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Monoclonal Antibodies (History (Antibody Engineering (Chimeric, Humanized,…

- - - - Bevacizumab + FOLFIRI
        
        metastatic colorectal cancer
      - Trastuzumab + Chemotherapy
        
        Trastuzumab + paclitaxel
        
        advanced breast cancer
        
        metastatic breast cancer
      - Rituximab + chemotherapy
        
        diffuse large B-cell lymphoma
    - - Enhanced anti-tumour immunity
        
        radiation therapy might activate innate immune effector cells through toll-like receptor (TLR)-dependent mechanisms, thereby augmenting the adaptive immune response to cancer
      - Cetuximab + Primary radiotherapy
        
        advanced squamous-cell carcinoma of the head and neck
      - neoadjuvant bevacizumab + Chemoradiotherapy
        
        advanced rectal cancer
    - - Cytokines such as IL-2 and IFNγ have been shown to enhance ADCC by stimulating or expanding NK cells, macrophages and monocytes
      - IL-2 and rituximab
    - - Combination therapy employing monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKI), which act to block activation of intracellular signalling in tumour cells or stromal cells following receptor engagement, has been proposed as an approach to enhance clinical efficacy through more effective cancer-specific signalling perturbation with concurrent activation of immune effector mechanisms.
    - - Given the evidence suggesting that monoclonal antibody therapy can have both direct and indirect effects on the adaptive immune response, combining antibody therapy with vaccination strategies may prove to be efficacious.
      - pre-clinical data support the idea of combining antibodies that target the immunosuppressive tumour microenvironment with vaccination
  - - - targeting epitopes on tumour as well as immune effector cells have long been shown to have equivalent or superior potency as compared to their IgG counterparts
      - host toxicities caused by concurrent T cell costimulation and short half lives
      - BiTE molecules, which employ a new format of bispecific anti-CD3 antibody
        
        BiTE molecules show enhanced tumour cell lysis, high protein stability and efficacy at low T cell to target cell ratio
    - - monomeric proteins or a stably folded extramembrane domain of a surface receptor that is highly stable
        
        designed ankyrin repeat domains (DARPins)
        
        Adnectins, which are composed of the 10th extracellular domain of fibronectin III
- - - - Radioisotopes
      - chemotherapeutic
      - Good against haematological malignancies
    - - Non-Leukaemia cancers
      - Target growth factors receptors
        
        Epidermal growth factor receptor (EGFR)
        
        Epidermal growth factor 2 (HER2)
    - - Slow tumour growth
        
        Enhance host immune response to self-tumour antigens
        
        Curtailing pro-tumourigenic factors
  - - - Examples
        
        EGFR
        
        Panitumumab
        
        Cetuximab
        
        Combination with
        
        5-fluorouracil
        
        irinotecan
        
        Folinic Acid
        
        Block Ligand binding
        
        HER
        
        Block dimerization and internalisation
        
        Trastuzumab
        
        pertuzumab
    - - VEGF
        
        Angiogenesis
        
        Bevacizumab
        
        Ramucirumab antibody against VEFRF2)
      - Counteracting immunosuppressive tumour microenvironments
        
        anti-TGFβ
        
        depletion of TREG cells
        
        daclizumab
    - - Tremelimumab (IgG2 isotype)
      - ipilimumab (IgG1 isotype)
    - - Fc domains with higher affinity for FcγRIIIA
        
        AME-133
        
        ocrelizumab
      - Modification of Fc domain oligosaccharide (Defucosylation)
- - - - IgM, IgD, IgG, IgE and IgA
    - - fragment of antigen binding (Fab)
        
        Variable region
        
        three hypervariable complementarity determining regions (CDRs)
      - constant fragment (Fc)
        
        immune effector functions
        
        complement-dependent cytotoxicity (CDC)
        
        Recruit C1q to initiate complement cascade resulting in tumour cell lysis by the Membrane Attack Complex (MAC)
        
        Chemotaxis
        
        C3a
        
        C5a
        
        Immune cells
        
        macrophages
        
        Neutrophils
        
        Basophils
        
        Mast cells
        
        Eosinophils
        
        binding to Fc γ-receptors (FcγR)
        
        signal transduction
        
        Immunoreceptor Tyrosine-based activation motifs (ITAMs)
        
        FcyRI (CD64)
        
        3 more items...
        
        FcyRIIIA (CD16A)
        
        4 more items...
        
        Immunoreceptor Tyrosine-based inhibitory motifs (ITIMs)
        
        Single chain FcyRIIB (CD32)
        
        Enable recognition by immune effector cells
        
        Cross-linking of FcyRs
        
        Cell destruction
        
        Activation
        
        2 more items...
        
        Induction of T-Ccell immunity
        
        neonatal Fc receptor (FcRn)
        
        Maintenance of serum IgG and contribute to long half-life