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Human CD40

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Function

CD40 is a type I transmembrane glycoprotein belonging to the tumor necrosis factor receptor (TNFR) superfamily. It serves as a crucial costimulatory receptor expressed primarily on antigen-presenting cells (APCs) including B cells, dendritic cells, and macrophages. CD40 plays essential roles in adaptive immune responses by facilitating communication between T cells and APCs through its interaction with CD40L (CD154) expressed on activated T cells.

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Biological Functions

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B Cell Activation and Development

  • Class Switch Recombination: Essential for immunoglobulin class switching
  • Germinal Center Formation: Required for germinal center development and maintenance
  • B Cell Survival: Provides survival signals to activated B cells
  • Memory B Cell Generation: Important for B cell memory formation

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Dendritic Cell Maturation

  • DC Activation: Promotes dendritic cell maturation and antigen presentation
  • Cytokine Production: Enhances IL-12 production for Th1 differentiation
  • Cross-Presentation: Improves cross-presentation of antigens to CD8+ T cells
  • Migration: Facilitates DC migration to lymph nodes

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Macrophage Activation

  • M1 Polarization: Promotes pro-inflammatory macrophage activation
  • Antimicrobial Activity: Enhances killing of intracellular pathogens
  • Antigen Presentation: Improves macrophage antigen presentation capacity
  • Tissue Repair: Involved in wound healing and tissue remodeling

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Target Details

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Therapeutic Applications

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Cancer Immunotherapy

CD40 agonism represents a promising approach for cancer treatment:

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Mechanism of Action

  • DC Activation: Enhances tumor antigen presentation
  • T Cell Priming: Improves anti-tumor T cell responses
  • Macrophage Repolarization: Converts tumor-associated macrophages to anti-tumor phenotype
  • Tumor Microenvironment: Modifies immunosuppressive tumor environment

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Clinical Development

  • Agonistic Antibodies: CP-870,893, dacetuzumab, lucatumumab
  • CD40L Mimetics: Small molecules and peptides mimicking CD40L
  • Combination Therapies: CD40 agonists with checkpoint inhibitors, chemotherapy
  • Solid Tumors: Pancreatic cancer, melanoma, lymphoma

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Autoimmune Diseases

CD40 blockade is being explored for autoimmune conditions:

  • Rheumatoid Arthritis: Blocking aberrant B cell and macrophage activation
  • Systemic Lupus Erythematosus: Reducing autoantibody production
  • Multiple Sclerosis: Modulating CNS inflammation
  • Transplant Rejection: Preventing graft rejection

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Research Applications

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Vaccine Development

  • Adjuvant Effects: CD40 agonists as vaccine adjuvants
  • Enhanced Immunity: Improving vaccine-induced immune responses
  • Mucosal Immunity: Enhancing mucosal vaccine efficacy
  • Cancer Vaccines: Therapeutic cancer vaccine development

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Immunological Research

  • B Cell Biology: Understanding B cell activation and differentiation
  • T Cell-APC Interactions: Studying immune synapse formation
  • Germinal Center Biology: Investigating antibody affinity maturation
  • Tolerance Mechanisms: Understanding peripheral tolerance breakdown

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Drug Discovery

  • Agonist Development: Small molecule and biological CD40 agonists
  • Antagonist Screening: Inhibitors for autoimmune disease treatment
  • Bispecific Antibodies: CD40-targeted combination therapies
  • Delivery Systems: Targeted drug delivery via CD40

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Clinical Considerations

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CD40 Agonist Therapy

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Potential Benefits

  • Enhanced Anti-Tumor Immunity: Improved T cell and NK cell responses
  • Durable Responses: Potential for immunological memory
  • Combination Potential: Synergy with other immunotherapies
  • Biomarker-Guided: Predictive biomarkers for response

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Safety Concerns

  • Cytokine Release Syndrome: Systemic inflammatory responses
  • Autoimmunity: Risk of autoimmune reactions
  • Hepatotoxicity: Liver inflammation and damage
  • Dosing Challenges: Narrow therapeutic window

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CD40 Antagonist Therapy

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Applications

  • Autoimmune Diseases: Blocking pathogenic immune responses
  • Transplantation: Preventing graft rejection
  • Allergic Diseases: Reducing allergic inflammation
  • Inflammatory Conditions: Treating chronic inflammatory diseases

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Considerations

  • Immunosuppression: Risk of infections and malignancies
  • B Cell Function: Impaired humoral immunity
  • Vaccine Responses: Reduced vaccine efficacy
  • Long-term Effects: Unknown consequences of chronic CD40 blockade

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Biomarker Applications

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Disease Monitoring

  • Soluble CD40: Serum levels correlate with disease activity
  • CD40 Expression: Tissue expression patterns in various diseases
  • Signaling Activity: Downstream pathway activation
  • Response Prediction: Biomarkers for therapy response

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Research Tools

  • Flow Cytometry: CD40 expression analysis
  • Functional Assays: CD40 signaling pathway studies
  • Imaging: CD40 distribution in tissues
  • Proteomics: CD40 interactome analysis

CD40 is available in our target library as both membrane-bound and soluble forms. The extracellular domain construct (Glu 21 - Arg 193) is most commonly used for binding studies and therapeutic development. We also offer CD40L for studying the CD40-CD40L interaction.

CD40 represents both an agonist target (for cancer immunotherapy) and an antagonist target (for autoimmune diseases). When designing binding studies, consider whether you’re developing agonistic or antagonistic molecules, as this will influence your experimental design and interpretation of results.