bDMARDS Flashcards
What does bDMARDS stand for
biologic disease modifying anti rheumatic drugs
what are bDMARDs approved for
approved for use against RA
- can be TNFa antagonists or work on other targets
give examples of bDMARDs that are TNFa antagonists
etanercept, infliximab, adalimumab
give examples of bDMARDs that act on other targets
rituximab- CD20
what do the TNFa inhibitors target
target soluble TNFa or cellular TNFa receptors
describe the structures of adalimumab, infliximab and golimumab
- these 3 TNFa inhibitors are structurally all produced as recombinant, glycolated, full length IgG monoclonal antibodies
- in contrast to etanercept and certolizumab pegol, these drugs are all full length Mabs
how do adalimumab, infliximab and golimumab work
- like etanercept and certolizumab pegol, they bind to TNFa and prevent it signalling through its cellular TNF receptors, TNFR1 and TNFR2
what is the structure of infliximab
- a purified recombinant chimeric human mouse IgG Mab
- mouse heavy and light chain variable regions and human heavy and light chain constant regions
what does infliximab have a greater risk of
greater risk of inducing anti drug antibodies than adalimumab and golimumab
what is the structure of adalimumab
- first fully human mab approved for use by FDA
what is the structure of golimumab
fully human mab
what is humira
human monoclonal antibody in RA
What is the mechanism of action of monoclonal antibodies in RA
- neutralise TNFa by binding with high affinity to both soluble and transmembrane TNFa, plus TNF bound to the soluble form of TNF receptors
what is the primary mechanism of action of monoclonal antibodies
blocking cytokine signalling
what is the secondary mechanism of action of monoclonal antibodies
1.Fc domain binds to FcY receptors on immune cells, signalling them for destruction by killer cells through antibody dependent cellular cytotoxicity (ADCC)
2. or, Fc domain binds to fix complement, activating complement mediated lysis
what is certolizumab pegol (cimzia)
a modified antibody fragment
explain how certolizumab pegol works
- it is composed of the antibody binding fragment (Fab) of a humanised monoclonal antibody against TNF
- this is conjugated to polyethylene glycol which:
- increases its plasma half life to 14 days, allowing fortnightly sc use
- increases bioavailability
- increases drug stability and retention time by reducing renal clearance, proteolysis and immunogenicity - like other TNF antagonists, cimzia binds to soluble and membrane bound TNFa, inhibiting its proinflammatory actions
what are the benefits of cimzia
- has no Fc domain, so cannot fix complement or trigger ADCC
- makes it less immunogenic than full length mabs, so reduces immune related side effects - doesn’t appear to cross placenta so can be used by pregnant and breastfeeding women
what is pegylation
the process of covalent or non covalent attachment of polyethylene glycol to a drug which is then described as PEGylated
what are the advantages of pegylation
- covalent attachment of PEG to a therapeutic protein such as certolizumab pegol can mask the drug from immune surveillance, reducing immunogenicity and increasing its hydrodynamic size
- prolonging its plasma half life by reducing renal clearance - PEG is an attractive polymer for conjugation as it enhances water solubility of the conjugate, gives high drug mobility in solution and has low inherent toxicity and immunogenicity
describe the use of full length antibody fragments in therapy
- big IgG molecules may have trouble penetrating into an inflamed knee joint
- full size anti TNFa IgG has a distribution volume of 0.03-0.08L/kg
- but a single domain equivalent has a 10x greater value
- there is some evidence that cimzia shows enhanced penetration
what is etanercept
a recombinant form of the soluble TNFR2 soluble receptor
- binds TNFa 1000x more strongly than native monomeric receptor
describe the effects of etanercept
- fusion of the IgG Fc domain with p75 greatly extended the drugs half life in the bloodstream, over p75 alone and provided more profound and long lasting biological effect than the naturally occurring soluble TNFa receptor
- the dimeric form of the TNFR2 based fusion protein has more enhanced activity compared to monomeric form
how is etanercept different to adalimumab, infliximab and golimumab
doesn’t bind to transmembrane TNFa or TNFa bound to the soluble form of the TNFa receptors
- can’t target the cells for lysis
how does etanercept prevent RA
by binding to and inactivating soluble TNFa in the circulation
- TNFa can’t bind to its cellular receptors and trigger proinflammatory responses
what is tocilizumab
a full size, humanised IgG mab with high affinity for IL6 receptors
how is tocilizumab useful in RA
- Autoimmune diseases are associated with abnormally high IL6 levels
