B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice

C57BL/6-Pdcd1tm3(PDCD1)Bcgen Cd274tm1(CD274)Bcgen Vegfatm1(VEGFA)Bcgen Ctla4tm1(CTLA4)Bcgen/Bcgen • 114147

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B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice

Catalog Number: 114147
Strain Name: C57BL/6-Pdcd1tm3(PDCD1)Bcgen Cd274tm1(CD274)Bcgen Vegfatm1(VEGFA)Bcgen Ctla4tm1(CTLA4)Bcgen/Bcgen
Strain Background: C57BL/6
NCBI gene ID: 5133,29126,7422,1493 (Human)
Aliases: ADMIO4, AIMTBS, CD279, PD-1, PD1, SLEB2, hPD-1, hPD-l, hSLE1; ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1, PDL1, hPD-L1; L-VEGF, MVCD1, VEGF, VPF; ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4, GSE, IDDM12
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B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice

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  • Description
  • Targeting strategy
  • Phenotypic analysis

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      Description

      PD-1 & PD-L1: An immune-checkpoint and tumor-associated target for therapeutic intervention

      • Gene Information: PD-1 is encoded by the PDCD1 gene on chromosome 2q37.3, while PD-L1 is encoded by CD274 on chromosome 9p24.1. Both are type I transmembrane proteins; PD-1 belongs to the immunoglobulin superfamily and functions as an inhibitory receptor, whereas PD-L1 is a member of the B7 family of co-stimulatory molecules.
      • Protein Expression: PD-1 is primarily expressed on activated T cells, B cells, and NK cells, whereas PD-L1 is expressed on antigen-presenting cells and many tumor cells, with expression often induced by IFN-γ.
      • Signaling Pathway: Binding of PD-L1 to PD-1 recruits SHP2 phosphatase and suppresses TCR/CD28-mediated PI3K–AKT signaling, resulting in reduced T-cell proliferation, cytokine production, and cytotoxic activity.
      • Therapeutic Inhibition: Anti-PD-1 and anti-PD-L1 antibodies block this inhibitory pathway, restoring T-cell function and enhancing anti-tumor immune responses.、

      VEGFA: a master regulator of angiogenesis and therapeutic intervention 

      • Gene Information: VEGFA is a protein-coding gene located on chromosome 6p21.1. It encodes a potent angiogenic growth factor that belongs to the PDGF/VEGF family, with multiple isoforms generated by alternative splicing.
      • Protein Expression: VEGFA is secreted by tumor cells, cancer-associated fibroblasts, tumor-infiltrating macrophages, and endothelial cells themselves. Its expression is strongly upregulated by hypoxia, oncogenic mutations, and inflammatory mediators such as IL-6 and TGF-β, creating a pro-angiogenic gradient within the tumor microenvironment.
      • Signaling Pathway: VEGFA binds with high affinity to receptor tyrosine kinases VEGFR-1 and VEGFR-2 on endothelial cells. This drives endothelial cell proliferation, migration, tube formation, vascular permeability, and survival. Additionally, VEGFA promotes the recruitment of immunosuppressive cells and upregulates PD-L1 on endothelial and tumour cells, directly linking angiogenesis to immune evasion.
      • Therapeutic Inhibition: Anti-VEGFA monoclonal antibodies and small-molecule multikinase inhibitors targeting VEGFRs block ligand-receptor binding or downstream kinase activity.
      CTLA4: A key immune checkpoint in T-cell regulation and its therapeuticintervention
      • Gene Information: Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) isa protein-coding gene located on chromosome 2q33.2. It encodes animmune receptor belonging to the immunoglobulin superfamily, which isstructurally homologous to the co-stimulatory molecule CD28.
      •  Protein Expression: CTLA4 is primarily expressed on activated T cells andregulatory T cells (constitutively in Tregs), and is transiently upregulated onconventional T cells following TCR engagement. The protein exists mainly asa membrane-bound form
      • Signaling Pathway: CTLA4 inhibits T-cell activation by competing withCD28 for B7 ligands and recruiting phosphatases to dampen TCR/CD28signaling, thereby suppressing proliferation and cytokine production.
      • Therapeutic Inhibition: By blocking TSLP binding to its receptor,tezepelumab inhibits downstream inflammation and improves clinicaloutcomes, including reduced serum IgE levels, decreased airway eosinophils,reduced mucus production, and lowered cytokine secretion.
      Targeting Strategy

