Accepted Manuscript Insights from immunology: new targets for new drugs? Tim Raine , MB BChir PhD
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 5 March 2014 Revised Date:
27 March 2014
Accepted Date: 13 April 2014
Please cite this article as: Raine T, Insights from immunology: new targets for new drugs?, Best Practice & Research Clinical Gastroenterology (2014), doi: 10.1016/j.bpg.2014.04.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Insights from immunology: new targets for new drugs?
Tim Raine, MB BChir PhD
Cambridge, Cambridge, CB2 0QQ UK
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tel: +44 1223 331130 [email protected]
Department of Medicine, Addenbrooke’s Hospital, University of
ABSTRACT Rapid advances in our understanding of inflammatory bowel diseases have resulted from the synthesis of data from experimental and genetic studies. These have suggested a wide range of potential immunological targets with both local
and systemic scope. Drugs to several of these targets have now reached phase I/II studies, and are discussed in the context of their scientific rationale.
However, despite the advent of new classes of therapeutics targeting cellular
trafficking and intracellular mediators of cytokine signalling, the
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armamentarium of effective therapeutics remains sparse. Only with more detailed experimental medicine studies will this imbalance be resolved.
Key words: mucosal immunology, inflammatory bowel diseases, Ulcerative
colitis, Crohn’s disease, therapeutics, immunotherapeutics, innate immunity
ACCEPTED MANUSCRIPT Introduction Crohn’s disease (CD) and ulcerative colitis (UC), the two key forms of inflammatory bowel disease (IBD), have long been understood to represent a chronic inflammatory response mounted by the immune system against a poorly
defined target antigen or antigens. As early as the 1959, antibodies reactive to
extracts prepared from macerated human colon were demonstrated in the sera of paediatric UC patients , whilst 1963 saw the demonstration in the same
patient population of cytotoxic leucocytes reactive against human colonic cells
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Subsequent advances in our understanding of the immunopathogenesis of IBD have drawn insight from animal models, studies of mucosal immunology and, more recently, genetic studies. These point to a paradigm of IBD as a set of
inappropriate immune responses to commensal flora in the host gastrointestinal mucosa, which is itself altered in a state of so-called dysbiosis . Such
responses appear more vigorous or sustained in a genetically susceptible individual, accounting for the familial nature of IBD. In the immunology of this
complex host-microbiota interplay, increasingly rich lines of evidence now point to roles for multiple different cellular players, which set the context for an immunological understanding of opportunities for therapeutic intervention in IBD.
Mucus and innate immune defence As a primary interface between the host and the commensal microbiota, as well as a key site of potential pathogenic challenge, the intestinal immune mucosa
ACCEPTED MANUSCRIPT must function not only as an absorptive epithelium for nutrients, but as a barrier capable of sensing and responding to changes in luminal contents. To this end a range of specialised cell types and functions cooperate to regulate mucosal
Separating the luminal contents from the cells of the mucosal immune system
are the dense mucus layers of the intestine. Formed from high-molecular weight
glycoproteins with a high negative surface charge, mucins exist in both cell-
surface anchored and secreted forms. 6 human genes encoding a secreted mucin
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have been described, 5 of which may in turn associate into complex oligomers that form a gel overlying the mucosal surface . A further 9 cell surface mucins extend over 100nm from the apical membranes of enterocytes, but may be cleaved by sheer stress  or inflammatory cues . Whilst cell surface mucins
are expressed across a range of cells within the gastrointestinal tract, in particular enterocytes, secreted mucins are predominantly formed within
specialised secretory cells, notably goblet cells. The mucus layer of the small intestine is less viscous and homogenous, but in the colon two distinct layers are
formed: an outer, loosely adherent layer that is colonised by luminal flora and a more viscous inner layer that excludes the overwhelming majority of luminal bacteria .
A common feature of active inflammation in UC is the loss of mucus through a variety of pathways, including goblet cell depletion , activation of goblet cell endoplasmic reticulum (ER) stress by accumulation of misfolded mucins  and altered mucin post-translational modification . Mice deficient or harboring
ACCEPTED MANUSCRIPT missense mutations in the major colonic mucin Muc2 show spontaneous colitis associated with goblet and Paneth cell ER stress responses [9, 11], suggesting that alterations in mucin function may be a primary driver of inflammation, rather than a bystander phenomenon. In contrast, in CD goblet cell numbers and
mucus layer thickness are preserved or even increased , although expression of particular mucin genes and hence mucus composition may change [13, 14].
