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>Single Humanized Immune-Checkpoint Mice

TNFRSF9 (TNF receptor super family member 9), also called CD137 or 4-1BB, is mainly expressed on the surface of activated T, NK,and mononuclear cells. CD137 is activated by its ligand CD137L or an activating CD137 monoclonal antibody, and stimulates T cell activation, proliferation and cytokine production.

Strain description

 

Strain   Name

C57BL/6-Tnfrsf9tm1(hTNFRSF9)/Bcgen

Background

C57BL/6

Related Genes

Tnfrsf9 (tumor   necrosis factor receptor superfamily,   member 9)

Gene description

 

TNFRSF9 (TNF receptor super family member 9), also called CD137 or 4-1BB, is mainly expressed on the surface of activated T, NK,and mononuclear cells. CD137 is activated by its ligand CD137L or an activating CD137 monoclonal antibody, and stimulates T cell activation, proliferation and cytokine production. This co-stimulatory signal can also multiply antigen presenting cells and result in cell factor secretion. Experiments show that CD137 co-stimulation regulates T cell and antigen presenting cell function for antitumor immunity, providing new targets for tumor immunological therapies.


Protein expression analysis

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Fig 1. Splenocytes from both wild type (WT) C57BL/6 and homozygous B-h4-1BB mice were analyzed by flow cytometry. T cells from WT mice express the murine 4-1BB receptor while the human 4-1BB receptor was detected on T cells from B-h4-1BB homozygous mice.



Human 4-1BB (Urelumab Analog) mAb efficacy evaluation


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Fig 2. Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-h4-1BB mice. Mice were divided into control and treatment groups (n=6), when the tumor size was approximately 150±50 mm3. Three doses Urelumabshowed substantially inhibitory effects in the homozygous B-h4-1BB mice, suggesting that B-h4-1BB mouse model is a useful tool for in vivo h4-1BB antibody efficacy study. The average ± SEM of tumor sizes are shown in the figure.


Human 4-1BB mAb(Urelumab Analog ) toxicity evaluation


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Fig 3. Anti-h4-1BB antibody was injected into homozygous B-h4-1BB mice. Human 4-1BB mAb(Urelumab Analog) were i.p. injected into homozygous B-h4-1BB mice. Blood were collected two days after the second treatment and analyzed by Blood Routine Test.  


Abbreviation

Stands for

Abbreviation

Stands for

WBC

White   Blood Cell Count

MCV

Mean   Corpuscle (Cell) Volume  

NE#

Neutrophil Count

MCH

Mean   Corpuscular Hemoglobin

LY#

Lymphocyte   Count

MCHC

Mean   Corpuscular Hemoglobin Concentration

MO#

Monocyte Count  

MPV

Mean   Platelet Volume

RBC

Red   Blood Cell Count

PLT

Platelet   Count  

Hb

Hemoglobin  

RDW

Red   Cell Distribution Width

HCT

Hematocrit  

 

4-1BB mAb (Urelumab Analog) comprehensive metabolic penal


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Fig 4. Anti-h4-1BB antibody was injected into homozygous B-h4-1BBmice. Blood were collected at study endpoint and analyzed by Blood Biochemical Test.


Abbreviation

Stands for

Explanation

ALT

Alanine transaminase

High level indicates liver injured

AST

Aspartate transaminase

High level indicates liver damage

CHOL

Cholesterol  

High level indicates high blood lipid  

CR

Creatinine

High level indicates low glomerular filtratio 

GLU

Glucose

Hyperglycemia or hypoglycemia


TRIG 

Triacylglycerol

High level indicates high blood lipid

UREA

Urea

High level indicates kidney damage,   liver disease, diabetes or infection.


Human 4-1BB (Utomilumab Analog) mAb efficacy evaluation(MC38 cell line)


image.png

Fig 5. Murinecolon cancer MC38 cells were subcutaneously implanted into homozygous B-h4-1BB mice. Mice were divided into control and treatment groups (n=5), when the tumor size was approximately 150±50 mm3. Two doses Urelumab showed substantially inhibitory effects in the homozygous B-h4-1BB mice, suggesting that B-h4-1BB mouse model is a useful tool for in vivo h4-1BB antibody efficacy study. (A) Tumor average volume ± SEM, (B) Mice average weight ± SEM.


Human 4-1BB mAb (Urelumab Analog) toxicity evaluation


image.png

Abbreviation

Stands for

Explanation

ALT

Alanine transaminase

High level indicates liver injured

AST

Aspartate transaminase

High level indicates liver damage

CR

Creatinine

High level indicates low glomerular filtratio 

Fig 6. The blood biochemical index was examined with anti-human 4-1BB antibody on B-h4-1BB mice at the termination of efficacy evaluation experiment. 



Pharmacodynamic test using B-h4-1BB mice


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Fig 7. Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-h4-1BB mice. Mice were divided into control and treatment groups (n=8) when the tumor size was approximately 150±50mm3.

Both two dose of human 4-1BB antibody significantly inhibited tumor growth, confirming that the B-h4-1BB mouse model is a powerful tool for in vivo 4-1BB antibody pharmacological efficacy studies.

(A) Tumor average volume ± SEM, (B) Mice average weight ± SEM.



Tumor infiltrating lymphocyte(TILs) analysis


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Fig8. 4-1BB Abefficacy evaluation.Tumor cells are isolated at the endpoint of experiment, analyzed by flow cytometry.


Ratio of tumor infiltrating lymphocyte(TILs)


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Fig9. 4-1BB Abefficacy evaluation.Tumor cells are isolated at the endpoint of experiment, analyzed by flow cytometry.


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