Anticytokines Flashcards
what do rheumatoid arthritis, inflammatory bowel disease (Crohn’s, ulcerative colitis), psoriasis, and psoriatic arthritis have in common, regarding cause and potential therapy
chronic autoimmune inflammation
anti-cytokine therapy can be therapeutic
how are soluble receptor antagonists such as etanercept used against TNF-alpha
fuse Fc of antibody with piece of TNF-a receptor (fusion protein)
binds TNF-a in circulation and acts as a sponge to soak it up
use of
a. infliximab
b. adalimumab
c. ustekinumab
d. secukinumab
remember -mab = monoclonal antibody
these are therapeutic antibodies or antibodies fragments that target cytokines
infliximab, adalimumab: target TNF-alpha
ustekinumab: targets IL-12/23
secukinumab: targets IL-17A
function of tocilizumab and sarilumab?
remember -mab = monoclonal antibody
therapeutic antibody to IL-6 receptor
*Too Soon for all these acute phase inflammation proteins from the liver! (induced by IL-6),
T = Tocilizumab
S = Sarilumab
anakinra
recombinant non-glycoslyated IL-1 receptor antagonist (anti-cytokine therapy)
recombinant form of an endogenous protein, targets cytokine receptor
translate meaning of each of these therapeutic antibody suffixes:
a. -omab
b. -ximab
c. -zumab
d. -umab
a. -omab = murine
b. -ximab = chimeric (mostly human)
c. -zumab = humanized (90%)
d. -umab = 100% human
highest potential for immunogenicity with -omab (murine), lowest with -umab (human)
adalimumab and infliximab both target TNF-alpha
based on their nomenclature, describe their difference
-mab = monoclonal antibody
-umab = human (adalimUMAB is human mAb)
-ximab = chimeric (infliXIMAB is chimeric mAb) - Fc region of human IgG and Fab sequence of mouse anti-TNF-alpha antibody
*both target TNF-alpha
DMARDs
disease-modifying anti-rheumatic drugs: anti-cytokine therapy for rheumatoid arthritis (autoimmune inflammation)
csDMARDs (Conventional Synthetic): prevent proliferation of lymphocytes
bDMARDs (Biologic): target cytokine pathways (TNF-alpha, IL-1)
—> examples: etanercept, adalimumab, infliximab, anakinra
what cytokines are unhinged in inflammatory bowel disease such as Crohn’s and ulcerative colitis? (4)
TNF-a: inflammation, NFkB and c-JUN expression
IL-6: inflammation, acute phase proteins from liver
IL-12: activates NK cells
IL-23: Th17 differentiation (—> neutrophil activation)
the following biological agents target TNF-alpha, describe how:
a. etanercept
b. infliximab
c. adalimumab
d. golimumab
e. certolizumab
a. etanercept: soluble receptor fusion protein, binds TNF-a
b/c/d: infliximab (*Crohn’s), adalimumab, golimumab: mAb to TNF-a, binds soluble and transmembrane TNF-a
e. certolizumab: PEG conjugated Fab fragment, binds TNF-a
*all treat rheumatoid arthritis
*remember: Eat Crap, Get Acute Inflammation (like that caused by TNF-alpha!)
E = Etancercept
C = Certolizumab
G = Golimumab
A = Adalimumab
I = Infliximab
tocilizumab and sarilumab
mAb to IL-6 receptor (blocks binding)
bind both soluble and transmembrane form of receptor
ustekinumab is a mAb to the common subunit of IL ___ and ____
and is indicated in treatment for ____
ustekinumab: mAb against common subunit of IL-12 and IL-23 (p40 subunit)
indicated in treatment for psoriasis
tildrakizumab and guselkumab are biological agents that act as mAb to ___ subunit of IL-23, thereby binding the cytokine
and are used in treatment for ____
tildrakizumab and guselkumab are mAb to p19 subunit of IL-23, treat psoriasis
secukinumab, ixekizumab, and brodalumab treat ____ by binding or blocking action of IL-____
treat psoriasis, bind/block IL-17A
secukinumab: bind IL-17A
ixekizumab: bind IL-17A
brodalumab: block IL-17A binding (mAb to receptor)
how does abatacept treat rheumatoid arthritis
blocks co-stimulation of T cells by inhibiting B7 binding to CD28
fusion protein of CTLA-4 (cytotoxic T lymphocyte associated antigen) linked to IgG1
aba[T cell]a[interCEPTion]
how does belimumab treat Lupus?
belimumab is mAb to BAFF/BLyS (B-cell activation factor/ B lymphocyte stimulator)
*Belimumab prevents *B cell development
explain tocilizumab and COVID19
tocilizumab helps manage cytokine storm in patients with severe COVID19 disease
(was originally implicated in treating cytokine storm associated with CAR-T therapy for cancer)
TOXilizumab treats TOXIC cytokine storm
describe how trans signaling of IL-6 induces cytokine storm
IL-6 (pro-inflammation) can bind soluble form of IL-6R when at high levels
this can form complex with gp130 dimer on any cell surface (trans signaling), whereas normally it only binds membrane receptor on immune cells (Cis signaling)
trans signaling is activated in cells that don’t express membrane IL-6 receptor and cytokine storm ensues
which of these binds IL-6 receptor?
a. tocilizumab
b. adalimumab
c. rituximab
d. ustekinumab
e. ixekizumab
a. tocilizumab: binds IL-6R
*sarilumab also binds IL-6R
b. adalimumab: binds TNFa
c. rituximab: binds CD20 (eliminates B cells)
d. ustekinumab: binds IL-12,23 (prevent NK cell activation)
e. ixekizumab: binds IL-17A (prevent neutrophil activation)
which of these bind IFN-alpha to treat SLE?
a. etanercept
b. golimumab
c. sifalimumab
d. tabalumab
e. brodalumab
c. sifalimumab: binds IFN-alpha (Type I IFN, global antiviral response)
a. etanercept: binds TNFa (fusion protein)
b. golimumab: binds TNFa
d. tabalumab: binds BAFF/BLyS
e. brodalumab: binds IL-17A receptor
sort these into anti-cytokines that bind IL-17A and IL-12/23:
a. secukinumab
b. guselkumab
c. ustekinumab
d. ixekizumab
e. tildrakizumab
f. brodalumab
bind IL-12/23: tildrakizumab, ustekinumab, guselkumab (TUG at NK to get them away)
bind IL-17A: secukinumab, ixekizumab, brodalumab (SIB - neutrophils are the first SIBling to arrive [at site of infection])