Regardless of the cause/effect relationship, restoration of normal mucus barrier
function may represent an important therapeutic goal in IBD. To this end,
delivery of phospholipids to the colon using delayed release oral formulations
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has proven effective in placebo-controlled phase II studies in chronic active UC as an adjunct to 5-aminosalicylate (5-ASA) therapy , with current preparations for phase III studies of one particular formulation, LT-02.
As well as serving as a physical barrier, intestinal mucus also has important immunoregulatory functions, including the modification of T cell priming by
dendritic cells (DC) within the small intestinal lamina propria and the stimulation of enterocyte secretion of anti-inflammatory cytokines by MUC2
. Whether synthetic phospholipid preparations will have similar antiinflammatory properties beyond simple restoration of barrier function remains to be evaluated fully. Alternative strategies include the targeted upregulation of endogenous mucin production. Notably, probiotic bacteria including Lactobacillus spp. upregulate mucin production by cultured epithelial cells in vitro and reduce the adherence of enteropathogenic strains of E. coli .
Antimicrobial peptides and modulation of host microflora
ACCEPTED MANUSCRIPT Treatment with probiotic strains may also upregulate a number of other important mediators of innate immunity. Treatment with the non-pathogenic E. coli strain Nissle 1917 is as effective as 5-ASA therapy for maintaining remission in patients with UC . Potentially underlying this clinical efficacy and in
contrast to other E. coli strains, Nissle 1917 induces production of the
antimicrobial peptide beta-defensin-2 (BD-2) by cultured colonic epithelial cells . Defensins are small antimicrobial peptides stored within the cytoplasmic
granules of a range of leukocytes and secreted by epithelial cells into the
extracellular environment. Within the small intestinal lumen, Paneth cells
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provide the principle source of secreted defensins. Paneth cell depletion is a feature of murine models of spontaneous ileitis [20, 21], and Paneth cells are a site of convergence for multiple genetic risk factors in the pathogenesis of ileal CD . Reduced expression of Paneth cell defensins HD5 and HD6 has been
reported in ileal CD. However, defensins have not undergone clinical tests in IBD, and no trial data currently exist to support the use of probiotics in CD [23, 24],
despite initial promising results from small-scale randomised placebo controlled
studies of E. coli Nissle 1917 .
In contrast, modulation of intestinal flora with antibiotics is an alternative and increasingly evidence-based therapeutic strategy in IBD, particularly for CD [26, 27]. Difficulties with antibiotic side-effects, proliferation of resistant strains, and rebound bacterial regrowth after cessation of therapy have added interest to initial promising phase II studies of an extended release formulation of the minimally absorbed oral broad-spectrum antibiotic rifaximin in patients with moderately active CD .
Immunomodulation by commensal flora may be attributed to specific bacterial components. For example, the induction of BD-2 production from enterocytes discussed above by E. coli Nissle 1917 is dependent upon bacterial flagellin .
In addition, a capsular polysaccharide of E. coli Nissle 1917 potentiates the
effects of flagellin through upregulation of expression of Toll-like receptor 5
(TLR5, an innate immune receptor activated by flagellin) and of down-stream
signalling molecules MyD88 and TRIF . Likewise, agonists for TLR2 reduce
colonic inflammation in murine models by stabilising intercellular gap junctions
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 and tight junctions , as well as promoting goblet cell secretion of trefoil factor 3 (TFF3), a component of the mucus layer that promotes intestinal mucosal healing . This raises the possibility of therapeutic manipulation of immunity by targeting similar pathogen-associated molecular pattern (PAMP)
receptors. In this regard, it is intriguing to note the amelioration of multiple experimental colitis models with a TLR9 agonist , as well as the initial
uncontrolled report of therapeutic manipulation of chronic active UC by targeting TLR9 using the topically applied synthetic oligonucleotide DIMS0150
. A phase III trial of DIMS0150 as an add-on therapy in treatment-refractory active UC has completed recruitment and results are awaited.
