Leading soluble ligand: an overview of treatment targets for inflammatory bowel disease

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by persistent inflammation in genetically susceptible hosts.

More and more evidence supports that cytokines against IBD can effectively control inflammation.

Compared with traditional drug targets (such as receptors) used for the treatment of IBD, at least three factors have contributed to the increasing importance of soluble ligands as drug targets.

The ultimate goal of IBD treatment is to improve the quality of life of patients by achieving clinical, patient report or endoscopic remission.

In the past two decades, with the development and application of biopharmaceuticals, IBD treatment strategies, especially moderate to severe IBD, have undergone tremendous changes.

In the past two decades, a large number of soluble ligand-targeted drugs represented by anti-TNF-α monoclonal antibodies (mAb) have significantly improved the remission and maintenance efficacy of IBD patients.

According to a rough analysis of the database, cytokines accounted for 82.

Currently, inflammatory cytokines are the main soluble ligands for targeted therapy, and twenty drugs targeting soluble ligands have been approved for clinical treatment of IBD (Figure 1).

According to Johnson & Johnson’s 2020 financial report, the market performance of Starnox (usnumab) was exceptionally strong, with revenues of USD 7.

The financial data of the top 20 targets reported in 2018 shows that TNF is the most valuable drug, with total sales of US$163 billion from 2011 to 2015.

Tumor necrosis factor superfamily and its targeted drugs

A large number of studies have proved that TNF-α plays an important role in the pathogenesis of IBD, especially CD.

Four anti-TNF mAbs have been approved for the treatment of IBD: Infliximab, Adalimumab, Certuzumab, and Golimumab.

Two multicenter, randomized, double-blind, placebo-controlled studies showed that after 8 weeks of induction, patients who received IFX showed clinical remission than patients who received placebo.

TL1A (also known as TNFSF15) is another ligand for targeted anti-TNF therapy.

PF-06480605 is a fully human immunoglobulin G1 mAb targeting TL1A.

Tumor necrosis factor superfamily and its targeted drugs

Interleukin and its targeted drugs

The development of drugs targeting interleukins offers some advantages over anti-TNF drugs.

IL-12 is a type I heterodimeric cytokine composed of p35 and p40 subunits.
IL-12p40 subunit can also be combined with specific IL23p19 subunit to form a closely related cytokine IL-23.
IL-12 and IL-23 are mainly secreted by activated dendritic cells, monocytes and macrophages.
In the early stages of IBD, IL-12 is the main p40-containing cytokine, not IL-23.
It mainly induces Th1 cell differentiation, activates macrophages and induces the production of IFN-γ.
The IL-23-dependent inflammatory response promotes the chronicity of the disease and promotes the secretion of a variety of inflammatory factors by inducing the Th17 phenotype.
It has been found that the expression of IL-12/IL-23 is significantly increased in IBD.

UST is produced by immunizing human immunoglobulin (hu-Ig) transgenic mice with recombinant human IL-12, which binds to the soluble cytokines IL-12 and IL-23 and blocks its binding to the receptor.
It was approved for moderate to severe CD in the United States in 2016 and Europe in 2017.
The European Medicines Agency and the FDA approved moderate to severe UC in September 2019 and October 2019, respectively.
UST was officially launched in China in June 2019 and was approved in 2020 for the treatment of adults with CD who have insufficient or intolerance to traditional therapies or TNF-α antagonists.

The clinical efficacy and safety data of UST with moderate to severe CD were collected in two 8-week induction trials (UNITI-1 and UNITI-2) and a 44-week maintenance trial (IM-UNITI).
A total of 52 weeks of treatment (Feagan, et al.
, 2016).
These are double-blind, placebo-controlled trials in patients who have failed anti-TNF or conventional therapies.
Intravenous UST patients who respond to induction therapy can significantly improve the remission rate and maintain remission.
In the three trials, the rates of serious adverse events and serious infections were similar in all treatment groups.
The relationship between the serum concentration of UST and the remission of CD disease within 2 weeks of treatment was also studied.
The serum concentration of UST 1 hour after intravenous infusion is considered to be the most appropriate marker for predicting endoscopic remission in CD patients.
UST is also effective in inducing and maintaining remission in patients with moderate to severe active UC.
The UNIFI trial evaluated the role of UST in the 8-week induction and 44-week maintenance study of patients with moderate to severe UC.
Compared with the placebo group, patients who received UST at a dose of 130 mg or 6 mg/kg showed significant clinical remission at week 8.

Lymphocyte homing is one of the causes of mucosal inflammation and tissue damage in IBD.
As shown in Figure 2 (bottom left), lymphocytes enter the intestine mainly through α4β7 integrin heterodimer that binds to MAdCAM1 expressed by intestinal endothelial cells.
In animal studies and clinical trials, by preventing the binding of α4β7 integrin and MAdCAM1 to inhibit lymphocyte homing, it can simultaneously inhibit UC and CD.
However, side effects that also need to be worried about, such as progressive multifocal leukoencephalopathy and increased risk of surgical site infection, still exist.

In addition to α4β7 integrin, mAb PF-00547659 also has the potential to target its ligand MAdCAM1.
In a phase II, randomized, double-blind, placebo-controlled trial, PF00547659 was shown to be safe and well tolerated in patients with moderate to severe UC.
In addition to α4β7 integrin, other soluble forms of adhesion molecules (ligands/proteins), such as selectin (Figure 3, top right) and chemokine signaling pathways have also been targeted for IBD treatment.
In a study by Ajdukovic et al.
, compared with healthy subjects, UC patients had a higher serum sPSGL-1 concentration, and anti-PSGL-1 antibodies could significantly reduce the symptoms of UC.
However, due to the limited evidence currently available, the clear role of PSGL-1 in the pathogenesis of IBD has not yet been determined.

to sum up

According to the results of clinical studies, soluble ligands may have become the most promising target for the development of anti-IBD drugs.
Specifically, antibodies against inflammatory cytokines represented by TNF-α and IL-12/23 have made great progress in the treatment of IBD.
In addition to these biopharmaceuticals, finding some orally active small molecules that target soluble ligands (such as sEH) is also very promising.
These small molecules also show some clinical benefits in the treatment of IBD in animals or clinical studies.
In short, soluble ligands are the third largest class of drug targets, and drugs that target them have great potential in the treatment of IBD.

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