10 - MAb in Inflammation Flashcards
1
Q
Describe the process of inflammation
A
- A protective response involving host cells, blood vessels, and proteins
- Potentially harmful process b/c components of inflammation that are capable of destroying microbes can also injury bystander normal tissue
- Components of inflammatory process include WBCs and plasma proteins normally present in the blood
- Inflammatory reaction’s goal is to bring these to the site of infection and/or tissue damage
- Inflammation is induced by chemical mediators produced by damaged host cells
- Normally controlled and self-limited
2
Q
What are the goals of inflammation?
A
- Eliminate initial cause of cell injury
- Remove necrotic cells and tissues
- Initiate process of repair
3
Q
Components of inflammation
A
- Blood cells – platelets, granulocytes, monocytes/macrophages, lymphocytes, fibroblasts
- Proteins – complement, coagulation, kininogens, proteoglycans
4
Q
Onset of acute vs. chronic inflammation
A
- Acute = fast (minutes, hours, days)
- Chronic = slow (days, months, years)
5
Q
Causative agents of acute vs. chronic inflammation
A
- Acute = bacteria and injured tissues
- Chronic = persistent acute, viral infection and autoimmune
6
Q
Cellular mediation of acute vs. chronic inflammation
A
- Acute = mainly neutrophils
- Chronic = monocytes/ macrophages, lymphocytes, and plasma cells
7
Q
Outcome of acute vs. chronic inflammation
A
- Acute = resolution, abscess formation, and/or chronic inflammation
- Chronic = tissue destruction, fibrosis, necrosis
8
Q
Severity of local and systemic signs of acute vs. chronic inflammation
A
- Acute = prominent
- Chronic = less prominent, may be subtle
9
Q
Causes of chronic inflammation
A
- Persistent injury or infection (ulcer, TB)
- Prolonged exposure to a toxic agent (pulmonary silicosis – silica in the lung)
- Autoimmune disease – self-perpetuating immune reaction that results in tissue damage and inflammation (RA, systemic lupus erythematosus, MS)
10
Q
Components of chronic inflammation
A
- Lymphocyte, monocytes/macrophage infiltration
- Tissue destruction by inflammatory cells
- Repair w/ fibrosis and angiogenesis (new vessel formation)
11
Q
Systemic effects of inflammation
A
- Inflammatory cytokines generated by inflammation reactions may have protective and pathologic effects on systemic organs
- Systemic protective effects – brain, liver, bone marrow
- Systemic pathologic effects – heart, endothelial cells, blood vessels, and multiple tissues such as skeletal muscle
12
Q
Anti-inflammatory drugs
A
- Steroidal anti-inflammatory drugs
- Corticosteroids are cornerstone of therapy for inflammatory condition
- Reduce inflammation or swelling by binding to cortisol receptor
- Non-steroidal anti-inflammatory drugs
- NSAIDs alleviate pain by counteracting the COX enzyme
- COX enzyme synthesizes prostaglandins, creating inflammation
- NSAIDs prevent prostaglandins from ever being synthesized, reducing or eliminating the pain
13
Q
Inflammation and the immune system; how do drugs fit into this?
A
- Inflammation always involved local vascular system, immune system, and various cells w/in the injured tissue
- Immunomodulatory agents are often referred to as disease-modifying anti-rheumatic drugs (DMARDs)
- Anti-metabolites = methotrexate, azathioprine, leflunomide
- Gold salts = D-penicillamine, chloroquine, sulfasalazine
14
Q
What do biologic DMARDs do?
A
- Block TNF-alpha or interleukin-1 pathways
- Block lymphocyte activation or migration
- Deplete lymphocyte subsets
- Target allergic inflammation
15
Q
Rheumatoid arthritis – sx, cause, drug treatments
A
- Most prevalent arthritis in autoimmune arthritis
- RA sx = joint pain/swelling/stiffness, general physical sx (fatigue, muscle pain), weakness, worse joint stiffness after sleeping or prolonged sitting
- Exact cause unknown; may result from a combination of genetic predisposition, environmental influences, and immune system
- Over time, RA can cause progressive damage to cartilage, bone, and joint-related tissue
- Steroids, NSAIDs, and DMARDs have been demonstrated to interrupt and delay the inflammatory course of RA
- Downsides = significant SE and not sufficient for many px
- Biologic DMARDs -> Enbrel, Humira, etc.
