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B-hSIRPA/hCD47 mice
Strain Name C57BL/6-Sirpatm1(SIRPA)Cd47tm1(CD47)/Bcgen Common Name  B-hSIRPA/hCD47 mice
Background C57BL/6 Catalog number  120525
Aliases 
CD47 (CD47 molecule) ;
SIRPα
(Signal regulatory protein alpha)

Gene description



SIRPα (Signal-regulatory protein alpha) is a transmembrane protein widely expressed in myeloid cells , stem cells and neurons. Its extracellular part include 3 Immunoglobulinlike domains. SIRPα binds to its ligand CD47 through the variable IgV-like domains. CD47 is also widely expressed in multiple tissue cells. CD47+ cells activate SIRPα on macrophage surface to prevent its phagocytosis. Previous studies reveal that the diversity of SIRPα is the key to human hematopoietic stem cell suppression, especially tumor suppression. The interruption of SIRPα-CD47 interaction substantially inhibits a variety of tumors. SIRPα/CD47 antibodies are considered as the next star target for tumor immunosuppression following PD1/PD-L1 antibodies.

CD47 is an integrin associated protein (IAP) and is an immunoglobulin superfamily member. CD47 is widely expressed on cell surface and interacts with the signal regulatory protein α (SIRPα), thrombospondin-1 (TSP1) and integrins to mediate a series of responses including apoptosis, proliferation and immunity. CD47 is an important “self” mark on the cell surface and inhibits macrophagocytosis by interaction with SIRPα on macrophage surface. Animal studies have shown that a CD47 antibody is an effective treatment for multiple types of tumors. CD47 is another target for tumor immunity following PD-1/PD-L1.

Protein expression analysis





Strain specific CD47 and SIRPα expression analysis in homozygous B-hSIRPA/hCD47 mice by flow cytometry. Splenocytes were collected from WT (+/+) and homozygous B-hSIRPA/hCD47 (H/H) mice stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific anti-CD47 and anti-SIRPα antibodies. Mouse CD47 was exclusively detectable in WT mice. Mouse SIRPα was detectable in WT mice. This anti-mouse SIRPα antibody also reacts crossly with human SIRPα. Human CD47 and SIRPα were exclusively detectable in homozygous B-hSIRPA/hCD47 mice but not in WT mice.


Blood routine test in B-hSIRPA/hCD47 mice




Complete blood count (CBC). Blood from female C57BL/6 and B-hSIRPA/hCD47 mice (n=3, 6-week-old) was collected and analyzed by CBC. There was no differences among any measurement between C57BL/6 and B-hSIRPA/hCD47 mice, indicating that introduction of hSIRPα and hCD47 in place of its mouse counterpart does not change blood cell composition and morphology. Values are expressed as mean ± SEM.

Blood chemistry of B-hSIRPA/hCD47 mice

Blood chemistry tests of B-hSIRPA/hCD47 mice. Plasma from the C57BL/6 and B-hSIRPA/hCD47 mice (n=3, 6 week-old) was collected and analyzed for levels of ALT and AST. There was no differences on either measurement between C57BL/6 and B-hSIRPA/hCD47 mice, indicating that introduction of hSIRPα and hCD47 in place of its mouse counterpart does not change ALT and AST levels or health of liver. Values are expressed as mean ± SEM.

In vivo efficacy of anti-human CD47 antibody





Antitumor activity of anti-human CD47 antibody Hu5F9 (in house) in B-hSIRPA/hCD47 mice. (A) anti-human CD47 antibody inhibited MC38-hCD47 tumor growth in B-hSIRPA/hCD47 mice. Murine colon cancer MC38-hCD47 cells were subcutaneously implanted into homozygous B-hSIRPA/hCD47 mice (female, 6-8 weeks old, n=5). Mice were grouped when tumor volume reached approximately 150 mm3, at which time they were treated with anti-human CD47 antibody with doses and schedules indicated in panel. (B) Body weight changes during treatment. As shown in panel A, anti-human CD47 antibody was efficacious in controlling tumor growth in B-hSIRPA/hCD47 mice, demonstrating that the B-hSIRPA/hCD47 mice provide a powerful preclinical model for in vivo evaluation of anti-human CD47 antibodies. Values are expressed as mean ± SEM.


In vivo efficacy of anti-human SIRPα antibodies





Antitumor activity of anti-human SIRPα antibody in B-hSIRPA/hCD47 mice. (A) anti-human SIRPα antibody inhibited MC38-hCD47 tumor growth in B-hSIRPA/hCD47 mice. Murine colon cancer MC38-hCD47 cells were subcutaneously implanted into homozygous B-hSIRPA/hCD47 mice (female, 6-8 week-old, n=5). Mice were grouped when tumor volume reached approximately 150 mm3, at which time they were treated with anti-human SIRPα antibody with doses and schedules indicated in panel. (B) Body weight changes during treatment. As shown in panel A, three human SIRPA antibodies differently inhibited tumor growth in B-hSIRPA/hCD47 mice, demonstrating that the B-hSIRPA/hCD47 mice provide a powerful preclinical model for in vivo evaluation of anti-human SIRPα antibodies. Values are expressed as mean ± SEM.