10 - MAb in Inflammation Flashcards

Question

What is the difference between ACR20, ACR50, and ACR70? When are they used?

Answer 1

- ACR20 = 20% improvement from baseline on therapy - ACR50 & ACR70 = 50% and 70% improvement respectively - Used to assess data in clinical trials

Answer 2

- Decreases C-reactive proteins (reactants of inflammation), ESR (erythrocyte sedimentation rate; non-specific screening test that indirectly measures how much inflammation is in the body) and cytokines (IL-6) - Decreases serum levels of matrix metalloproteinase (MMP-1 and MMP-3) - - MMPs are responsible for tissue remodeling and cartilage destruction - Clearance increased in the presence of anti-adalimumab Abs and decreased in px > 40 y/o

Answer 3

- SC injection 40 mg once every other week - - Can be used every week in px not receiving methotrexate - Often used in conjunction w/ methotrexate in RA (methotrexate prolongs Humira t1/2) - May be administered w/ other DMARDs

Answer 4

- Kineret (Anakinra) -> not recommended b/c may increase risk of infections & neutropenia - Methotrexate decreases clearance of adalimumab - Vaccines -> not recommended to administer live vaccines during Adalimumab therapy - > 10% = CNS (headache), dermatologic (rash), respiratory - 5-10% = CV (HTN), endocrine & metabolic, GI, genitourinary (UTIs)

Answer 5

- For RA, approved in combination w/ MTX for reducing signs and sx, inhibiting progression of structural damage, and improving physical function - Neutralizes biological activity of both soluble and transmembrane forms of TNF-alpha, but doesn’t neutralize TNF-beta, preventing TNF-alpha from binding to its receptor in the cell - The only anti-TNF agent given IV (longest potential dosing interval)

Answer 6

- Bind to human TNF-alpha w/ high specificity, affinity, and avidity - Targets all TNF-alpha including soluble, transmembrane and receptor bound

Answer 7

- Recommended dose = 3 mg/kg IV infusion - Given on induction schedule at 0, 2, and 6 weeks followed by infusions q8weeks - Px w/ incomplete responses may be given up to 10 mg/kg IV q4weeks

Answer 8

- As a chimeric antibody, infliximab is expected to have a higher rate of immunogenicity - Package insert mentions a rate of formation of antidrug antibodies of ~ 10%; literature cites higher rates - Px w/ antidrug antibodies are more likely to have higher rates of drug clearance, reduced efficacy, and 2-3-fold increase in incidence of infusion reactions - SE = increased risk of serious and opportunistic infections, malignancy, and heart failure - Significantly increased incidence of seroconversion for anti-nuclear (ANA) Abs and anti-dsDNA Abs

Answer 9

- Dimeric soluble fusion protein composed of parts of the ligand binding regions of the p75 high-affinity type 2 TNF receptor (which binds both TNF-alpha and TNF-beta) linked to parts of the IgG1 Fc regions - Doesn’t induce complement-mediated lysis of cells expressing TNF on their surface - FDA approved for use in px w/ moderate to severe active RA (alone or in combo w/ MTX) and polyarticular juvenile RA, PsA, AS

Answer 10

For adults w/ RA, PsA, or AS recommended dose is 50 mg SC weekly, given either as one 50 mg injection or two 25 mg injections on the same day or up to 4 days apart

Answer 11

- Indicated for use as monotherapy or in combination w/ DMARDs in px w/ moderate to severe active RA who have had an inadequate response to DMARDs or TNF antagonists - Fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and a modified Fc portion of IgG1 - - Doesn’t fix complement due to the modification of Fc portion

Answer 12

- Interaction of CD80 and CD86 w/ CD28 is the costimulatory signal for full activation of T-lymphocytes - Abatacept is a co-stimulation modulator that binds CD80 and CD86 and blocks their interaction w/ CD28 => inhibiting T-cell activation - Affinity of abatacept for its ligand is greater than the natural ligand CD28

Answer 13

- In vitro studies demonstrated abatacept decreases T-cell proliferation and inhibits production of TNF-alpha, IFN gamma, and IL-2 - In vivo study -> suppressed inflammation, decreased anti-collagen antibody production, and reduced antigen specific production of IFN gamma - Half-life around 13 days

Answer 14

- Comes lyophilized and is administered after reconstitution in water by IV infusion over 30 mins - Dose depends on body weight - Dosing regimen = 1st and 2nd dose given 2 weeks apart followed by monthly dosing thereafter

