cell migration inhibitors
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Introduction
Immune cells are recruited to sites of inflammation
through
– binding to adhesion molecules on vascular endothelial cells
– and by chemoattractants produced locally.
A potential strategy to treat and prevent inflammatorydiseases is to inhibit the processes of adhesion,
migration, and recruitment of leukocytes.
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Adhesion and Recruitment of Inflammatory Cells
Multistep process involving
– adherence of circulating leukocytes to endothelial
cells on post - capillary venules
– migration through the vessel wall.
Each step is orchestrated by several different types of
molecules, all of which provide potential targets for
inhibition of this process
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Leukocyte adhesion cascade
Leukocyte extravasation usually occurs through a multistep process,
involving first the selectins, then chemoattractant receptor signaling,
followed by firm adhesion to vessel walls through the actions of integrins
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Selectins
CD62 family of cell adhesion molecules
TNF, IFN - γ and IL - 1 are major inducers of selectin expression.
Endothelial cells express P- selectin and E - selectin.
Leukocytes express a third selectin,
– L-selectin (CD62L),
– carbohydrate ligands for P - and E - selectins on their
surface, facilitating interactions with endothelial surface
molecules
These are low affinity interactions.
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Chemokines
Small polypeptide molecules produced by numerous celltypes in the inflammatory microenvironment.
Chemokines stimulate chemotaxis of cells toward a
concentration gradient of these proteins.
The CC chemokines are distinguished by adjacent
cysteines and attract monocytes and T cells.
The CXC chemokines have motifs with two cysteines
separated by another amino acid and attract neutrophils,
dendritic cells and naïve T cells.
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Chemokines
Chemokines bind to specific chemokine receptors on the
surface of rolling leukocytes.
Chemokine receptor signaling results in enhanced affinity of
leukocyte integrins for their endothelial ligands.
The number of chemokines and other chemoattractants
suggest that these latter molecules must be prominent in
dictating the precise placement of leukocyte subsets.
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Integrins
Plays role in stable adhesion of leukocytes to the
endothelium occurs.
Heterodimeric cell surface proteins composed of two non-
covalently linked polypeptide chains, α and β , expressed
on the surface of leukocytes .
Leukocyte integrin binding to endothelial ligands mediates
cell type - and organ - specific cell recruitment to sites of
inflammation.
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Integrins
For example, the α4β1 integrin heterodimer recognizes the
vascular cell adhesion molecule- 1 (VCAM- 1).
Inflammatory cytokines such as TNF and IL- 1 also enhance
endothelial expression of integrin ligands, such as VCAM - 1 and
intercellular adhesion molecule- 1 (ICAM - 1; the ligand for αLβ 2
integrin or LFA - 1).
When α4 pairs with the integrin molecule β7, this is an intestine -
specific signal through recognition of its endothelial ligand
MadCAM- 1.
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Integrins
Tissue specific and inflammatory zip codes” directing
leukocytes to a specific endothelial “mailbox” to initiate
the next step of transmigration.
When these interactions occur, leukocytes attach firmly
to the endothelium.
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Leukocyte transmigration
In the final step, leukocytes transmigrate through the endothelium.
Chemokines play an important role by directing cells to migrate
through inter - endothelial spaces along a chemical concentration
gradient.
Combinations of adhesion molecules and chemokine receptors on
distinct leukocyte populations, and expression of respective ligands on
endothelial cells result in cell type- and tissue - specific leukocyte
recruitment.
understanding specificity behind these processes has led to the
development of therapies that inhibit recruitment of inflammatory
cells in an organ - specific manner.
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Points where cell migration molecules operate
during inflammatory responses
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Cell migration inhibitors
Four classes.
Three of these represent the three types of molecules
involved in cell migration and adhesion:
I. the selectins and their receptors,
II. the chemoattractants and their receptors, and
III. the integrins and their receptors.
A fourth class includes
IV. the signaling molecules downstream from adhesion or
chemoattractant receptors, such as phosphoinositide-3-OH
kinase-γ (PI(3)K- γ ).
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Selectin inhibitors
P-selectin glycoprotein ligand-1 (PSGL-1) - mucin-like
glyco-protein that binds P- , L- and E-selectin.
It is expressed on certain leukocytes, as well as inflamed
endothelial cells.
Cutaneous lymphocyte-associated antigen (CLA)
represents a modified form of PSGL-1 that interacts with
E-selectin for skin homing by T cells.
