Human CTLA4
Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) is a critical immune checkpoint receptor and major target for cancer immunotherapy.
Human CTLA4
Function
Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), also known as CD152, is a crucial immune checkpoint receptor that regulates T cell activation and immune tolerance. CTLA4 is expressed on activated T cells and regulatory T cells (Tregs), where it functions as a negative regulator of T cell responses. By competing with the costimulatory receptor CD28 for binding to B7 ligands (CD80 and CD86), CTLA4 delivers inhibitory signals that dampen T cell activation and prevent excessive immune responses.
Mechanism of Action
Immune Checkpoint Function
- Competitive Inhibition: Competes with CD28 for B7-1 (CD80) and B7-2 (CD86) binding
- Signal Transduction: Delivers inhibitory signals through its cytoplasmic domain
- T Cell Regulation: Reduces T cell proliferation, cytokine production, and effector function
- Tolerance Maintenance: Essential for preventing autoimmunity and maintaining self-tolerance
Regulatory T Cell Function
- Treg Development: Important for Treg cell generation and maintenance
- Suppressive Function: Enhances Treg-mediated immune suppression
- Trans-endocytosis: Removes B7 ligands from antigen-presenting cells
- Immune Homeostasis: Maintains balance between immunity and tolerance
Target Details
Therapeutic Significance
Cancer Immunotherapy
CTLA4 was the first immune checkpoint successfully targeted for cancer treatment:
- Ipilimumab: First FDA-approved anti-CTLA4 antibody (2011)
- Tremelimumab: Second-generation anti-CTLA4 antibody
- Mechanism: Blocks CTLA4 inhibitory signals, enhancing anti-tumor T cell responses
- Clinical Success: Significant survival benefits in metastatic melanoma and other cancers
Approved Indications
- Melanoma: First indication, dramatic survival improvements
- Renal Cell Carcinoma: Combination with PD-1 inhibitors
- Hepatocellular Carcinoma: Emerging indication
- Lung Cancer: Non-small cell lung cancer (NSCLC) combinations
- Colorectal Cancer: Microsatellite instability-high (MSI-H) tumors
Combination Therapies
- PD-1/PD-L1 Inhibitors: Synergistic effects with dual checkpoint blockade
- Chemotherapy: Enhanced responses when combined with conventional treatments
- Radiation: Improved abscopal effects
- Vaccines: Enhanced vaccine-induced immune responses
Research Applications
Drug Development
- Next-Generation Inhibitors: Improved selectivity and reduced toxicity
- Agonists: CTLA4 agonists for autoimmune disease treatment
- Bispecific Antibodies: Targeting CTLA4 plus other immune checkpoints
- ADCs: Antibody-drug conjugates for targeted cancer therapy
Biomarker Development
- Predictive Biomarkers: Identifying patients likely to respond to CTLA4 blockade
- Resistance Mechanisms: Understanding why some patients don’t respond
- Toxicity Prediction: Predicting and managing immune-related adverse events
- Combination Strategies: Optimizing dual and triple checkpoint blockade
Basic Research
- T Cell Biology: Understanding T cell activation and tolerance mechanisms
- Autoimmunity: Role of CTLA4 in preventing autoimmune diseases
- Tumor Immunology: Mechanisms of tumor immune evasion and resistance
- Vaccine Development: Enhancing vaccine-induced immunity
Clinical Considerations
Immune-Related Adverse Events (irAEs)
CTLA4 blockade can cause significant autoimmune-like side effects:
- Gastrointestinal: Colitis, diarrhea (most common)
- Dermatological: Rash, pruritus, vitiligo
- Hepatic: Hepatitis, elevated liver enzymes
- Endocrine: Hypophysitis, thyroid dysfunction, adrenal insufficiency
- Neurological: Neuropathy, encephalitis (rare but serious)
Management Strategies
- Early Detection: Regular monitoring for signs of irAEs
- Immunosuppression: Corticosteroids for severe irAEs
- Supportive Care: Symptom-specific treatments
- Treatment Discontinuation: Permanent discontinuation for severe toxicities
Patient Selection
- Biomarker Testing: Tumor mutational burden, microsatellite instability
- Performance Status: Good performance status associated with better outcomes
- Prior Treatments: Response to previous immunotherapies
- Contraindications: Active autoimmune disease, organ transplant recipients
CTLA4 blockade can cause severe and potentially life-threatening immune-related adverse events. Patients require careful monitoring and prompt management of toxicities. Healthcare providers should be experienced in recognizing and treating irAEs.
CTLA4 is available in our target library as both full-length protein and extracellular domain constructs. The extracellular domain is most commonly used for binding studies as it contains the B7 binding site and represents the target for therapeutic antibodies.