      PD-1

      •  A chimeric CDS that encodes human PDCD1 extracellular domain, mouse Pdcd1 transmembrane and cytoplasmic domain, followed by WPRE-pA is inserted right after mouse Pdcd1 ATG to replace the exon 1 of mouse Pdcd1 gene.

      PD-L1

      • The exon 3 of mouse Cd274 gene that encodes the IgV domain was replaced by human CD274 exon 3. Sequences of other regions still belonged to mice.

      VEGFA

      • The exons 1-8 of mouse Vegfa gene that encode the full-length protein were replaced by human VEGFA exons 1-8 in B-hPD-1plus/hPD-L1/hVEGFA/hCTLA4 mice.

      CTLA4

      • The exon 2 of mouse Ctla4 gene that encode the extracellular domain was replaced by human CTLA4 exon 2 in B-hPD-1plus/hPD-L1/hVEGFA/hCTLA4 mice.
      PD-1 Protein Expression Analysis in Spleen

      Strain specific PD-1 expression analysis in wild-type C57BL/6JNifdc mice and homozygous B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice by flow cytometry. Splenocytes were collected from wild-type C57BL/6JNifdc mice (+/+) and B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice (H/H) (Female, 9-week-old, n=1) unstimulated or stimulated with anti-mouse CD3ε antibody (7.5 μg, i.p.) in vivo for 24 hrs. Protein expression was analyzed with anti-human PD-1 antibody (Biolegend, 329908) and anti-mouse PD-1 antibody (Biolegend, 109104) by flow cytometry.

      PD-L1 Protein Expression Analysis in Spleen

      Strain specific PD-L1 expression analysis in wild-type C57BL/6JNifdc mice and homozygous B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice by flow cytometry. Splenocytes were collected from wild-type C57BL/6JNifdc mice (+/+) and B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice (H/H) (Female, 9-week-old, n=1) unstimulated or stimulated with anti-mouse CD3ε antibody (7.5 μg, i.p.) in vivo for 24 hrs. Protein expression was analyzed with anti-human PD-L1 antibody (Biolegend, 329706) and anti-mouse PD-L1 antibody (Biolegend, 124312) by flow cytometry.

      CTLA4 Protein Expression Analysis in Spleen

      Strain specific CTLA4 expression analysis in wild-type C57BL/6JNifdc mice and homozygous B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice by flow cytometry. Splenocytes were collected from wild-type C57BL/6JNifdc mice (+/+) and B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice (H/H) (Female, 9-week-old, n=1) unstimulated or stimulated with anti-mouse CD3ε antibody (7.5 μg, i.p.) in vivo for 24 hrs. Protein expression was analyzed with anti-human CTLA4 antibody (Biolegend, 349906) and anti-mouse CTLA4 antibody (Biolegend, 106305) by flow cytometry.

      VEGFA Protein Expression Analysis in Lung

      Strain specific VEGFA expression analysis in wild-type C57BL/6JNifdc mice and homozygous humanized B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice by ELISA. Lung tissue homogenate was collected from wild-type C57BL/6JNifdc mice (+/+) (Female, n=3, 6-week-old) and homozygous B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice (H/H) (Female, n=3, 6-week-old). Expression level of mouse and human VEGFA were analyzed by ELISA (anti-mouse VEGFA antibody: R&D, MMV00; anti-human VEGFA antibody: R&D, DVE00).

      * When publishing results obtained using this animal model, please acknowledge the source as follows: The animal model [B-hPD-1 plus/hPD-L1/hVEGFA/hCTLA4 mice] (Cat# 114147) was purchased from Biocytogen.