bDMARDS

Question 1

What does bDMARDS stand for

Answer 1

biologic disease modifying anti rheumatic drugs

Question 2

what are bDMARDs approved for

Answer 2

approved for use against RA
- can be TNFa antagonists or work on other targets

Question 3

give examples of bDMARDs that are TNFa antagonists

Answer 3

etanercept, infliximab, adalimumab

Question 4

give examples of bDMARDs that act on other targets

Answer 4

rituximab- CD20

Question 5

what do the TNFa inhibitors target

Answer 5

target soluble TNFa or cellular TNFa receptors

Question 6

describe the structures of adalimumab, infliximab and golimumab

Answer 6

1. these 3 TNFa inhibitors are structurally all produced as recombinant, glycolated, full length IgG monoclonal antibodies
2. in contrast to etanercept and certolizumab pegol, these drugs are all full length Mabs

Question 7

how do adalimumab, infliximab and golimumab work

Answer 7

1. like etanercept and certolizumab pegol, they bind to TNFa and prevent it signalling through its cellular TNF receptors, TNFR1 and TNFR2

Question 8

what is the structure of infliximab

Answer 8

1. a purified recombinant chimeric human mouse IgG Mab
   - mouse heavy and light chain variable regions and human heavy and light chain constant regions

Question 9

what does infliximab have a greater risk of

Answer 9

greater risk of inducing anti drug antibodies than adalimumab and golimumab

Question 10

what is the structure of adalimumab

Answer 10

1. first fully human mab approved for use by FDA

Question 11

what is the structure of golimumab

Answer 11

fully human mab

Question 12

what is humira

Answer 12

human monoclonal antibody in RA

Question 13

What is the mechanism of action of monoclonal antibodies in RA

Answer 13

1. neutralise TNFa by binding with high affinity to both soluble and transmembrane TNFa, plus TNF bound to the soluble form of TNF receptors

Question 14

what is the primary mechanism of action of monoclonal antibodies

Answer 14

blocking cytokine signalling

Question 15

what is the secondary mechanism of action of monoclonal antibodies

Answer 15

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

Question 16

what is certolizumab pegol (cimzia)

Answer 16

a modified antibody fragment

Question 17

explain how certolizumab pegol works

Answer 17

1. it is composed of the antibody binding fragment (Fab) of a humanised monoclonal antibody against TNF
2. 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
3. like other TNF antagonists, cimzia binds to soluble and membrane bound TNFa, inhibiting its proinflammatory actions

Question 18

what are the benefits of cimzia

Answer 18

1. 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
2. doesn’t appear to cross placenta so can be used by pregnant and breastfeeding women

Question 19

what is pegylation

Answer 19

the process of covalent or non covalent attachment of polyethylene glycol to a drug which is then described as PEGylated

Question 20

what are the advantages of pegylation

Answer 20

1. 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
2. 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

Question 21

describe the use of full length antibody fragments in therapy

Answer 21

1. big IgG molecules may have trouble penetrating into an inflamed knee joint
2. 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

Question 22

what is etanercept

Answer 22

a recombinant form of the soluble TNFR2 soluble receptor
- binds TNFa 1000x more strongly than native monomeric receptor

Question 23

describe the effects of etanercept

Answer 23

1. 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
2. the dimeric form of the TNFR2 based fusion protein has more enhanced activity compared to monomeric form

Question 24

how is etanercept different to adalimumab, infliximab and golimumab

Answer 24

doesn’t bind to transmembrane TNFa or TNFa bound to the soluble form of the TNFa receptors
- can’t target the cells for lysis

Question 25

how does etanercept prevent RA

Answer 25

by binding to and inactivating soluble TNFa in the circulation - TNFa can't bind to its cellular receptors and trigger proinflammatory responses

Question 26

what is tocilizumab

Answer 26

a full size, humanised IgG mab with high affinity for IL6 receptors

Question 27

how is tocilizumab useful in RA

Answer 27

1. Autoimmune diseases are associated with abnormally high IL6 levels 2. by binding to both soluble and cell surface membrane bound receptors, tocilizumab prevents IL6 from exerting its proinflammatory effects

Question 28

how is tocilizumab useful in RA

Answer 28

1. Autoimmune diseases are associated with abnormally high IL6 levels 2. by binding to both soluble and cell surface membrane bound receptors, tocilizumab prevents IL6 from exerting its proinflammatory effect

Question 29

when is tocilizumab generally used

Answer 29

generally only used after failure of 1 or more TNF inhibitor biologics

Question 30

what is sarilumab

Answer 30

a full size IgG mab with high affinity for IL6 receptors, but it is fully human

Question 31

how does sarilumab work

Answer 31

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

Question 32

what is rituximab

Answer 32

a mouse/human chimeric antibody that binds to CD20

Question 33

what is CD20

Answer 33

a receptor expressed on the surface of mature B cells

Question 34

what is the role of rituximab

Answer 34

causes a selective depletion of the CD20+ B cell population

Question 35

what is the mechanism of action of rituximab

Answer 35

1. kills target CD20 B cells via complement and antibody mediated cytotoxicity 2. induces programmed cell death- apoptosis 3. 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 4. like abatacept, modulates the immune system by targeting and destroying normal or malignant immune cells 5. 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

Question 36

what is abatacept

Answer 36

a fusion protein consisting of the external domain of CTLA 4 fused to fully human IgG Fc - targets receptor on APCs

Question 37

what is CTLA-4

Answer 37

an antagonist of the T cell co-stimulatory molecule CD28 and when bound to CD80/86, down regulates T cell activation

Question 38

what is the role of abatacept

Answer 38

shown to reduce T cell proliferation with a concomitant inhibition of proinflammatory cytokines, TNFa, interferon y and IL2

Question 39

how are naive T cells activated

Answer 39

1. 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

Question 40

What is the mechanism of action of abatacept

Answer 40

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

Question 41

outline the pharmacokinetic properties of bDMARDS

Answer 41

1. can be administered IV, IM or SC 2. oral administration is precluded by their large size, hydrophilicity and gastric degradation of proteinaceous drugs - have difficulty entering their target tissues and cells 3. Sc, bDMARDs are slowly absorbed from site of injection 4. due to their large size, glomerular filtration in kidneys or metabolism in liver contributes very little to their removal from circulation 5. 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 6. 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 7. this explains the long elimination half lives and slow clearance

Question 42

what are the main pharmacokinetic trends of bDMARDs

Answer 42

1. time taken to reach peak serum concentration is measured in days rather than hours - these drugs distribute slowly 2. Max values for sc administration at Max vary between 2-50um/ml 3. bioavailability for sc administration of mabs and fusion proteins is between 51-80% 4. 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

Question 43

how are fully murine mAbs indicated in monoclonal antibody nomenclature

Answer 43

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

Question 44

how are humanised mAbs indicated in monoclonal antibody nomenclature

Answer 44

1. if parts of the variable domain are replaced by human portions, humanised antibodies are obtained - indicated by using -zu- - tocili-zu-mab 2. a fully human mab is indicated by -u- - adalim-u-mab

Question 45

describe the role of antibody Fc fragment

Answer 45

1. Fc fragment of a full length antibody binds to various cell receptors and complement proteins 2. in this way, it mediates the different physiological effects of antibodies - eg. IgG binds to pathogens via Fab