Preclinical Humanized VISTA Mouse Model

Humanized Immune Checkpoint Mouse Models

Design of the hVISTA mouse

The humanized VISTA mouse model (hVISTA) is developed by Knockin at the mouse VISTA locus, and expresses a chimeric VISTA with a human extracellular, human transmembrane and murine intracellular domain.

The design also gives access to VISTA conditional Knockout mice for a tissue-specific assessment of compounds’ specificity and toxicity.

Applications in immuno-oncology

The hVISTA mouse enables the in vivo efficacy assessment and profiling of immuno-oncology agents targeting the human immune checkpoint VISTA in fully immunocompetent mice.

Access to conditional VISTA Knockout mouse:
The conditional Knockout model allows the tissue-specific assessment of compounds’ specificity and toxicity.

hVISTA mice were crossed with hPD-1 mice (hPD-1/hVISTA):
This double-humanized hPD1/hVISTA model enables assessment of both compounds targeting human VISTA and/or human PD‑1 in immunocompetent mice.

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hVISTA features

The VISTA extracellular domain is entirely humanized
Physiological regulation and expression pattern of the human VISTA
Fully functional mouse immune system
Lack of expression of the murine target gene, thus avoiding cross-reactivity

hVISTA validation*

The model has been co-validated by BMS, our partner of the precompetitive consortium of company leaders in immuno-oncology and immunotherapy.

A scientific poster was presented at the Tumour Models 2019 in Boston. Download poster

hVISTA ICP model validation 1

hVISTA expression pattern recapitulates mVISTA

hVISTA and mVISTA expression on freshly isolated splenocytes on A) Tregs, B) CD11b^High, C) conventional CD4 (CD4conv), and D) CD8 T cells. VISTA is not detected on cells from VISTA Knockout homozygous mice.

hVISTA ICP model validation 2

Anti-tumor effects in response to anti-human VISTA + anti-mouse PD-1 treatment

Mice of indicated genotype were inoculated with MC38 tumor cells s.c. and treated αKLH (control), αmPD-1, αhVISTA or αmPD-1 + αhVISTA (combination). Tumor volume measurement in A) wild-type and B) hVISTA Knockin (KI) homozygous mice at different time points. Results are expressed as mean±SEM. C) Survival of treated hVISTA KI homozygous mice analyzed up to 50 days post MC38 tumor inoculation.

* For more validation data please contact us.

References

ElTanbouly MA, Zhao Y, Nowak E, Li J, Schaafsma E, Le Mercier I, Ceeraz S, Lines JL, Peng C, Carriere C, Huang X, Day M, Koehn B, Lee SW, Silva Morales M, Hogquist KA, Jameson SC, Mueller D, Rothstein J, Blazar BR, Cheng C, Noelle RJ.
VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance.
Science. 2020 Jan.

Johnston RJ, Su LJ, Pinckney J, Critton D, Boyer E, Krishnakumar A, Corbett M, Rankin AL, Dibella R, Campbell L, Martin GH, Lemar H, Cayton T, Huang RY, Deng X, Nayeem A, Chen H, Ergel B, Rizzo JM, Yamniuk AP, Dutta S, Ngo J, Shorts AO, Ramakrishnan R, Kozhich A, Holloway J, Fang H, Wang YK, Yang Z, Thiam K, Rakestraw G, Rajpal A, Sheppard P, Quigley M, Bahjat KS, Korman AJ.
VISTA is an acidic pH-selective ligand for PSGL-1.
Nature. 2019 Oct.