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B6-hPD1/hLAG3

 

Strain Name: B6/JGpt-Pdcd1 em1Cin(hPDCD1) Lag3 emCin(hLAG3) /Gpt

Strain Type: Knock-in

Strain ID: T004621

Background: C57BL/6JGpt

 

Application

1. Evaluation of efficacy and safety of human LAG3 inhibitors

2. Evaluation of the combined efficacy of human LAG3 inhibitor and human PD1 inhibitor

3. Anti-tumor Drug Research and Development

4. Research on autoimmune diseases

 

Description

LAG3(Lymphocyte activation gene3), a cell surface molecule expressed on activated T cells, NK cells, B cells and plasmacytoid dendritic cells. Studies have shown that knock out the LAG3 gene or in vivo antibodies blocking LAG3 function can increase the aggregation and effector function of antigen-specific CD8+ T cells in organs or tumors, Therefore, blocking LAG3 is a potential tumor treatment. B6-hPD1/hLAG3 mice is ideal animal model to evaluate the efficacy of human LAG3 antibody, human PD1 antibody and their combo treatment.

 Data support

Detection of PD1 and LAG3 expression

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B6-hPD1/hLAG3 homozygous mice expressed human PD1 on T cell surface.

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B6-hPD1/hLAG3 homozygous mice expressed human LAG3 on T cell surface.

The T/B/NK cell ratio detection

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Fig.5 Detection the T/B/NK cell ratio in B6-hPD1/hLAG3 mice. B6-hPD1/LAG3 homozygous, heterozygous and wild type mice have the same T/B/NK cell ratio.


Anti-tumor Efficacy Test

Evaluation of in vivo efficacy of Anti-hLAG3 and Anti-hPD1 by subcutaneous inoculation of MC38 model in B6-hPD1/hLAG3 mice

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Fig.6 In vivo efficacy test based on B6-hPD1/hLAG3.

Murine colon cancer MC38 cells was cultured to logarithmic growth phase and inoculated subcutaneously into 6-8 weeks old B6-hPD1/hLAG3 mice. Mice were divided into Vehicle groups, Anti-hPD1 groups, Anti-hPD1 + Anti-hLAG3 groups when the tumor size was about 120 mm3, and were treated with the appropriate medication. Administer twice a week for a total of 4 times.

Result Anti-hPD1 group inhibit tumor growth (TGI = 71.88%), Anti-hPD1 + Anti-hLAG3 group inhibit tumor growth (TGI = 76.03%)(Fig.6A).The trend of weight change in mice is consistent(Fig.6B).

Indicating B6-hPD1/hLAG3 mice are powerful tools to evaluate the combined efficacy of anti-hPD1 and anti-hLAG3 antibodies in vivo.

References

1. Liang, S. C., et al. "Regulation of Pd-1, Pd-L1, and Pd-L2 Expression During Normal and Autoimmune Responses." Eur J Immunol 33 10 (2003): 2706-16.

2. Mamalis, A., M. Garcha, and J. Jagdeo. "Targeting the Pd-1 Pathway: A Promising Future for the Treatment of Melanoma." Arch Dermatol Res 306 6 (2014): 511-9.

3. Sierro, Sophie, Pedro Romero, and Daniel E. Speiser. "The CD4-like molecule LAG-3, biology and therapeutic applications." Expert opinion on therapeutic targets 15.1 (2011): 91-101. 

4. Goldberg, Monica V., and Charles G. Drake. "LAG-3 in cancer immunotherapy." Cancer Immunology and Immunotherapy. Springer, Berlin, Heidelberg, 2010. 269-278. 

5. Triebel, Frederic, et al. "LAG-3, a novel lymphocyte activation gene closely related to CD4." Journal of Experimental Medicine 171.5 (1990): 1393-1405.

6. Huard, Bertrand, et al. "CD4/major histocompatibility complex class II interaction analyzed with CD4‐and lymphocyte activation gene‐3 (LAG‐3)‐Ig fusion proteins." European journal of immunology 25.9 (1995): 2718-2721.

7. Hannier, Sigrid, et al. "CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling." The Journal of Immunology 161.8 (1998): 4058-4065.



Time:2020-01-14

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