TIM3 Humanized Mouse Models
TIM3 humanized mice enable preclinical testing of anti human TIM3 therapeutic antibodies in immunocompetent mice for next generation checkpoint immunotherapy development.
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TIM3 in Cancer Immunotherapy
T cell immunoglobulin and mucin domain containing 3 (TIM3, also known as HAVCR2) is an immune checkpoint receptor under active clinical development, with multiple anti TIM3 antibodies in trials for various malignancies.
TIM3 Biology
TIM3 is expressed on multiple immune cell populations and contributes to immune regulation:
T Cell Expression
TIM3 is upregulated on activated and exhausted T cells. Co expression of TIM3 with PD1 marks the most dysfunctional T cell population in chronic infection and cancer.
Innate Immune Cell Expression
TIM3 is constitutively expressed on macrophages, dendritic cells, and mast cells, regulating their inflammatory responses.
NK Cell Expression
TIM3 is expressed on natural killer cells and can inhibit their cytotoxic function.
TIM3 Ligands
TIM3 has multiple ligands affecting its function:
Clinical Anti TIM3 Antibodies
Multiple anti TIM3 antibodies are in clinical development:
Cobolimab (TSR 022)
Anti TIM3 antibody in combination trials with anti PD1
Sabatolimab (MBG453)
Anti TIM3 antibody being evaluated in hematologic malignancies and solid tumors
Additional Candidates
Multiple other anti TIM3 antibodies are in early clinical development
Species Specificity
Clinical anti TIM3 antibodies are designed for human TIM3 and typically do not cross react with mouse Tim3, necessitating humanized models for preclinical evaluation.
TIM3 Humanization Strategies
Complete Gene Replacement
Full replacement of mouse Havcr2 with human HAVCR2 (TIM3) coding sequences:
Endogenous Regulatory Control
Human TIM3 expressed from the native mouse promoter maintains physiological expression patterns.
Functional Preservation
The humanized allele preserves TIM3 function on T cells, NK cells, and myeloid populations.
Extracellular Domain Humanization
Humanization of the extracellular domain provides human epitopes for antibody binding.
Design Considerations
Expression on Multiple Cell Types
TIM3 is expressed on T cells, NK cells, dendritic cells, and macrophages. Humanization should preserve expression across these populations.
Ligand Binding
Consider whether human TIM3 appropriately binds mouse galectin 9 and other ligands.
Signaling Compatibility
Mouse intracellular domains may be retained for compatibility with mouse signaling machinery.
Applications of TIM3 Humanized Mice
Monotherapy Evaluation
- Syngeneic Tumor Models:TIM3 humanized mice combined with syngeneic tumors enable efficacy assessment
- Dose Response:Establish pharmacologically relevant dosing for clinical candidates
- Target Engagement:Measure antibody binding to TIM3 positive cells in tumor and lymphoid tissues
Combination Checkpoint Blockade
- TIM3 plus PD1:The most common combination under investigation. Dual humanized models expressing both human TIM3 and human PD1 enable testing
- TIM3 plus LAG3:Alternative checkpoint combinations
- Triple Combinations:TIM3 plus PD1 plus CTLA4 or other three way combinations
T Cell Exhaustion Studies
- Exhaustion Reversal:Assess whether TIM3 blockade reinvigorates exhausted T cells
- Combination Effects:Evaluate synergy with PD1 blockade in reversing exhaustion
- Phenotypic Analysis:Characterize changes in exhaustion markers following TIM3 blockade
Multi Checkpoint Humanized Models
Combination checkpoint approaches require models expressing multiple human targets:
Dual Humanized Models
| TIM3 plus PD1 | Both checkpoints humanized for testing emerging combinations |
| TIM3 plus LAG3 | For alternative combination studies |
Higher Order Combinations
| TIM3 plus PD1 plus LAG3 | Triple humanization for comprehensive checkpoint blockade studies |
| TIM3 plus PD1 plus CTLA4 | Alternative triple combination |
Model Design Considerations
Background Strain Selection
C57BL/6
Standard background for immuno oncology studies. Compatible with commonly used syngeneic tumor models.
BALB/c
Alternative for specific tumor models.
Syngeneic Tumor Compatibility
TIM3 humanized mice should be crossed to appropriate syngeneic compatible backgrounds:
Expression Validation
Before experimental use, confirm:
Surface Expression
Flow cytometry for human TIM3 on T cells, NK cells, and myeloid populations
Inducible Expression
TIM3 upregulation following T cell activation
Antibody Binding
Clinical candidates bind to humanized TIM3
Phenotyping TIM3 Humanized Models
Immune Characterization
T Cell Populations
Flow cytometry for CD4, CD8 T cells with TIM3 and PD1 co staining
Exhaustion Phenotype
TIM3/PD1 double positive cells represent exhausted population
NK Cell Expression
TIM3 on NK cells
Myeloid Expression
TIM3 on dendritic cells and macrophages
Our Approach to TIM3 Humanized Models
Quality Assurance
ingenious targeting laboratory validates TIM3 humanized models:
- ✓Flow Cytometry: Confirms human TIM3 surface expression
- ✓Functional Testing: Binding of clinical antibody candidates
- ✓Baseline Immune Status: Normal immune development and function
Selected Publications in TIM3 Research
According to PubMed, recent publications demonstrate the importance of TIM3 in checkpoint immunotherapy:
Chen C et al. (2024)
Soluble Tim 3 serves as a tumor prognostic marker and therapeutic target for CD8 T cell exhaustion and anti PD1 resistance
Cell Reports Medicine
Soltantoyeh T et al. (2024)
Simultaneous targeting of Tim3 and A2a receptors modulates MSLN CAR T cell antitumor function in a human cervical tumor xenograft model
Frontiers in Immunology
What Researchers Say
“iTL produced a new conditional mouse model for us and the quality of service was exceptional. The team is extremely knowledgeable and the work was completed at the highest possible standards. My project manager was excellent and always happy to answer technical questions and keep me up to date with progress and potential problems. I would recommend iTL highly and will use them again in the future if I need to generate a new mouse line.”
— Albert Basson, PhD
King's College London
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