16
Q
Tumour necrosis factor (TNF)
A
- Family of cytokines which are involved in regulating immune response -> TNF-alpha and TNF-beta
- Produced mainly by macrophages but also by a broad variety of other cell types including lymphoid, mast and endothelial cells
- TNF plays major role in many autoimmune and inflammatory conditions (ex: high concentration in synovial fluid in RA, psoriatic arthritis, and ankylosing spondylitis)
17
Q
Pathophysiology of TNF
A
- Abnormal immune response to unknown stimuli
- Prolonged inflammation
- Damage to healthy body structures followed by increased tissue growth
18
Q
Physiology of TNF
A
- Inflammatory mediator (heat, swelling, redness, pain)
- Increased tissue damage (apoptosis)
- Increased cellular proliferation and aggregation
- Regulation of immune cells/ cytokine release (ex: interleukin-1)
19
Q
Role of TNF-alpha in RA
A
- Drives events in pro-inflammatory cytokines cascade
- Triggers production of other pro-inflammatory cytokines, including IL-1, -6, and -8
- Facilitates activation of T lymphocytes by foreign antigens
- Causes T cell accumulation in tissues and neutrophil accumulation in the synovial fluid
- Stimulates fibroblasts and macrophages to release destructive enzymes (MMPs)
- Stimulates osteoclastogenesis directly through differentiation of progenitor cells and through enhanced expression of RANKL
20
Q
Examples of TNF-alpha antagonists
A
- Infliximab (Remicade) = mouse/human chimeric anti-TNF-alpha monoclonal antibodies (IgG1)
- Etanercept (Enbrel) = TNF-alpha receptor p75-Fc fusion protein
- Adalimumab (Humira) = fully human anti-TNF-alpha monoclonal antibodies (IgG1)
- Humira = human immunoglobulin rheumatoid arthritis
- Currently FDA approved for px w/ RA (moderate and severe), Crohn’s disease (moderate and severe), psoriatic arthritis (active), and ankylosing spondylitis (active)
21
Q
Crohn’s disease – what is it and when are TNF-alpha antagonists indicated
A
- Inflammatory bowel disease
- Patchy ulcers in interstitial tract that may cause fistulas and fibrosis
- TNF-alpha antagonists indicated for severe active disease not responsive to a full course of conventional tx
- Also indicated for fistulizing Crohn’s disease
22
Q
Ankylosing spondylitis - what is it and when are TNF-alpha antagonists indicated
A
- Chronic inflammatory disease of the spine and tendons
- Progressive stiffening of spinal joints leading to bony ankylosis
- May affect organs (eyes, heart, lungs)
- TNF-alpha antagonists indicated for reduction of signs and sx
- Poor response to conventional tx
23
Q
Psoriatic arthritis - what is it and when are TNF-alpha antagonists indicated
A
- Inflammatory arthritis associated w/ psoriasis
- Non-symmetrical, no predictable joints
- Pain and tenderness more pronounced than RA
- TNF-alpha antagonists indicated for active progressive disease w/ inadequate response to conventional therapy
24
Q
Mechanism of Humira
A
- Recombinant MAb that binds to human tumour necrosis factor alpha (TNF-alpha) to prevent its binding to TNF-alpha receptor, thereby interfering w/ endogenous TNF-alpha activity (only binds to soluble TNF-alpha, not receptor bound)
- Humira doesn’t block TNF-beta from binding to the same receptor
- Reduces signs and sx of RA and inhibits the progression of structural damage
25
Q
What is the difference between ACR20, ACR50, and ACR70? When are they used?
A
- ACR20 = 20% improvement from baseline on therapy
- ACR50 & ACR70 = 50% and 70% improvement respectively
- Used to assess data in clinical trials
26
Q
PD and PK of Humira
A
- 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
27
Q
Dosage and administration of Humira
A
- 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
28
Q
Drug interactions and adverse effects of Humira
A
- 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)
29
Q
Infliximab (Remicade) – function, administration (IV, PO, IM) and indication
A
- 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)
30
Q
Mechanism of infliximab
A
- Bind to human TNF-alpha w/ high specificity, affinity, and avidity
- Targets all TNF-alpha including soluble, transmembrane and receptor bound
31
Q
PK and dose of infliximab
A
- 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
32
Q
Antibodies against Remicade and adverse effects
A
- 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
33
Q
Etanercept (Enbrel) – function and indication
A
- 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
34
Q
Dosing of Enbrel
A
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
35
Q
Abatacept (Orencia) – indication and function
A
- 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
36
Q
Mechanism of abatacept
A
- 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
37
Q
Efficacy and PD of abatacept
A
- 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
38
Q
Dosing of abatacept
A
- 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
39
Q
Omalizumab (Xolair) – function and indication
A
- 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
40
Q
Allergic asthma
A
- 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)
41
Q
Dosing, administration, and SE of omalizumab
A
- 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
42
Q
Natalizumab (Tysabri)
A
- 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
43
Q
Pathophysiology of MS
A
- 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)
44
Q
What are integrins?
A
- 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
45
Q
Adhesion of leukocytes to BBB
A
- 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
46
Q
Mechanism of natalizumab
A
- 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
47
Q
Dosing, administration, and SE of natalizumab
A
- 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
48
Q
AFFIRM trial
A
- 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
49
Q
SENTINEL trail
A
- 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
50
Q
Natalizumab use today
A
- 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
