Humanized Immune Checkpoint Models
Why Humanize Checkpoints
Many therapeutic antibodies targeting immune checkpoints are designed specifically for human proteins and show limited or no cross reactivity with mouse orthologs. Humanized checkpoint models express human versions of these targets, enabling:
Single vs Dual Humanization
Single humanization
One checkpoint target humanized for monotherapy studies
Dual humanization
Two checkpoints humanized (e.g., PD1 + CTLA4) for combination studies
Multi target
Three or more checkpoints for complex combination evaluation
Available Checkpoint Targets
| Target | Function | Therapeutic Applications |
|---|---|---|
| PD1 (PDCD1) | T cell inhibitory receptor | Anti PD1 antibody efficacy |
| PDL1 (CD274) | PD1 ligand on tumor/immune cells | Anti PDL1 antibody efficacy |
| CTLA4 | T cell inhibitory receptor | Anti CTLA4 efficacy, combinations |
| LAG3 | T cell exhaustion marker | LAG3 inhibitor evaluation |
| TIM3 (HAVCR2) | T cell exhaustion marker | TIM3 pathway studies |
| TIGIT | NK and T cell inhibitory receptor | TIGIT inhibitor development |
| GITR | Costimulatory receptor | Agonist antibody evaluation |
| OX40 | Costimulatory receptor | Agonist antibody evaluation |
| 4-1BB (CD137) | Costimulatory receptor | Agonist antibody evaluation |
Genetic Tumor Models
Tumor Suppressor Knockouts
Conditional knockout of tumor suppressors enables controlled tumor development in immunocompetent hosts:
Oncogene Activation Models
Conditional expression of activated oncogenes enables controlled tumor initiation:
Combining Genetic Models with Checkpoint Humanization
Genetic tumor models can be combined with humanized checkpoint alleles to create sophisticated platforms for immunotherapy evaluation: autochthonous tumors in checkpoint humanized hosts, spontaneous tumor development with human checkpoint targets, and physiologically relevant tumor microenvironment.
Syngeneic Tumor Models
Syngeneic tumor cells transplanted into checkpoint humanized mice enable rapid evaluation of clinical antibody candidates:
| Cell Line | Tumor Type | Background | Common Applications |
|---|---|---|---|
| MC38 | Colon carcinoma | C57BL/6 | Checkpoint inhibitor efficacy |
| CT26 | Colon carcinoma | BALB/c | Immunotherapy combinations |
| B16 | Melanoma | C57BL/6 | Immunotherapy, checkpoint studies |
| LLC | Lung carcinoma | C57BL/6 | Metastasis, immunotherapy |
| 4T1 | Breast carcinoma | BALB/c | Metastatic disease, immunotherapy |
| EMT6 | Breast carcinoma | BALB/c | Immunotherapy response |
Model Types for Immuno-Oncology
Humanized Knockin Models
Humanized checkpoint knockins replace mouse genes with human orthologs at the endogenous locus:
- Physiological expression levels
- Normal tissue distribution
- Endogenous regulatory control
- Maintained immune system function
Conditional Knockout Models
Conditional knockouts enable tissue specific or temporal gene manipulation:
- Immune cell specific deletions (T cell, B cell, myeloid)
- Tumor cell specific deletions
- Inducible knockouts modeling therapeutic intervention
- Target validation through genetic ablation
Reporter Models
Reporter knockins enable visualization and tracking of immune cells:
- Fluorescent reporters for immune cell tracking
- Luciferase reporters for in vivo imaging
- Lineage tracing of tumor infiltrating lymphocytes
- Real time monitoring of immune activation
Research Applications
Therapeutic Antibody Development
- Anti checkpoint antibody efficacy testing
- Agonist antibody evaluation
- Antibody effector function studies
- Combination therapy optimization
- Dose response and scheduling studies
Mechanism of Action Studies
- T cell exhaustion and reinvigoration
- Tumor microenvironment dynamics
- Resistance mechanism identification
- Biomarker discovery and validation
Combination Immunotherapy
- Checkpoint combinations (PD1 + CTLA4)
- Checkpoint plus chemotherapy
- Checkpoint plus targeted therapy
- Checkpoint plus radiation
Selected Publications
Models generated by ingenious targeting laboratory have supported immuno oncology research:
Mlynarczyk C et al. (2023).
BTG1 mutation yields supercompetitive B cells primed for malignant transformation. ↗Science 379(6629): eabj0412
Clausen BE et al. (1999).
Conditional gene targeting in macrophages and granulocytes using LysMcre mice. ↗Transgenic Research 8(4): 265-277
Chakrabarti S et al. (2024).
Touch sensation requires the mechanically gated ion channel ELKIN1. ↗Science 383(6686): 992-998
What Researchers Say
“I'd like to thank the ingenious team for making this mouse for us. We are so excited! Everyone at ingenious has been wonderful to work with throughout the entire process. We will definitely be in contact the next time we need a mouse!”
— Julia Maxson, PhD
Knight Cancer Institute, Oregon Health & Science University
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Our scientific consultants are ready to discuss your immuno oncology research requirements and recommend the optimal model design for your therapeutic program. Initial consultation is provided at no charge and includes target analysis, checkpoint humanization strategy, and timeline estimates.
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