TLR9, in common with other PAMP receptors, is widely expressed on a range of cell types within the gastrointestinal mucosa, including both epithelial cells and immunocytes with a wide range of contrasting functions . Even at the level of a single enterocyte, effects of TLR9 stimulation may vary depending upon the polarity of TLR9 activation, with stimulation of TLR9 through the apical
ACCEPTED MANUSCRIPT membrane resulting in downregulation of subsequent responses to TLR signalling, but stimulation of TLR9 at the basolateral membrane (as might occur following a breakdown in epithelial integrity) leading to an inflammatory response . Thus, therapeutic use of topical PAMP receptor agonists will
Autophagy as a therapeutic target?
require careful dissection and may well not fit with the predictions of in vitro
One of the major conceptual advances from studies of the genetic basis of
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susceptibility to IBD came with the recognition of the importance of autophagy – the process of destruction of intracellular contents through engulfment into vesicles known as autophagosomes and subsequent targeting for enzymatic degradation through fusion of autophagosomes with lysozomes. Indeed,
mutations in the autophagosome assembly gene ATG16L1 are one of the single biggest determinants of genetic risk in IBD . Defects in autophagy result in
defective epithelial barrier function through defective clearance of intracellular bacteria , impair resolution of ER stress leading to transmural inflammation
in murine models , and increase pro-inflammatory cytokine secretion in response to cellular stress . In this context, the successful use of sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR) with potent autophagy inducing properties, to treat an individual with refractory CD  suggests induction of autophagy as a therapeutic target. However, a phase II study in CD of everolimus, a related mTOR inhibitor, failed to demonstrate benefit [42, 43]. Whether the targeted augmentation of autophagy in individuals with genetic defects, may emerge as a therapeutic adjunct in IBD remains to be tested.
Subverting communications If PAMP receptor stimulation in the gut can have pleiotropic effects, this is even more true for immunomodulation through the targeting of cytokines. This is one
of the most active areas of IBD therapeutics research, and involves subversion of inter-cellular communication by targeting the small protein messengers of the immune system. In this regard, the development of monoclonal antibodies
binding to tumour necrosis factor-α (TNFα) has resulted in arguably the single
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greatest advance in the IBD therapeutic armamentarium since corticosteroids. TNFα is secreted by a range of cell types including activated macrophages and T cells within the lamina propria and may induce responses both locally (through the effects of membrane-anchored TNFα), as well as systemically (after
proteolytic cleavage of the membrane anchor to yield soluble TNFα). A wide range of effects have been demonstrated for anti-TNFα therapy, including neutralisation and clearance of soluble TNFα, the induction of T cell apoptosis,
generation of regulatory T cells and regulatory macrophages, reduction of T cell activation and cell cycling, and inhibition of inflammatory cell migration .
Indeed, whilst the hierarchy of these and other potential mechanisms within the response to anti-TNFα therapy remains to be determined, it is likely that multiple mechanisms synergise in reducing intestinal inflammation.
Identifying the principle mechanisms behind the therapeutic effects of anti-TNFα therapies might allow for more targeted immunomodulation with a concomitant reduction in the risk of immunosuppression. In this regard, the contrasting
ACCEPTED MANUSCRIPT clinical efficacies of different anti-TNFα agents is informative. Infliximab, and adalimumab are monoclonal immunoglobulin G (IgG) antibodies capable of binding both soluble and membrane associated forms of TNFα. Etanercept, a soluble fusion protein of TNF-receptor 2 with the constant region of IgG1, binds
soluble TNFα but is less effective at blocking membrane-bound TNFα. The
clinical utility of infliximab and adalimumab in IBD contrasts with the lack of
efficacy of etanercept . This suggests binding of membrane bound TNFα is
more important than neutralisation of soluble TNFα for efficacy in IBD
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treatment. A different monoclonal antibody, certolizumab, consists of the variable Fab’ fragment of the IgG molecule, responsible for antigen binding, but lacks the constant Fc region tail. Whilst infliximab and adalimumab have been shown to induce a population of macrophages in vitro associated with mucosal
repair, this effect is dependent upon the Fc domain and hence certolizumab lacks this capacity . Nonetheless, certolizumab is a clinically effective IBD therapy, suggesting that induction of regulatory macrophages is a less important
mechanism of action in vivo. Whilst previous reports differ in the extent to which clinically effective anti-TNFα therapies may directly induce apoptosis in mucosal
lymphocytes, infliximab, adalimumab and certolizumab, but not etanercept, have been shown to induce apoptosis of CD4+ T cells within the lamina propria in an indirect manner requiring binding to membrane associated TNFα on CD14+ intestinal macrophages . This effect was only seen in T cells bearing TNFreceptor 2 (TNFR2) and T cells could be rescued from apoptosis by increased signalling through the interleukin-6 receptor (IL6R). Thus simultaneous
ACCEPTED MANUSCRIPT blockade of TNFR2/IL6R signalling in mucosal T cells might prove a more effective and targeted route in IBD treatment.
