Supplementary Table 1 - Word file (124 KB )

advertisement
Table 1 | Biologic therapies for RA: immune targets
Biologic therapies for RA: immune targets
Target
Reason for targeting
Cytokine
TNF


Activates multitude of cells and promotes production of chemokines and proinflammatory cytokines
Promotes articular destruction by induction of RANKL on synovial fibroblasts
Therapeutic
agent
Structure
*Status
Adalimumab
Etanercept
mAb against TNF
Fusion protein consisting of
human soluble TNFR (p75) linked
to the Fc portion of human IgG1
Chimeric mAb against TNF
mAb against TNF
Composed of the Fab’ antigen
binding domain of a humanized
monoclonal anti-TNF antibody
bound to two molecules of PEG
Adeno-associated virus serotype 2
vector (AAV2) containing the
cDNA for the TNFR–Fc gene
(protein sequence identical to
etanercept)
Licensed
Licensed
Infliximab
Golimumab
Certolizumab
Pegol
tgAAC94
Licensed
Licensed
Licensed
Phase
I/II
IL-1


Induces expression of cell-adhesion molecules, cytokines, and chemokines.
Mediates destruction of bone and cartilage by production of MMPs and increased expression of RANKL
on synovial fibroblasts
Anakinra
AMG-108
Canakinumab
Recombinant form of IL-1RA
mAb for IL-1β
mAb for IL-1β
Licensed
Phase II
Phase II
IL-6

Activates DCs, monocytes, osteoclasts and chondrocytes in addition to enhancing T-cell and B-cell
differentiation.
Attenuates function of TREG cells by inducing TH17 cells
Tocilizumab
Humanized anti-IL-6 receptor
mAb
Phase III
Recruitment of leukocytes (neutrophils, T cells)
Stimulates release of IL-1 and TNF by macrophages and enhances the production of IL-6 and IL-8 by
synovial fibroblasts
Upregulates RANKL expression on osteoblasts and mesenchymal cells
Induces RANK on precursor osteoclasts
AIN-457
mAb for IL-17
Phase
I/II
STA-5326
Oral inhibitor of p40 subunit
shared by IL-12 and IL-23
Phase II
STA-5326
Oral inhibitor of p40 subunit
shared by IL-12 and IL-23
Phase II

IL-17






IL-23
IL-12




IL-17–/– mice or mice treated with anti-IL-17 antibodies have reduced severity of CIA and EAE (for
review see reference 1)
Blocking of IL-17 leads to reduction in bone erosion by suppressing joint inflammation, and suppressed
expression of IL-1ß and TNF 2
Member of the IL-12 superfamily and composed of p40 and p19 subunits
Required for the maturation of TH17 cells
Mice lacking the p19 or p40 components but not the p35 (needed for IL-12) subunit are protected from
EAE and CIA 3
IL-12 (formed from p40 and p35 subunits) is required for generation of TH1 cells producing TNF and
IFNγ
IL-15

Enhances T-cell and NK cell proliferation
AMG-714
mAb for 1L-15
Phase II
B cells
CD20

Expressed on pre-B and mature B lymphocytes but not on plasma cells
Rituximab
Ocrelizumab
Ofatumumab
Antibody to CD20
antibody to CD20
Antibody to CD20
Licensed
Phase III
Phase III
TRU-015
Single-chain construct containing
a single-chain Fv specific for
CD20 linked to human IgG1
hinge, CH2, and CH3 domains but
devoid of CH1 and CL domains
Phase II
CD19


Expressed at earlier stages of B cells, even before expression of pre-BCR
Essential for key B-cell differentiative events including the formation of B-1, germinal center, and MZ B
cells
MDX-1342
Human mAb for CD19
Phase I
BAFF



A critical factor for B cell maturation and survival
Overexpressed by DCs
Autoantibody levels and clinical activity correlates with BAFF levels in RA
Atacicept
Recombinant fusion protein of
BAFF and APRIL receptor
Phase II
Abatacept
CTLA4–Ig fusion protein
Licensed
CD80 on DCs provides a co-stimulatory signal necessary for T-cell activation
RhuDex
Oral inhibitor of CD80
Phase II
Promotes osteoclastogenesis
Denosumab
mAb against RANKL
Phase II
CP-690550
Oral JAK3 inhibitor
Phase II
Costimulatory molecule inhibitors
CTLA-4
 Expressed on TREG cells, has a key task in maintaining self tolerance
 Binds the costimulatory molecules CD80 and CD86 on DCs and blocks interaction with CD28 on T cells
CD80

Osteoclastogenesis
RANK–

RANKL
Inhibitors of intracellular signaling molecules
JAK3
 Signal transduction by receptors that employ the common gamma chain common gamma chain
Syk

Blocks activation of mast cells, macrophages and B cells
Fostamatinib
Oral Syk inhibitor
Phase II
p38

Blocks cytokine production (IL-1β, IL-6, TNF)
VX-702
SCIO-469
SB-681323
Oral p38 inhibitor
Phase II
Phase II
Phase II
*Posted on Clinicaltrials.gov
Abbreviations: APRIL, a proliferation inducing ligand; BAFF, B-cell activating factor of the TNF family; BCR, B-cell receptor; CH, constant heavy; CIA, collagen-II-induced arthritis; CL, constant
light; CTLA-4, cytotoxic T lymphocyte antigen 4; DCs, dendritic cells; EAE, experimental autoimmune encephalomyelitis; IFNγ, interferon γ; IL, interleukin; IL-1RA, IL-1 receptor antagonist; JAK,
Janus kinase; mAb, monoclonal antibody; MMP, matrix metalloproteinase; MZ, marginal zone; NK, natural killer; PEG, polyethylene glycol; RA, rheumatoid arthritis; RANK, receptor activator of
nuclear factor κB; RANKL, RANK ligand; TNF, tumor necrosis factor; .TREG cells, regulatory T cells; TH1 cells, type 1 T helper cells; TH17 cells, type 17 T helper cells.
References
1.
2.
3.
Oukka, M. Th17 cells in immunity and autoimmunity. Ann Rheum Dis 67 Suppl 3, iii26-9 (2008).
Koenders, M.I. et al. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by
decreasing RANKL and interleukin-1. Am J Pathol 167, 141-9 (2005).
Murphy, C.A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198, 19517 (2003).
Download