Table 1 Biologic Therapies for RA: Immune Targets

Table 1 | Biologic therapies for RA: immune targets

Biologic therapies for RA: immune targets Target Reason for targeting Therapeutic Structure *Status agent

Cytokine TNF  Activates multitude of cells and promotes production of chemokines and proinflammatory cytokines Adalimumab mAb against TNF Licensed  Promotes articular destruction by induction of RANKL on synovial fibroblasts Etanercept Fusion protein consisting of human Licensed soluble TNFR (p75) linked to the Fc portion of human IgG1 Infliximab Chimeric mAb against TNF Licensed Golimumab mAb against TNF Licensed Certolizumab Composed of the Fab’ antigen Licensed Pegol binding domain of a humanized monoclonal anti-TNF antibody bound to two molecules of PEG tgAAC94 Adeno-associated virus serotype 2 Phase vector (AAV2) containing the I/II cDNA for the TNFR–Fc gene (protein sequence identical to etanercept)

IL-1  Induces expression of cell-adhesion molecules, cytokines, and chemokines. Anakinra Recombinant form of IL-1RA Licensed  Mediates destruction of bone and cartilage by production of MMPs and increased expression of RANKL AMG-108 mAb for IL-1β Phase II on synovial fibroblasts Canakinumab mAb for IL-1β Phase II

IL-6  Activates DCs, monocytes, osteoclasts and chondrocytes in addition to enhancing T-cell and B-cell Tocilizumab Humanized anti-IL-6 receptor mAb Phase III differentiation.

 Attenuates function of TREG cells by inducing TH17 cells

IL-17  Recruitment of leukocytes (neutrophils, T cells) AIN-457 mAb for IL-17 Phase  Stimulates release of IL-1 and TNF by macrophages and enhances the production of IL-6 and IL-8 by I/II synovial fibroblasts  Upregulates RANKL expression on osteoblasts and mesenchymal cells  Induces RANK on precursor osteoclasts

 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

IL-23  Member of the IL-12 superfamily and composed of p40 and p19 subunits STA-5326 Oral inhibitor of p40 subunit shared Phase II

 Required for the maturation of TH17 cells by IL-12 and IL-23  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  IL-12 (formed from p40 and p35 subunits) is required for generation of TH1 cells producing TNF and STA-5326 Oral inhibitor of p40 subunit shared Phase II IFNγ by IL-12 and IL-23 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 Antibody to CD20 Licensed Ocrelizumab antibody to CD20 Phase III Ofatumumab Antibody to CD20 Phase III

TRU-015 Single-chain construct containing a Phase II single-chain Fv specific for CD20 linked to human IgG1 hinge, CH2, and CH3 domains but devoid of CH1 and CL domains

CD19  Expressed at earlier stages of B cells, even before expression of pre-BCR MDX-1342 Human mAb for CD19 Phase I  Essential for key B-cell differentiative events including the formation of B-1, germinal center, and MZ B cells

BAFF  A critical factor for B cell maturation and survival Atacicept Recombinant fusion protein of Phase II  Overexpressed by DCs BAFF and APRIL receptor  Autoantibody levels and clinical activity correlates with BAFF levels in RA

Costimulatory molecule inhibitors

CTLA-4  Expressed on TREG cells, has a key task in maintaining self tolerance Abatacept CTLA4–Ig fusion protein Licensed  Binds the costimulatory molecules CD80 and CD86 on DCs and blocks interaction with CD28 on T cells

CD80  CD80 on DCs provides a co-stimulatory signal necessary for T-cell activation RhuDex Oral inhibitor of CD80 Phase II

Osteoclastogenesis RANK–RANKL  Promotes osteoclastogenesis Denosumab mAb against RANKL Phase II

Inhibitors of intracellular signaling molecules JAK3  Signal transduction by receptors that employ the common gamma chain common gamma chain CP-690550 Oral JAK3 inhibitor Phase II

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 Oral p38 inhibitor Phase II SCIO-469 Phase II SB-681323 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. Oukka, M. Th17 cells in immunity and autoimmunity. Ann Rheum Dis 67 Suppl 3, iii26-9 (2008). 2. 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). 3. Murphy, C.A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198, 1951- 7 (2003).