The clinical efficacy of anti-TNFα therapeutics in IBD remains suboptimal, with
only approximately 40-60% of patients achieving initial remission, and
subsequent loss of response in around 70% these initial responders. Set against this need for new therapeutics, a litany of failed trials in anti-cytokine
therapeutics highlights difficulties of predicting the effects of blockade of
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pleiotropic molecules in vivo and the dangers of an oversimplistic interpretation of data from model systems, as reviewed elsewhere in this issue by Kaser. To take but one informative example, secukinumab is a monoclonal antibody against IL-17A that showed initial positive results in trials with plaque psoriasis, rheumatoid arthritis, non-infectious uveitis  and psoriatic arthritis  but a
phase II study in CD proved ineffective and even showed a tendency towards disease exacerbation . IL-17A emerged as an attractive therapeutic target
out of data from murine models and IBD patients suggesting upregulated IL-17A and other related T helper 17 (Th17) cytokines within inflamed tissue [51, 52].
Studies of genetic susceptibility to IBD have also implicated genes associated with Th17 biology in disease causation . However, murine data also highlight the complexity within the Th17 family, with functional redundancy and reciprocal regulation by various family members including IL-17A, IL-17F and IL-22 . Transfer of T cells from mice with genetic deletion of IL-17A causes colitis in immunodeficient recipient mice that is indistinguishable from that seen in mice receiving T cells from wild-type donors, and that depends on IL-17F upregulation, indicating redundancy between IL-17A and IL-17F . In
ACCEPTED MANUSCRIPT contrast, IL-22 appears protective in similar murine models [56, 57] and has been shown to drive epithelial cell proliferation and production of anti-microbial peptides and mucins . Moreover, the balance of pro- and anti-inflammatory effects of IL-22 appears to be modulated by the presence of IL-17A .
Furthermore, Th17 cytokine production within the intestinal mucosa is not limited to T cells, with other important sources of Th17 family members
including innate lymphoid populations with both colitogenic and regulatory
potential [60, 61]. Thus blockade of a single cytokine might result in unforeseen
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and complex reciprocal effects in multiple cell populations.
Despite this rather cautious note, a number of potential cytokines remain as attractive and untested targets in IBD. As already discussed, IL-6 mediates resistance of luminal T cells to apoptosis and may synergise with the effects of
anti-TNFα therapeutics . Mucosal T cells from patients with CD show IL-6 mediated resistance to apoptosis through upregulation of the anti-apoptotic
mediators bcl-2 and bcl-xl and blockade of IL-6R signalling ameliorates colitis in a variety of animal models via the induction of lamina propria T cell apoptosis
. Tocilizumab, a monoclonal neutralising antibody to IL-6R showed significant benefit over placebo in the primary outcome of clinical response in a phase II study in active CD  but did not result in phase III studies. A potentially more broad-ranging strategy would involve targeting gp130, a subunit of the IL-6R that also mediates signals for a number of IL-6 related cytokines, including IL-11 and IL-27. Antagonism of IL-6R signalling, using engineered variants of gp130 fused to an IgG Fc domain represents such an approach and may be entering clinical trials .
Alternative novel cytokine blockade strategies currently attracting attention include targeting of IL-13. IL-13 is produced from natural killer T (NKT) cells within the lamina propria in murine models of UC in which IL-13 neutralisation
is protective . Increased production of IL-13 by immunocytes in the lamina propria has been linked to decreased barrier function and epithelial apoptosis
, although IL-13 has also been reported to stimulate goblet cell hyperplasia
and mucin secretion . However, recent phase II trial data in UC from
tralokinumab, an anti-IL-13 monocloncal antibody, have proven disappointing
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Evidence is emerging for the role of multiple other newly described cytokines in murine models of colitis and in IBD. Potential new targets with promising animal
model data include IL-21, IL-27 and IL-33 . However, the successes of antiTNFα therapy notwithstanding, clinical failures of therapeutics targeting a single
cytokine must raise a note of caution. Alternative therapeutic strategies involve targeting a broad range of pro-inflammatory cytokines through the inhibition of
shared pathways of intracellular signalling. Such targets include the janus kinase (JAK) family, which transduce signals from a wide range of cytokine receptors . The 4 human JAK family members, JAK1, JAK2, JAK3 and TYK2 share a high degree of homology and hence small molecular inhibitors show cross-reactivity across the whole family. JAK1 and JAK3 transduce signals through the IL-2 receptor common γ-chain, a core component of the receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 and hence play a key role in the activation and maintenance of T cells, as well as other immunocytes. Signal transduction functions of JAK2
ACCEPTED MANUSCRIPT include signals through the IL-6R gp130 discussed above, a shared component of signalling for IL-6, IL-11, IL-27 and other cytokines. The first oral inhibitor or JAK signalling to enter clinical studies was Tofacitinib, a potent JAK1/3 antagonist, with limited JAK2 antagonism. Tofacitinib has shown promising
results in phase II studies in UC  and has now entered phase III studies, whilst a phase II study in CD demonstrated no benefit over placebo .
