Emerging immunotherapies for rheumatoid arthritis

Figures & data

Figure 1. Schematic demonstration of intracellular signaling targets currently of therapeutic interest in rheumatoid arthritis. Green text: licensed for RA and currently in use. Orange text: undergoing clinical trials in RA. Blue text: evidence of therapeutic effect in animal inflammatory arthritis models. Brown text: evidence of therapeutic effect or undergoing trials in malignancy. Purple text: evidence of therapeutic benefit or undergoing trials in other conditions. JAK-STAT, Janus Kinases-signal transducer and activator of transcription; BTK, Bruton’s tyrosine kinase; SyK, Spleen Tyrosine Kinase; PI3K/Akt/mTOR, mammalian target of rapamycin / serine/threonine kinase Akt / phosphatidyloinositide 3-kinases; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; TWEAK, TNF-like weak inducer of apoptosis; RANK-Ligand, receptor activator of NFkB-ligand; IDO, Indoleamine 2,3-dioxygenase; RORγt, Retinoic acid receptor-related orphan nuclear receptor gamma; ITP, idiopathic thrombocytopenic purpura.

Figure 2. Cytokines targeted in rheumatoid arthritis. Main cell populations and sources of named cytokines. Green: licensed and currently in use. Yellow: currently undergoing trials. Red: ineffective or not taken forward to further trials. FB, synovial fibroblast; M0, macrophage; T, T cell; Imm B, immature B cell; Mat B, mature B cell. *Note anakinra is not licensed for use in the United Kingdom for RA.

Table 1. Completed anti-cytokine trials

Target (structure)	Name	Phase	Clinical trial number	Completion date	Trial cohort	Comment
GM-CSF	KB003	II	NCT00995449	Feb 2012	Biologic-IR	Continuing development in severe asthma
Lymphotoxin β (LTβR-Ig)	Baminercept	II	NCT00664716	October 2008	DMARD-IR	Did not meet primary endpoint for efficacy (Ref. 79)
IL-17	Ixekinumab	II	NCT00966875	March 2011	DMARD-IR and TNF-IR	Ref. 80
BAFF	Tabalumab	II	NCT00785928	January 2010	MTX-IR	Ref. 81

Trials registered at clinicaltrials.gov of agents that target cytokines for which therapies currently exist (for example, IL-6 and its receptor) not included, nor trials that have progressed to a later trial (in Table 2). Abbreviations: IR, inadequate responder; DMARD, disease-modifying anti-rheumatic drug; MTX, methotrexate); BAFF, B cell activating factor; LTβR, lymphotoxin β receptor).

Table 2. Currently recruiting anti-cytokine trials

Target (structure)	Name	Phase	Clinical trial number	Completion date	Trial cohort	Comment
IL-20	NNC0109–0012	IIb	NCT01636843	December 2015	MTX-IR
IL-20	NNC0109–0012	IIb	NCT01636817	September 2015	TNF-IR
IL-17 and TNFa	ABT-122	I	NCT01853033	December 2013	RA	Dual variable domain-Ig
GM-CSFRa	Mavrilimumab	II	NCT01712399	January 2019	RA	Extension study
GM-CSFRa	Mavrilimumab	II	NCT01715896	July 2015	MTX-IR	Comparison study against Golimumab
GM-CSF	MORAb-022	I	NCT01357759	May 2014	RA
IL-17	Secukinumab	III	NCT01640938	August 2019	TNF-IR	Extension study to initial phase III study
IL-17	Secukinumab	III	NCT01770379	January 2020	TNF-IR	REASSURE 2
IL-17	Secukinumab	III	NCT01377012	August 2013	TNF-IR	REASSURE trial extension
IL-17	Secukinumab	III	NCT01350804	August 2015	TNF-IR	NURTURE-1 (including Abatacept comparator arm)

Trials registered at clinicaltrials.gov.

Table 3. Currently licensed anti-TNFα therapies

	Structure	Target	Administ-ration	Comment
Infliximab	Chimeric antibody (25% murine, 75% human sequence)	Soluble and transmembrane TNF	IV monthly	Does not target lymphotoxin-α; First anti-TNF
Adalimumab	Humanised	Soluble and transmembrane TNF	SC two weekly
Etanercept	Fusion protein (x2 p75 human TNF receptor 2 bound to-Fc)	Predominantly soluble TNF	SC two weekly	Reduced efficacy in granulomatous conditions (polyangiitis with granulomatosis, Crohn's, sarcoidosis) but reduced risk from infections in which immune protection is dependent upon granuloma formation (tuberculosis, histoplasmosis, listeriosis)
Golimumab	Humanised	Soluble and transmembrane TNF	SC or IV monthly
Certolizumab pegol	Fab fragment of an IgG1 against TNFa covalently linked to 2 polyethylene glycol molecules	Soluble and transmembrane TNF	SC monthly	No Fc region hence does not fix complement or induce antibody-dependent cell-mediated cytotoxicity. Pegylation reduces elimination permitting monthly administration. Potentially prevents the development of anti-drug antibodies

IV, intravenous; SC, subcutaneous.

Table 4. Clinical trials using MSC or TolDC for the treatment of RA

Cell type	Disease	Phase^1	Location	Clinical trial number
Allogeneic umbilical cord derived MSC	RA	I/II	The 323 Hospital of Chinese People’s Liberation Army, China	NCT01547091
Allogeneic adipose-derived MSC	RA	I	23 Hospitals in Spain	NCT01663116
Allogeneic mesenchymal precursor cells	RA	I	Arthritis Treatment Centre, Maryland, USA	NCT01851070
Bone marrow derived MSC^2	RA with OA	II	Royan Institute, Iran	NCT01873625
Autologous TolDC (BAY)	RA	I	University of Queensland, Australia	Unknown
Autologous TolDC (Dex/D3)	RA psoriatic arthritis	I	Newcastle University, UK	NCT01352858

BAY, DC tolerised by treatment with BAY 11–7082; Dex/D3, DC tolerised by treatment with dexamethasone and vitamin D3; MSC, mesenchymal stromal cells; TolDC, tolerogenic dendritic cells. ¹Phase I is testing of safety, Phase II is determining the effective dose. ²Allogeneic/autologous not defined.

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