic region. hCD47 is widely present, especially highly expressed in hematopoietic cells. hCD47 is also highly expressed in various tumors, such as ovarian cancer, acute myeloid leukemia, non-Hodgkin's lymphoma, bladder cancer, liver cancer, and other solid tumors.
Tumor cells take advantage of the characteristics of the human immune system. Specifically, they adopt the immunosuppressive pathway “hPD-1/hPD-L1” to suppress the response of the human immune system, to escape human immune surveillance and killing, thereby promoting the growth of tumor cells.
The signaling system of hSIRPα/hCD47 has a negative regulatory effect on the immune system. The short IRP-like domain of hSIRPα N-terminal on macrophages binding to the hCD47 Ig-like domain of neighboring cells leads to molecular aggregation, which causes phosphorylation of tyrosine and inhibits the accumulation of synaptic myosin in macrophages. In this process, hSIRPα with phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) is used as an adaptor protein to recruit and activate protein tyrosine phosphatase SHP-1 or SHP-2, transmitting inhibitory signals to inhibit phagocytosis. Accordingly, hCD47 is like sending a "don't eat me" signal.
Fig.1 SIRPα/CD47 pathway in cancer. (Chao, 2012)
Clinical practice has proved that the therapeutic effect of a single immunotherapy strategy is limited, and it is generally necessary to combine two or more immunotherapy methods in clinical practice. hSIRPα/hCD47 signaling pathway is a newly discovered mechanism of tumor immune escape. The combinational usage of anti-hSIRPα, anti-hCD47, and anti-hPD-1 antibodies may improve the anti-tumor immune response. Creative Biolabs provides multiple Magic™ “humanized” animal models, including the hSIRPα/hCD47/hPD-1 triple humanized mice and the related analysis services. We have many years of experience in assisting our global clients to perform their preclinical drug development. If you have any questions or problems in your study, please feel free to contact us for further discussions. Our professional R&D team will provide you with scientific solutions and assist you in your study project.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
For Research Use Only.