The broad array of cytokines (and other signalling pathways) inhibited by
tofacitinib raise considerable concerns of immunosuppressant and off-target
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effects. Indeed, whilst the US Food and Drug Administration (FDA) have granted tofacitinib its first license for use in rheumatoid arthritis, the European Medicines Agency (EMA) refused a similar request owing to unresolved safety concerns. Meanwhile, multiple other oral JAK inhibitors with differing degrees of
specificity have entered pre-clinical studies and clinical trials, mostly in rheumatoid arthritis. Whether these will impact upon the IBD therapeutic
armamentarium remains to be seen.
Anti-inflammatory cytokine signalling: Bolstering the defences? As an alternative to blockade of inflammatory cytokines, augmentation of antiinflammatory cytokine signalling is theoretically attractive. IL-10 is a prototypic anti-inflammatory cytokine and IL-10 knockout mice develop spontaneous colitis . Patients with germ-line mutations in the IL-10 receptor have been reported to develop severe, early-onset IBD [74, 75]. However, subcutaneous delivery of recombinant IL-10 did not benefit patients with active CD . Alternative approaches may involve the use of bacteria engineered to express IL-
ACCEPTED MANUSCRIPT 10 to deliver recombinant cytokine topically  or the use of probiotic strains with the capacity to upregulate production of IL-10 from intestinal macrophages .
In both UC and CD, defective activity of the anti-inflammatory cytokine
transforming growth factor (TGF)-β has been linked to upregulation of SMAD7, an inhibitor of TGF-β signalling . Delivery of antisense oligonucleotides to
SMAD7 to 15 CD patients in a phase I study was associated with changes in proinflammatory cytokine secretion profiles of circulating peripheral T cells and a
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significant decrease in disease activity . Since TGF-β has pro-fibrotic as well as anti-inflammatory properties, increased CD-related stricturing is a concern, though none of the phase 1 patients demonstrated any evidence of stricture
formation or upregulation of growth factors associated with stricture formation
As discussed above, the Th17 family member IL-22 is associated with protection in murine models of colitis, stimulation of epithelial repair and mucin formation
[56-58]. IL-22 induction through the delivery of ligands for the aryl-hydrocarbon receptor (AhR) was associated with protection in murine models of colitis, suggesting that delivery of IL-22 or targeting of AhR might offer therapeutic potential in IBD . Other potentially protective cytokines still at the very early stage of biological exploration in IBD include IL-35  and IL-25 .
Cellular traffic: Therapeutic roadblocks?
ACCEPTED MANUSCRIPT Although many of the cytokines discussed in the preceding sections may be produced by cell populations ordinarily resident within the intestine, the massive upregulation of pro-inflammatory mediators seen in both CD and UC is associated with an influx of cells of the adaptive immune system. The homing
and retention of these cells to the gut has been well studied and is dependent
upon the expression of specific adhesion molecules and chemokine receptors
along with their ligands . For example, naïve T cells encountering antigen
presented by DCs in the gut-draining mesenteric lymph nodes undergo
upregulation of the integrin α4β7 and the chemokine receptor CCR9 (the
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receptor for the chemokine CCL25 expressed in the small-bowel epithelium), and down-regulation of L-selectin .
Disruption of this gut-homing mechanism has emerged as an exciting area of IBD
therapeutics. Phase III studies of vedolizumab, a monoclonal antibody to the α4β7 integrin described above, have provided impressive evidence of efficacy for
induction and maintenance of remission in UC , as well as promising if less impressive data for CD . Etrolizumab, a monocloncal antibody to the β7
subunit has the potential to block α4β7, but also αEβ7, an integrin reported to be involved in the retention of T cells resident within the epithelial layer of the gut , with positive phase II results presented (and soon to be published) from the EUCALYPTUS study for induction therapy in UC. Although the studies were not powered for sub-stratification by prior anti-TNFα exposure, neither vedolizumab nor etrolizumab appears to give significantly better results in patients who have previously failed anti-TNFα therapy, confounding hopes that
ACCEPTED MANUSCRIPT this group of patients might be enriched for non-TNFα driven disease that might be more amenable to alternative therapeutic strategies.
