Term
| What are the 3 primary types of Biologics? |
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Definition
1) Signaling proteins (EPO, GH and insulin)
2) Monoclonal Ab (human or non-human source)
3) Receptor constructs (fusion proteins based on naturally-occurring receptor linked to Ig frame) |
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Term
| What are the 3 features used to characterize Biological therapies? |
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Definition
1) High specificity (specific binding site)
2) Effector function (often same region as specificity that confers action on tissue)
3) Longevity (something prevents immediate breakdown) |
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Term
| What are the 4 basic mechanisms of action of Biological Therapies? |
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Definition
1) Neutralization (Etanercept)will stop action but not circulating levels
2) Block receptor function (Tocilizumab binds IL-6R)
3) Depletion (Rituximab) involves binding and killing
4) Signaling (Adalimumab as an alternative to etanercept for TNF) |
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Term
| What are the important monoclonal antibodies and recombinant fusion proteins used to treat autoimmune diseases? |
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Definition
Antibodies end in "umab"
Fusion proteins end in "cept" with the exception of Anakinra. |
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Term
| How does the course of B-cell development influence the types of B-cell directed therapies that should be used? |
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Definition
Target the right surface molecules!
Pro-B= CD34, CD10, CD19
Pre-B= same as Pro-B but with CD20
Immature=IgD, high CD38, CD5, less CD10 and CD34
Mature= CD23, IgD/IgM, low levels of CD38
Memory= CD27, down-regulation of CD38 and IgD
Plasmoblasts= no CD20 |
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Term
| When would you use an anti-CD20 antibody? |
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Definition
Rituximab is one of these used in RA (most effective if ACPA is present)
If you are targeting Pre-B cells or Mature, naive B cells.
Results in decrease in circulating peripheral blood B cells (naive most diminished) and increase in BLyS.
Pro B cells and Plasmoblasts don't have it! |
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Term
| When would you use an anti-CD27 antibody? |
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Definition
| CD27 is mark of memory B cells! |
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Term
| Why might you prescribe an anti-BLyS (BAFF) antibody? |
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Definition
Neutralization is not enough; you need cell depletion
Belimumab- human mAb
BLyS is an activating factor in the TNF family that regulates B-cell development of transitional T2 and marginal zone B cells.
It is elevated in SLE, RA and Sjogrens' Syndrome
Side effects include price |
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Term
| What does Epratuzumab target? |
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Definition
| Antibody against CD22 on B cells |
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Term
| What clinical conditions is Rituximab approved to treat? |
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Definition
1) Non-Hodgkin's Lymphoma (NHL)
2) RA
3) Chronic lymphocytic leukemia (CLL)
4) Wegeners (ANCA-associated vasculitis)
NOT APPROVED
MS Pemphigus vulgaris, ITP, SLE |
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Term
| How does Retuximab deplete pre-B and mature, naive B cell populations in RA? |
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Definition
Usually in refractory cases
1) Autoantibody depletion (RF and anti-dsDNA)
2) Diminished antigen presentation (APC) by B cells
3) Diminished B-cel cytokine production and co-stimulation of T-cells
4) CD20+ T cell depletion |
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Term
| What Adhesion molecule inhibitors are available? |
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Definition
Want to prevent lymphocyte migration to tissue site.
1) Anti LFA-1 (lymphocyte)/ICAM-1 (endothelial)
2) Anti VLA-4 (lymphocyte)/VCAM-1 (endothelial) |
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Term
| When might you use the drug Natalizumab? |
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Definition
It is a mAb (adhesion molecule inhibitor) used in MS (B1 integrin to get to CNS) and Chrohn's (B7 integrin for tissue access) that binds A4 integrin and other integrins/adhesion molecules
1) Block migration of lymphocytes to CNS and intestinal parenchyma
2) Induce T-cell apoptosis and anergy and prevent T-cell-mediated inflammation
** Withdrawn because associated with PML, but recently brought back with restrictions for usage** |
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Term
| When might you use the drug Efalizumab? |
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Definition
IgG mAB against CD11a (LFA-1 molecule on T cells) used to treat Psoriasis.
1) Inhibits T-cell activation
2) Blocks trafficking of lymphocytes
Like Natalizumab, it has been withdrawn because of link to multifocal leukoenecephalopathy (PML) |
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Term
| What is Progressive multifocal leukoenecephalopathy and why is it important in drug treatment? |
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Definition
PML has been associated with Natalizumab (MS), Rituximab (RA) and Efalizumab (Psoriasis) treatments.
Also seen in HIV and after organ transplant.
Destructive infection of oligodendrocytes by JC virus. |
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Term
| Explain how TFN-targeting is used in the treatment of RA. |
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Definition
2/3 of patients benefit
Anti-TNF (Infliximab, Etanercept, Adalimumab, Golimumab, Certolizumab)
Transmembrane TNF made by macrophages is cleaved by TACE, and accumulates into trimeric complexes that bind fibroblasts, leukocytes and endothelial cells.
