Immunotherapy in inflammatory bowel disease: Novel and emerging treatments

Figures & data

Table 1. Novel drugs, therapeutic targets and current status in clinical studies.

Drug	Target	Pathway/mechanism of action	Administration	Tested in UC/CD	Main issues and side effects
Ustekinumab^Citation46	p40	IL-12/IL-23	IV, SC	CD (approved) UC phase III	Cardiovascular safety.
ABT-874 (briakinumab)^Citation49	p40	IL-12/IL-23	IV	CD phase II	No clear benefit. Cardiovascular safety. Discontinued.
AMG 139/MEDI2070 (brazikumab)^Citation53	p19	IL-12/IL-23	IV, SC	CD phase II	—
BI 655066 (risankizumab)^Citation54	p19	IL-12/IL-23	IV, SC	CD phase II	—
Tocilizumab^Citation68	IL-6R	IL-6	IV	CD	No further studies since 2004.
PF-04236921^Citation69	IL-6	IL-6	SC	CD phase II	Serious adverse events including 1 death, perforations and abscesses.
Tofacitinib^Citation74^,^Citation79	JAK-1, JAK-2, JAK-3	Jak inhibitor	Oral	UC phase III	Increased risk for infections. Alterations in serum lipids observed. Unclear efficacy in CD.
				CD phase III
Filgotinib^Citation80	JAK-1	Jak inhibitor	Oral	UC phase III	Increased risk for infections.
				CD phase III	Endoscopic improvement did not reach significance in UC.
Laquinimod^Citation86	—	Th1/Th17	Oral	CD phase II	Good safety profile. Ongoing long-term trials
Morgensen^Citation94	SMAD7	TGF-β1 pathway	Oral	UC phase II	Lack of endoscopic outcomes in the main studies. Concerns about stricture formation (fibrosis). Premature discontinuation of long-term studies for CD by October 2017.
				CD phase II
Alicaforsen^Citation105	ICAM-1	Blocking ICAM-1 production by complementary hybridization to mRNA target gene	IV	CD, UC, pouchitis	Intravenous formulation ineffective in CD.
			Enema
Natalizumab^Citation110	α4-subunit of α4β1 and α4β7 integrins	Inhibition of lymphocyte adhesion to VCAM-1 and MAdCAM-1	IV	CD	Not gut specific. PML.
Vedolizumab^Citation114^,^Citation115^,^Citation119	α4β7	Inhibition of lymphocyte adhesion to MAdCAM-1	IV	CD, UC	Currently approved for UC and CD.
AMG 181/MEDI7183 (abrilumab)^Citation120^,^Citation121	α4β7	Inhibition of lymphocyte adhesion to MAdCAM-1	SC	CD, UC	Primary end point not met in CD.
				phase II
PF-00547659^Citation122^,^Citation123	MAdCAM-1	Inhibition of lymphocyte adhesion to α4β7	SC	CD, UC	Not better than placebo in CD.
				phase II
Etrolizumab^Citation124	β7 of αEβ7 and α4β7 integrins	Inhibition of lymphocyte adhesion to E-cadherin and to MAdCAM-1	SC	CD, UC	—
				phase III
AJM300^Citation113	α4 of α4β1 and α4β7 integrins	Adhesion to VCAM-1 and MAdCAM-1	Oral	UC phase II	Concern for PML-risk as it targets α4β1 (as natalizumab)
Ozanimod^Citation126	S1PR1/5	Sphingosine-1-Phosphate (S1P) receptor agonist	Oral	UC phase III	Lymphopenia and risk for infections in the long term need to be addressed.
				CD phase II
Etrasimod (APD334)	S1PR1	Sphingosine-1-Phosphate (S1P) agonist	Oral	UC phase II	—
Amiselimod (MT-1303)	S1PR1/5	Sphingosine-1-Phosphate (S1P) agonist	Oral	CD phase II	_
Mesechymal Stem cells^Citation150-Citation152	Several immune-regulating targets	Several immune-regulating targets	IV	UC, CD	Small studies
					Unclear dosing
					Unknown dose or long-term safety
Tregs^Citation168^,^Citation169	Production of IL-10 and TGF-β	Several anti-inflammatory effects	IV	CD	Type of Treg to use not fully clear. Lack of clinical studies with placebo arm

Figure 1. Immunological pathways targeted by the main novel therapies for IBD. A loss of intestinal barrier integrity takes place in IBD, leading to translocation of bacteria that triggers an exaggerated immune response with secondary activation of Th cell responses (Th1, Th2, Th17). We show the main drugs inhibiting IL-6 pathway, IL-12/23 axis, Jak inhibitors, laquinimod and stimulators of TGF-β1 pathway (mongersen). Drugs inhibiting TNF-α already approved for use in IBD and cell therapies using MSCs and Tregs and their main immune-modulation functions are depicted in the centre. Substances targeting different adhesion molecules are described in the blood vessel and in the gut epithelium (etrolizumab). On the bottom right, we show the mechanism of action of drugs reducing the circulating lymphocytes by sequestering them in secondary lymphoid organs (sphingosine-1-phosphate receptor modulators). Main abbreviations: IEL, intraepithelial lymphocyte; DC, dendritic cell; JAK, Janus kinase; STAT, signal transducer and activator of transcription; IL, interleukin; Th, T helper lymphocyte; TGF-β, transforming growth factor-beta; RA, retinoic acid; IFNγ, interferon gamma; S1P, sphingosine-1-phosphate.

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