RA biologics Flashcards
rational and how the drug works of Adalimumab
rationale
RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
TARGET INFLAMMATION
how the drug works
Neutralising very specific pro-inflammatory signalling molecule called TNF
By creating an antibody that binds to TNF and clears it from circulation
Infliximab and Adalimumab
how are they created
Both TNF inhibitor antibodies BUT differ in origin and sequence:
Infliximab was a mouse antibody, engineered into human IgG sequence to avoid immunogenicity– CHIMERA - XI in name
Adalimumab is (and always was) a human antibody, selected using phage display
HUMAN – U in name
Etanercept - rationale and how the drug works
rationale
RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
TARGET INFLAMMATION
how the drug works
Neutralising very specific pro-inflammatory TNF signal
By taking RECEPTOR for TNF, and cutting the binding domain- to produce soluble high-affinity binding molecule that “mops up” TNF very specifically
Certolizumab pegol (Cimzia)- rationale and how the drug works
how the drug differs
rational
Same as other TNF inhibitors
how the drug works
Neutralising TNF inflammation
how the drug differs
Fragment of antibody that binds to TNF thereby blocking inflammatory signllaing
HOWEVER fragment alone loses the long half-life provided by the full IgG molecule (Fc portion)
PEG chains added to antibody fragment to prolong serum stability
Challenges with TNF neutralising therapy
RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
ONLY addressing the endpoint- not the cause of disease
Specific immunosuppression- dangerous for patients with latent Tuberculosis infection
Healthy, well nourished people can often control- but not eliminate- the Tuberculosis bacterium
TB lives in tiny ‘granulomas’ kept in place by macrophages and ongoing immune response
Immunosupression allows the TB bacteria to escape and grow
TNF neutralisation is therefore potentially lethal for patients with latent tuberculosis
Toxilizumab- rationale and how the drug works
rational
RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
TARGET INFLAMMATION but TNF is not the only inflammatory signalling molecule
Target IL-6 – inhibit another protein involved in inflammatory signalling
how the drug works
Neutralising/blocking signalling by very specific pro-inflammatory molecule called IL-6
By creating antibody that binds to and blocks IL-6 receptor (tocilizumab) (AlSO others which block by binding IL-6 directly siltuximab (Sylvant)
Rituximab rationale and how the drug works
rationale
RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
TARGET AUTOIMMUNE DISEASE PROCESS
how the drug works
Killing B lymphocytes which are involved in autoimmune response
By binding the CD20 molecule only found on surface of B cells, therapeutic mAb targets KILLING
Autoimmune disease – treatment challenges
Unclear fundamental pathogenesis
progressive
characteristically diverse
Trade off between adverse effects and disease severity
Pain and disability
Very many therapeutic options, some similar, some very diverse
Autoimmune disease – treatment challenges
Unclear fundamental pathogenesis
progressive
characteristically diverse
Trade off between adverse effects and disease severity
Pain and disability
Very many therapeutic options, some similar, some very diverse
Autoimmune disease – treatment challenges
Unclear fundamental pathogenesis
progressive
characteristically diverse
Trade off between adverse effects and disease severity
Pain and disability
Very many therapeutic options, some similar, some very diverse
summary
5 examples of biologics used to treat RA
Some have different structure/sequence but same mechanism (target TNF)
Some target different inflammatory signalling molecules (IL-6 instead of TNF)
Other has completely different mechanism of action (depletes B lymphocytes)
Formulation and delivery common- all BIOSYNTHETIC PROTEIN DRUGS
types of antibodies
binding and blocking
Toxins can be bound and inactivated by IgG and IgA
IgG and IgA antibodies can directly block viral infection
direct killing
Antigen bound by IgG and IgM activates ‘complement’ which can punch holes in cell walls
Macrophages are coated with receptors for IgG and rapidly kill antibody bound to CD20 on all B cells
CD20 antigen on ALL B cells bound by anti-CD20 IgG activates killing
(via macrophages, triggering ‘cell suicide’ and possibly also ‘complement’ which can punch holes in cell walls)