Blockade of selectins or PSGL-1 inhibits several
inflammatory conditions, at least in animal models
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Integrin inhibitors
Natalizumab
the mAb to α4 integrin developed by Biogen-Idec and Elan for the treatment of
multiple sclerosis and Crohn’s disease.
Several studies in rodents indicated that an α4integrin inhibitor should be highly
effective for human multiple sclerosis and inflammatory bowel disease.
The results of two phase 3 clinical trials showed that natalizumab markedly reduces
the number of relapses in individuals with multiple sclerosis.
The notable adverse effect of these trials was the development in two subjects of
progressive multifocal leukoencephalopathy, a condition caused by a polyoma virus, JC
virus.
This complication has resulted in restrictions on the type of patient that can receive
the drug.
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Integrin inhibitors
Efaluzimab
Humanized mAb that was approved in 2003 Targetting LFA-1 (CD11a)
For the treatment of moderate to severe plaque psoriasis.
A recently published long-term study demonstrated sustained improvement
in psoriasis symptoms in subjects throughout three years of continuous
Treatment
Thus, efaluzimab is one of the most effective treatments for psoriasis at
present.
The successful molecular modeling of integrins has allowed development
of small molecule allosteric antagonists and ligand mimetics.
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Chemoattractant receptor inhibitors
C5a receptors one of the most potent chemoattractants for neutrophils and
eosinophils. It also activates other leukocytes including mast cells
and basophils.
overproduced C5a or upregulated C5aR expression has been
implicated in the pathogenesis of rheumatoid arthritis, respiratory
distress syndrome, inflammatory bowel disease, systemic lupus
erythematosus (SLE), ischemia-reperfusion injury, COPD and sepsis.
Novo Nordisk and G2 Therapies have developed a high-affinity mAb
to human C5aR (ref. 19), which is now in early clinical trials.
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CXCR2 and CXCR1
A number of CXCR2 –CXCR1 antagonists are in human
clinical trials.
SCH 527123
The most advanced being Schering-Plough’s CXCR2
small molecule inhibitor already in phase 2 trials forCOPD and ‘neutrophilic’ asthma.
Chemoattractant receptor inhibitors
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CCR2 antagonists
INCB3284 by Incyte
which is now in phase 2a clinical trials in patients with
rheumatoid arthritis and type 2 diabetes.
MK0812 by Merck
in phase 2 trials in subjects with multiple sclerosis.
Chemoattractant receptor inhibitors
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tissue-specific cell migration inhibitors
CCX282 (Traficet-EN)
CCR9 inhibitor from ChemoCentryx.
CCR9+ T cells contribute to pathogenesis of inflammatory
bowel disease.
Now in late stage clinical trials.
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Blockade of lymphocyte egress
FTY-720 (Fingolimod)
S1P receptor agonist
FTY-720 causes lymphocyte retention in lymph nodes, with a consequent
lymphopenia in blood.
S1P
the “exit signal” for lymphocytes leaving lymphoid organs and
is present in blood and lymph at high concentrations due to the S1P
producing activity of sphingosine kinases.
Conversely, the S1P degrading enzyme, S1P lyase, maintains low amounts
of S1P in lymphoid organs.
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FTY-720 (Fingolimod)
Disrupting this concentration gradient by S1P receptor agonists, anti- S1P
antibodies or S1P lyase inhibitors have therapeutic potential for
autoimmune diseases like MS and rheumatoid arthritis.
FTY-720 sequesters lymphocytes in secondary lymphoid organs,
thereby preventing their migration to sites of inflammation.
This drug showed promising phase 2 clinical trial results in MS.
One potential side-effect of FTY-720 treatment is bradycardia due to
expression of certain S1P receptors, particularly S1P3, in the heart.
Hence, development of agonists that are
selective for one particular receptor subtype, S1P1, are being pursued
vigorously by several pharmaceutical companies.
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The signaling molecules downstream from
adhesion or chemoattractant receptors
The most promising class of such signaling molecules is PI(3)Ks
Mice lacking one of the four isoforms, PI(3)K γ , possess neutrophils
and macrophages that show impaired activation through
chemoattractant receptors and poor chemotac-tic responses.
These mice are also protected in various models of inflammation,
including inflammatory arthritis and glomerulo -nephritis
Several drug companies have produced effective small
molecule inhibitors of PI3K γ
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Promising targets and drug development programs for cell
migration inhibitor
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