AUTO - B. BIOLOGICS-COVERED Flashcards
what is a biologic or biopharmaceutical
medicinal product whose synthesis, extraction or manufacture involves living sources (human, animal, microbiological)
includes:
- protein based therapies
- gene and cellular therapies, stem cells, transplantation
- vaccines
- blood products for transfusion
- diagnostic reagents (eg - allergens)
insulin (biologic)
- initial from bovine/porcine pancreas
- then by recombinant DNA technology to make recombinant proteins for human version of insulin
Replacing endogenous hormone so more selective effect than pig/cow version
but
Injection rather than oral
formulation/stability
risk of immunogenicity (allergic reaction)
protein therapeutics
Theralizumab TGN1412 (mAb against CD28 protein on T-cell)
- anti-CD28 antibody activates T-cells without activation of T-cell receptor (superagonist)
- low dose in clinical trial
- immediate adverse effects due to cytokines from activated t-cells (cytokine storm)
- multiple organ malfunction
Polyclonal antibodies
- many different IgG molecules with high affinity for antigen purified from serum after immunisation
- interact with different epitopes on the same antigen
Monoclonal antibodies
- IgG producing B-cells isolated from immunised mouse, producing identical IgG molecules
- interact with a particular epitope on the antigen
*current therapeutic antibodies are monoclonal (-mab)
mechanism of action of antibodies
- bind to receptor (prevent agonist binding) ie - act as antagonist
- bind to endogenous ligand (prevent it binding to receptor)
- bind to receptor (activate receptor) ie - act as agonist: autoimmune
- biphasic antibodies (target immune system eg - to cancer cells)
bind to 1 protein on immune cell ie natural killer and specific protein on cancer cell
brings mAb to cancer cell so NK cell can attack cancer cell presenting cancer specific protein - direct cytotoxic drug to cancer cell
mAb bound to cancer-specific protein and then attach cytotoxic drug to other end of Ab
cytotoxic drug directed more selectively to cancer cell
TNF-alpha blocking
- TNF-alpha is a major cytokine
- blocking action of TNF-alpha will inhibit inflammation
Anti TNF-alpha therapy
Adalinumab (Humira)
- 40 mg sc alternate weeks
Infliximab (Remicade)
- 3mg/kg iv at 2,6,8 weeks
Etanercept (Enbrel)
- 25mg sc twice weekly
(fusion protein so will be broken down quicker)
Targeting IL-6 (cytokine)
- IL-6 binds to soluble IL-6 receptor
- IL-6 bound IL-6 receptor interacts with gp130 on cell membrane
- activates inflammation pathways - cytokine storm
Tocilizumab and Sarilumab
- bind to soluble IL-6 receptor
- prevents binding of IL-6
- so gp130 not activated and can’t signal transduction
- used in RA
Tocilizumab - COVID19
- severe COVID infection may lead to cytokine storm
- due to T-cells/neutrophils driven by IL6 release
- tocilizumab blocks IL-6 receptor signalling
- prevents cytokine storm
Siltuximab, Sirukumab, Clazakizumab
- binds to IL-6 to prevent interaction with IL-6 receptor
Olamkicept
- recombinant protein
extracellular portion of gp130 fused to Fc (constant portion) of a human IgG antibody which binds to IL-6 and prevents it activating gp130 - binds to IL-6/soluble IL-6 receptor complex to prevent it binding to gp130
Olokizumab
- binds to IL-6 to prevent it binding to gp130
Abatacept - same aa sequence as CTLA-4, recombinant protein
- co-stimulation by binding of MHC complex and CD80/86 protein required for T-cell activation
- Abatacept blocks CD80/86 binding to CD28
- fusion protein
- CTLA-4 analogue which binds to CD80/86 and prevents receptors interacting, T-cell not activated
- RA
- not recommended - cost
