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hPD1 humanized mice


BALB/c-hPD1


Strain Name: BALB/cJGpt-Pdcd1em1Cin(hPDCD1)/Gpt

Strain Type: Knock-in

Strain ID: T002726

Background: BALB/cJGpt


Application

1. Efficacy evaluation of human PD1 inhibitors

2. Safety assessment of human PD1 inhibitor

3. Research on immune system


Description

PDCD1(Programmed cell death protein 1,PD1),a member of the extended CD28/CTLA-4 family of T cell regulators,is involved in the regulation of T-cell function during immunity and tolerance.

PD1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. PD-L1 is highly expressed in several cancers. The expression of PD-L1 has been correlated with the progression and poor prognosis of certain types of human malignancies. Tumour-induced PDL1 appears to utilize multiple mechanisms to facilitate the evasion of host immune surveillance, including the promotion of T cell anergy, exhaustion, unresponsiveness and apoptosis, inducing the expansion of Tregs as well as enhancing tumour-intrinsic killing and apoptosis resistance. PD1 inhibitors, as a new class of drugs that block PD1, activate the immune system to attack tumors and are used to treat certain types of cancer.

Mice of BALB/c background can serve as a host and transplant almost all popular syngeneic murine tumor cell lines that currently available (e.g., CT26,4T1,H22,Renca). Additionally, unlike immunodeficiency models such as NCG and NSG, this type of strain has full functional immune system which could mimicking some human immune reactions. Therefore, this BALB/c-hPD1 strain will be a good model for anti-tumor drug evaluation and efficacy test.

GemPharmatech use gene editing technology to developed BALB/c-hPD1 humanized model independently. The coding sequence of extracellular domain of PD1 is replaced with human counterpart on BALB/c background. Intracellular region of murine PD1 was completely retained and normal intracellular signal transduction was guaranteed. hPD1 expression in homozygous BALB/c-hPD1 mice were similar to mPD1 expression in wildtype. These mice are ideal models for anti-PD1 drug evaluation and immunotherapy drug development.


Strategy

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Detection of PD1 expression in BALB/c-hPD1 mice

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Detection of hPD1 expression on BALB/c-hPD1 mice.hPD1 is expressed at comparable level in homo as mPD-1 expressing the wild type mice.

T/B/NK cell assay

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The proportion of T and B cells in spleen of BALB/c-hPD1 mice are similar with wild type, heterozygous and homozygous, and there were no significant difference in CD4+/CD8+ T cells.

In vivo efficacy test

Anti-tumor effect of KEYTRUDA® combination with ENT (mouse colon cancer cell line CT26)

Tumor volume changes of mice in different groups

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Body weight changes of mice in different groups

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BALB/c-hPD1 mice were inoculated subcutaneously with mouse colon cancer CT26 cells for anti-tumor evalution. Data show that 10 mpk KEYTRUDA® combination with 20mpk Entinostat have better anti-tumor effect compared with 10 mpk KEYTRUDA® or 20mpk Entinostat clone. These resultsindicate BALB/c-hPD1 mice are ideal models for anti-tumor efficacy evalution of anti-hPD1 in combination with other drugs.


C57BL/6-hPD1


Strain Name: B6/JGpt-Pdcd1em1Cin(hPDCD1)/Gpt

Strain Type: Knock-in

Strain ID: T003095

Background: C57BL/6JGpt


Application

1. Efficacy evaluation of human PD1 inhibitors

2. Safety assessment of human PD1 inhibitor

3. Research on immune system


Description

PDCD1(Programmed cell death protein 1,PD1),a member of the extended CD28/CTLA-4 family of T cell regulators,is involved in the regulation of T-cell function during immunity and tolerance.

PD1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. PD-L1 is highly expressed in several cancers. The expression of PD-L1 has been correlated with the progression and poor prognosis of certain types of human malignancies. Tumour-induced PDL1 appears to utilize multiple mechanisms to facilitate the evasion of host immune surveillance, including the promotion of T cell anergy, exhaustion, unresponsiveness and apoptosis, inducing the expansion of Tregs as well as enhancing tumour-intrinsic killing and apoptosis resistance. PD1 inhibitors, as a new class of drugs that block PD1, activate the immune system to attack tumors and are used to treat certain types of cancer.

C57BL/6 background can serve as a host and transplant almost all popular syngeneic murine tumor cell lines that currently available (e.g., CT26,4T1,H22,Renca). Additionally, different from immune deficient models such as NCG and NSG, this strain has full functional immune system which could mimicking some human immune reactions. Therefore, this BALB/c-hPD1 strain will be a good model for anti-tumor drug evaluation and efficacy test. 

GemPharmatech use gene editing technology to developed C57BL/6-hPD1 humanized model independently. The coding sequence of extracellular domain of PD1 is replaced with human counterpart on C57BL/6 background. Intracellular region of murine PD1 was completely retained and normal intracellular signal transduction was guaranteed. hPD1 expression in homozygous C57BL/6-hPD1 mice were similar to mPD1 expression in wildtype. These mice are ideal models for anti-PD1 drug evaluation and immunotherapy drug development.


Strategy

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Detection of PD1 expression in B6-hPD1 mice

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B6-hPD1 mice successfully express hPD1 on the surface of T cells, and hPD1 expressive abundance was similar to mPD1 in wild-type mice.

T/B/NK cell ratio assay

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There was no significant difference in T/B/NK cells proportion between wild-type, heterozygous and homozygous mice.

In vivo efficacy test

KEYTRUDA® Drug efficacy test(murine colon cancer cell line MC38)

Tumor volume changes of mice in different groups

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Body weight changes of mice in different groups

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Dose response of KEYTRUDA® on homozygous B6-hPD1 mice bearing murine colon cancer MC38 tumor. Data shown as Mean±SEM


OPDIVO® Drug efficacy test(murine colon cancer cell line MC38)

Tumor volume changes of mice in different groups 

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Body weight changes of mice in different groups

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Dose response of OPDIVO® on homozygous B6-hPD1 mice bearing murine colon cancer MC38 tumor. Data shown as Mean±SEM.


Time:2019-12-10