Several other inhibitors of integrin signalling are currently in clinical
development . These include PF-00547659, a monoclonal antibody against
mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) currently in
phase II trials in UC and CD. MAdCAM-1 is expressed on endothelial cells within
the gut, and a principal ligand for α4β7 integrin. Alicaforsen, is an anti-sense
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oligonucleotide to intercellular adhesion molecule-1 (ICAM-1) upregulated on inflamed endothelium as well as on leucocytes. Although alicaforsen failed to demonstrate benefit in studies of systemic administration in CD, phase II trials of topical delivery in UC yielded positive data . Currently, alicaforsen is being
developed as a treatment for chronic pouchitis.
Targeting chemokine signalling might offer an alternative to anti-adhesion
molecule therapies in the regulation of cell trafficking in IBD. Vercinon, an orally available inhibitor of CCR9 signalling, showed promise in phase II studies, but
failed to show benefit in phase III studies in CD. Likewise, monoclonal antibody therapy against CXCL10, a chemokine upregulated within inflamed mucosa in UC , failed to demonstrate benefit in phase II studies in UC . Functional redundancy within the complex network of chemokines and their receptors, inappropriate target selection, and difficulties achieving sufficient therapeutic concentrations may all account for difficulties with strategies focussed on single chemokine receptors or ligands . In this regard, the broad suppression of chemotactic responses mediated by agonists at sphingosine-1 phosphate (S1P)
ACCEPTED MANUSCRIPT receptors is being evaluated with recruitment currently underway for a phase II study in UC of RPC1063, a selective S1P1R modulator .
Conclusion – the devil is in the (lack of) detail
If in this brief overview one key theme emerges, it is of a series of promising ideas born out of experimental models, studies of mucosal immunology and
population genetics which ultimately succeed, but more often fail, in the context
of phase II/III clinical trials. In this simplistic binary approach the failure of a
study compound is often the last word on targeting a given pathway, with insight
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rarely gained (or at least, rarely shared) into reasons why the compound may have performed in a certain manner, or even what effects the compound actually has on the mucosal immune system of recipients. Moreover, for reasons that may have more to do with trial design and economics than scientific rationale, the
same drug is often tested for induction as well as maintenance of remission,
though on a biological level these two entities may differ.
Whilst the study of model systems and phenotypic analysis of patient data have
advanced our understanding of IBD, only with the study of the effects of immune perturbations in the context of clinical trials will we be able to refine our models of mucosal inflammation. Such studies have hitherto been scarce, but must be built in to the next generation of clinical trials if we are to avoid losing further valuable opportunities to extend our knowledge and refine our therapeutics. At the same time, consideration of the genotype and a more detailed immunophenotyping of study participants may allow the identification of responder subgroups classified not by traditional clinical parameters, but by
ACCEPTED MANUSCRIPT defects in key regulatory pathways, such as those discussed above. If through careful research planning and dialogue between academia and the pharma these challenges can be met, the prospects for future IBD therapeutics will be
What defines subgroups of patients who respond to existing therapeutics?
Can we identify different subtypes of disease based upon a synthesis of
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immunological and genetic risk classification?
Are effective induction and maintenance therapies necessarily the same? Can induction of remission be achieved with drugs targeting e.g. systemic inflammatory mediators, whilst remission is maintained with agents
bolstering mucosal immune homeostasis?
Why do drugs fail? What can we learn from building immunological
substudies into early phase I/II protocols?
Funding Supported by the Wellcome Trust (WT091993MA postdoctoral clinical
fellowship to TR), European Crohn’s and Colitis Organisation (ECCO research grant to TR), and the National Institute of Health Research (NIHR) Biomedical Research Centre award to Addenbrooke’s Hospital/University of Cambridge School of Clinical Medicine.
ACCEPTED MANUSCRIPT Conflict of interest: TR reports personal fees and non-financial support from GSK, MSD and Abbvie, and non-financial support from Ferring, Abbott, Shire, and Dr Falk, outside the submitted work.
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