Answer 15

- Medication originally designed to reduce sensitivity to allergens - Approved for tx of px 12 years and older w/ moderate to severe allergic asthma - Specifically binds to free human IgE in the blood and interstitial fluid and membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes - Doesn’t bind to IgE that is already bound by the high affinity IgE receptor (Fc-epsilon—RI) on the surface of mast cells, basophils, and antigen-presenting dendritic cells - Is a glycosylated IgG1 MAb

Answer 16

- One of the most common allergic diseases - Allergy occurs more frequently in individuals w/ higher serum IgE levels (though some allergic individuals have very low serum IgE and some people w/ very high IgE have no allergic problems)

Answer 17

- Administered SC once every 2-4 weeks - Dosing schedule (2 vs 4 weeks and the dosage of each injection) for each pt depends on serum IgE levels and body weight - - Rationale = IgE present at the time of the first injection and produced during the intervals of successive injections must all be neutralized by omalizumab - Main SE = anaphylaxis; small increased risk of stroke and heart disease

Answer 18

- Recombinant humanized IgG4K MAb - Approved as monotherapy for the tx of px w/ relapsing forms of MS to delay accumulation of physical disability and reduce frequency of clinical exacerbations

Answer 19

- Cause unknown – theory of “molecular mimicry” - Antigens expressed by APC may have cross-sensitivity to myelin antigens - Inflammatory process causes damage to the barrier (cytokine mediated, reactive metabolites) - Upregulation of adhesion molecules – T-cell binding via integrins, T-cells enter the CNS - Macrophage activation and attack on myelin sheath (inflammatory mediators play a role)

Answer 20

- Heterodimers of noncovalently associated glycoproteins composed of 2 subunits, alpha and beta - Cell adhesion receptors involved in interactions between cell-extracellular matrix and cell-cell interactions - The main way that cells bind to and respond to the extracellular matrix and are involved in a variety of cellular functions such as wound healing, cell differentiation, homing of tumour cells, and apoptosis

Answer 21

- Over 24 different types of integrins present on the surface of leukocytes - Most important integrin in adhesion to the CNS vascular endothelium is VLA-4 (very late antigen) - VLA-4 = transmembrane alpha-4 integrin receptor consisting of alpha-4 subunits and beta-1 subunit - - Binds to V-CAM-1, an adhesion molecule expressed on the CNS vascular endothelium (V-CAM-1 = member of immunoglobulin gene superfamily) - Expression of both V-CAM-1 and activated VLA-4 is increased in px w/ MS due to inflammatory mediated cytokine release - - Leads to binding of VLA-4 on surface of leukocytes to V-CAM-1 on CNS vascular endothelium => transmigration of leukocytes into CNS

Answer 22

- Binds to alpha-4 subunit of alpha-4-beta-1 and alpha-4-beta-7 integrins expressed on the surface of all leukocytes - - Competitively inhibits alpha-4 subunit-mediated adhesion of leukocytes to the adhesion molecules VCAM-1, MadCAM-1, fibronectin, and osteopontin - Natalizumab exerts its beneficial effects in MS by: - - Inhibiting migration of immune cells into the CNS - - Inhibiting interactions between beta 4-integrin and its ligands, thereby possibly reducing immune cell activation and promoting apoptosis of lymphocytes

Answer 23

- IV infusion 300 mg once every 4 weeks (not dosed by body weight) - Can only be mixed in a normal saline IV bag - Common SE = infusion related reactions, headache, fatigue, depression, UTI, LRTI, arthralgias

Answer 24

- Phase 3 clinical trial - Compared natalizumab vs. placebo - Results => natalizumab significantly reduced: - - Cumulative probability of sustained disability progression - - Annualized rate of clinical relapse - - Risk of relapse

Answer 25

- Compared natalizumab vs. placebo but both groups of px were also being treated w/ Avonex - Results => natalizumab significantly reduced: - - Cumulative probability of sustained disability progression - - Annualized rate of clinical relapse - - Development of lesions over the effect produced by Avonex alone

Answer 26

- SENTINEL trial showed that 2 px died of PML after receiving natalizumab + avonex - - PML = opportunistic infection of the brain, which usually leads to death or severe disability - Due to increased risk of PML, natalizumab is generally recommended for px who have had an inadequate response so, or are unable to tolerate alternate MS therapies - Only available through a restricted distribution