TNF:
blocks LPL (cachexia)
induces apoptosis
stimulates IL-1, IL-6 and IL-8
causes release of MMPs from fibroblasts, chondrocytes, neutrophils
increase in adhesion molecules for leukocyte migration |
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Term
| What are the 3 types of TNF receptors? |
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Definition
Type 1 (p55) receptor
Type 2 (p75) receptor
TACE-induced soluble receptor (natural inhibitors) |
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Term
| How does Etanercept work? |
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Definition
Soluble p75 recptor fusion construct.
Genetically engineered to contain 2 p75 extracellular domains linked to Fc portion of human IgG.
It basically "soaks" of TNF (also neutralizes lymphotoxin) |
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Term
| How does Infliximab work? |
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Definition
| Chimeric anti-TNF mAb often administered with MTX (reduce antibody reaction against murine portion of molecule) |
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Term
| How does Adalimumab work? How is it different than infliximab? |
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Definition
| Both are anti TNF mAB, but Adalimumab is fully humanized (injected every 2 weeks) |
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Term
| How do Golimumab and Certolizumab pegol work? |
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Definition
Golimumab- human anti-TNF (like Adalimumab) monoclonal antibody
Certolizumab- humanized Fab attached to polyethylene glycol (PEG), which increases its half-life. |
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Term
| What safety considerations are important for anti-TNF therapies? |
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Definition
Not too many found (Infliximab is a little worse- more potent)!
REACTIVATION OF LATENT TB
Maybe lymphoma?
Heart failure
Injection-site reactions and systemic infusion reactions with infliximab (it is human-mouse chimeric) |
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Term
| How does anti-IL-1 therapy work? |
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Definition
Anakinra (Kineret)(recombinant IL-1ra). Less effective than anti-TNF
IL-1 is major pro-inflammatory cytokine in RA, as well as causing erosion and bone destruction.
IL-1R antagonists and sIL-1R are natural inhibitors, but they are "out of wack" in RA. |
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Term
| How does anti-IL-6 therapy work in RA? |
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Definition
Tocizilumab against IL-6R
Can increase cholesterol, infection and cause transient neutropenia (use it after TNF)
Prevent vasculogenesis and Pannus formation, immune reactions and inflammation
IL-6 stimulates T and B cells, and via VEGF production, causes vasculogenesis leading to Pannus formation.
IL-6 also stimulates megakaryocytes, leading to thrombocytosis, hepatocytes to produce acute phase proteins and fibroblasts to produce MMPs. |
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Term
| Why use T-cell inhibitors in RA (Abatacept)? |
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Definition
Abatacept is a CTLA4/IgG1 fusion receptor protein that attenuates T-cell activation by blocking CD28-mediated co-stimulation.
Can be used if MTX/TNF blockage fails.
Slower to work. |
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Term
| How does Denosumab work to treat RA? |
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Definition
| Humanized mAB to RANKL used to prevent bone loss (mimics inhibitory effects of Osteoprotegerin). Prevents RANKL:RANK interaction and reduces bone resorption by osteoclasts. |
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Term
| How do Jannus Kinase Inhibitors work to treat RA? |
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Definition
Jannus Kinases are cytoplasmic Tyrosine Kinases that pair to integrate signaling in various cytokines and GFs.
JAK3 is important for common y-chain receptors (IL-2, IL-7, IL-9, IL-15, IL-21), and without it, mice have T/B/NK defects leading to SCID.
Can cause anemia and lipidemia |
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Term
| How does Ustekinumab work to treat RA? |
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Definition
Decrease IFN signaling in Psoriasis
Anti IL-12/IL-23 Ab against p4- subunit shared by these cytokines that prevents intracellular signaling in CD4+ T cells and decrease IFN-y. |
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Term
| Etanercept and Infliximib |
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Definition
Etanercept neutralizes while Inflixamib also KILLS
1) Etanercept involves 2 transient soluble receptors hooked up to an Fc region to increase half-life and neutralize TNF
2) Inflixamib binds to soluble TNF and KILLS CELLS that are expressing TNF |
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Term
| How can you determine the origin of an antibody biological therpay (i.e. mouse, human, ect) |
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Definition
1) -O- is mouse
2) -Xi- is chimeric (infliximab)
3) -zu- is humanized
4) -xizu- is chimeric humanize
5) -u is human |
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Term
| How can you tell if a drug is a fusion protein? |
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Definition
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Term
| How are B cells involved in RA pathogenesis? |
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Definition
1) produce cytokines (TNF-a, IL-6)
2) APC to T cells
3) Differentiate into plasma cells that make autoantibody |
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Term
| Why would you not start by treating with Rituximab? |
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Definition
| If it fails, you don't have any B-cells to work with. |
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Term
| What risks are associated with Rituximab use? |
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Definition
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Term
| When do you NOT provide anti-TNF therapy? |
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Definition
1) Active infection
2) CHF history
3) HepB
4) MS
5) Malignancy |
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