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Topic 9 monoclonal antibodies

  • Monoclonal antibodies are a kind of therapeutic class; targeting cancer, autoimmune diseases, and infectious diseases
  • Antibody Structure:
    • consists of variable light (V_L) and heavy (V_H) chains
    • Constant regions (C_L, C_H)
    • and CDRs: determine binding specificity
  • How it works
    • Antagonisms: Blocking receptor-ligand interactions
    • CDC-Complement-dependent cytotoxicity: inducing cell lysis via the complement system
    • ADCC- Antibody dependent cellular cytotoxicity: recruiting effector cells (like NK cells) to kill targets
    • Signaling: inducing direct signaling pathways

mAbs -- Suppressing inflammation

  • this function could be the way to treat autoimmune diseases
  • Example: In MS, activated T-cells (Th1, Th17) and B-cells cross the blood-brain barrier, attacking neurons and oligodendrocytes.
    • Anti-CD20: targets B cells
    • Anti-CD52: Depletes T and B cells
    • Anti-Integrin: Blocks entry into the brain
    • Anti-CD25: targets activated T cells
  • Systemic Lupus Erythematosus
    • Characterized by "butterfly rash" and systemic organ damage caused by autoantibodies. The process is driven by ==apoptotic== material activating dendritic cells (DCs), which then stimulate T and B cells.
    • Target Cytokines: Anti-IFN$\alpha/\beta$ and anti-TNF$\alpha$.
    • Target Co-stimulation: Anti-CD40L to block T-cell help.
    • B-cell survival: Anti-BAFF antibodies to reduce autoantibody production.
    • Could also, expand the active Tregs, to release anti-inflammatory cytokines

mAbs -- Stimulating, enhance inflammation

  • Example: mAbs are used to drive the immune system to attack tumors, counteracting the immunosupressive tumor microenvironment
  • In cancer: suppression of cytotoxic CD8+ T cells, by reducing MHC expression, increasing inhibitory molecules ==PD-L1==, increasing suppressor cells like ==Tregs and M2 macrophages==
  • mAbs block inhibitory signals to ==restore T-cell cytotoxicity==:
    • Anti-PD-L1: block interaction between the tumor and the T cell
    • Anti-CTLA-4: block the inhibitory signalling during T cell activation