- by binding to both soluble and cell surface membrane bound receptors, tocilizumab prevents IL6 from exerting its proinflammatory effects
how is tocilizumab useful in RA
- Autoimmune diseases are associated with abnormally high IL6 levels
- by binding to both soluble and cell surface membrane bound receptors, tocilizumab prevents IL6 from exerting its proinflammatory effect
when is tocilizumab generally used
generally only used after failure of 1 or more TNF inhibitor biologics
what is sarilumab
a full size IgG mab with high affinity for IL6 receptors, but it is fully human
how does sarilumab work
identical mechanism of action to tocilizumab and can be used with or without methotrexate
- treatment should be interrupted in patients who develop serious infections until the infection is under control
- dose may need to be lowered in patients with abnormal blood tests
what is rituximab
a mouse/human chimeric antibody that binds to CD20
what is CD20
a receptor expressed on the surface of mature B cells
what is the role of rituximab
causes a selective depletion of the CD20+ B cell population
what is the mechanism of action of rituximab
- kills target CD20 B cells via complement and antibody mediated cytotoxicity
- induces programmed cell death- apoptosis
- this eliminates B cells from body, allowing a new population of healthy B cells to arise from lymphoid stem cells
- but may make patients prone to opportunistic infections - like abatacept, modulates the immune system by targeting and destroying normal or malignant immune cells
- like infliximab, adalimumab and golimumab, has a Fc domain that can fix complement and bind to cell surface FcY receptors to trigger ADCC or complement dependent cytotoxicity in vivo of CD20 B cells
what is abatacept
a fusion protein consisting of the external domain of CTLA 4 fused to fully human IgG Fc
- targets receptor on APCs
what is CTLA-4
an antagonist of the T cell co-stimulatory molecule CD28 and when bound to CD80/86, down regulates T cell activation
what is the role of abatacept
shown to reduce T cell proliferation with a concomitant inhibition of proinflammatory cytokines, TNFa, interferon y and IL2
how are naive T cells activated
- naive T cells are activated by 2 signals provided by the APC
- 1st signal is that between the major histocompatibility complex on surface of APC which presents a polypeptide fragment to the T cell receptor
- 2nd signal is a co-stimulatory signal provided when the CD80/86 ligand on the APC binds to CD28 on the T cell
What is the mechanism of action of abatacept
abatacept binds to the CD80/86 ligand, preventing its interaction with CD28
- so the costimulatory signal is not provided, the T cell is not activated and the adaptive immune system damped down
outline the pharmacokinetic properties of bDMARDS
- can be administered IV, IM or SC
- oral administration is precluded by their large size, hydrophilicity and gastric degradation of proteinaceous drugs
- have difficulty entering their target tissues and cells - Sc, bDMARDs are slowly absorbed from site of injection
- due to their large size, glomerular filtration in kidneys or metabolism in liver contributes very little to their removal from circulation
- BDMARDs based on full size antibodies and the fusion proteins all contain a glycosylated IgG Fc domain which binds to the cellular neonatal Fc receptor and limits degradation
- such protection is enhanced by the glycosylation of the IgG domain or pegylation
- makes such proteins poor targets for proteolysis and reduces their access to metabolising enzymes - this explains the long elimination half lives and slow clearance
what are the main pharmacokinetic trends of bDMARDs
- time taken to reach peak serum concentration is measured in days rather than hours
- these drugs distribute slowly - Max values for sc administration at Max vary between 2-50um/ml
- bioavailability for sc administration of mabs and fusion proteins is between 51-80%
- with exception of etanercept, long serum half life and slow clearance of these drugs means most can be administrated sc every 2-4 weeks or longer
how are fully murine mAbs indicated in monoclonal antibody nomenclature
by -o- inserted into the non proprietary name
- ibritum-o-mab
- if murine constant region (Fc) is replaced by human Fc to form chimeric antibody, -xi- is inserted into non proprietary name
- infli-xi-mab
how are humanised mAbs indicated in monoclonal antibody nomenclature
- if parts of the variable domain are replaced by human portions, humanised antibodies are obtained
- indicated by using -zu-
- tocili-zu-mab - a fully human mab is indicated by -u-
- adalim-u-mab
describe the role of antibody Fc fragment
- Fc fragment of a full length antibody binds to various cell receptors and complement proteins
- in this way, it mediates the different physiological effects of antibodies
- eg. IgG binds to pathogens via Fab
