Current status of novel biologics and small molecule drugs in the individualized treatment of inflammatory bowel disease

Abstract

Treatment strategies for inflammatory bowel disease (IBD) are rapidly evolving with the development of biologics and small molecule drugs (SMDs). However, these drugs are not guaranteed to be effective in all patients, and a “ceiling effect” of biologic monotherapy may occur. This issue highlights an unmet need for optimizing the use of biologics and predicting therapeutic responses. Thus, the development of new drugs with novel mechanisms of action is urgently needed for patients with primary nonresponse and secondary loss of response to conventional biologics and SMDs. In addition, combining different biologics or SMDs has been proposed as a novel strategy to enhance treatment efficacy in IBD, which theoretically has multidimensional anti-inflammatory potential. Based on the current evidence available for IBD, dual targeted therapy may be a promising strategy for refractory IBD patients who have failed in multiple biologic trea-tments or who have extraintestinal manifestation. Additionally, identifying the subgroup of IBD patients who are responding to biological combination therapies is also equally important in stable disease remission. In this review, we sum-marize the newly developed biologics and SMDs and the current status of bio-logics/SMDs to highlight the development of individualized treatment in IBD.

Key Words: Inflammatory bowel diseases, Biologic, Dual targeted therapy, Therapeutic drug monitoring, Bispecific antibodies

Core Tip: The emergence of biologics and small molecules has significantly changed the therapies used for inflammatory bowel disease (IBD). However, the efficacy of these drugs is not satisfactory for every patient, which indicates an unmet need for optimizing the use of biologics/small molecules and for predicting therapeutic responses. Here, we describe the current status of novel biologics and small molecules and new treatment strategies to combat IBD by using more than one biologic.

INTRODUCTION

The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) are progressive inflammatory diseases with the gastrointestinal tract being the major site of inflammation. Patients require lifelong medical therapy in the context of the complicated aetiology of IBD[1]. Encouragingly, the advent of biologics and small molecule drugs (SMDs) has fundamentally changed patient prognoses and improved their quality of life. Strong evidence has indicated that early treatment with these drugs might lead to more favorable outcomes, such as deeper inflammation control and longer steroid-free remission[2]. Despite the optimization of biological therapies, the proportion of patients who exhibit primary nonresponse and secondary loss of response to biologics remains high, and approximately only 40% of patients who respond to biologic therapies maintain clinical remission in one year[3]. This highlights a potential “ceiling effect’’ of biological monotherapy and an unmet need for optimizing the use of biologics and for predicting therapeutic responses. Thus, patients need not only new drugs but also optimized treatment strategies. In the last decade, increasing numbers of new biologics and SMDs have been developed for IBD treatment[4], and a novel therapy combining different biologics and/or SMDs targeting multiple inflammatory signalling pathways, which is called dual targeted therapy (DTT), has begun to emerge in recent years[5]. However, whether DTT is superior to monotherapy in achieving the new target of long-term deep healing is uncertain. Additionally, DTT might only work in a selected subgroup of IBD patients, and indiscriminate use of DTT is expensive, ineffective, and unsafe[6]. Thus, in the era of biologics, it is important to identify eligible patients and treat them with individualized therapy. In this review, we describe newly emerging drugs and advanced strategies to provide insight for optimizing the current treatments for IBD in the context of individualized medicine.

EMERGING BIOLOGICS AND SMDS IN IBD

Currently, the goal of IBD treatment is not only to maintain clinical remission but also to achieve transmural healing to prevent further structural damage. Therefore, biologics and/or SMDs are recommended for patients with moderate to severe IBD. To date, the approved biological and small molecule therapies for IBD consist of the following anti-tumor necrosis factor (TNF) agents [infliximab (IFX), adalimumab (ADA), certolizumab (CZP), golimumab (GOL)], anti-adhesion agents [vedolizumab (VDZ), natalizumab (NAT)], anti-interleukin (IL)-12/23 agents [ustekinumab (UST)], and Janus kinase (JAK) inhibitors (tofacitinib). However, the current biological monotherapies are efficacious only in a certain proportion of patients. For example, only 30%-50% of active patients can achieve clinical or mucosal remission after biological inducing therapy. Besides, the rates of long-term corticosteroid-free remission are even lower and are less than 30%[7]. Thus, new drug development is rapidly advancing to meet the needs of patients with primary nonresponse, loss of response or intolerance to conventional biologics and SMDs (Table 1).

Table 1 Summary of emerging biologics and small molecule drugs in inflammatory bowel disease treatments.

Drug class	Agent	Target	Route	IBD type	Ref.
Anti-TNF	AVX470	Anti-TNF	Oral	UC	[11]
Anti-IL-23	Risankizumab	IL-23/p19 subunit	IV/SC	CD/UC	[17]
	Brazikumab	IL-23/p19 subunit	IV/SC	CD/UC	[15]
	Mirikizumab	IL-23/p19 subunit	IV/SC	CD/UC	[18]
	Guselkumab	IL-23/p19 subunit	IV/SC	CD/UC	[16]
Anti-lymphocyte trafficking	Etrolizumab	α4β7 and αEβ7 integrins	SC	CD/UC	[22]
	AJM300	α4 integrin	Oral	UC	[23]
	Ontamalimab	MAdCAM	SC	CD/UC	[38]
S1P receptor modulators	Ozanimod	S1PR1 and S1PR5	Oral	CD/UC	[24]
	Etrasimod	S1PR1, S1PR4 and S1PR5	Oral	CD/UC	[39]
JAK inhibitor	Filgotinib	JAK1	Oral	CD/UC	[27]
	Upadacitinib	JAK1	Oral	CD/UC	[28]
PDE4 inhibitor	Apremilast	PDE4	Oral	CD/UC	[30]

Anti-TNF: Anti-tumour necrosis factor; CD: Crohn’s disease; IBD: Inflammatory bowel disease; IL-23: Interleukin-23; IV: Intravenous; MAdCAM: Mucosal addressin cell adhesion molecule-1; PDE4: Phosphodiesterase 4; SC: Subcutaneous; SMDs: Small molecule drugs; SIP: Sphingosine-1-phosphate; UC: Ulcerative colitis.

Anti-TNF agents

Anti-TNF agents were the first class of biologics to be approved for IBD treatment, and since then, they have tremendously changed IBD management. However, even in patients who respond to anti-TNF agents, the scope of anti-TNF use is limited due to systemic effects, such as infection and immunosuppression[8]. In addition, immunogenicity is another complex problem in anti-TNF-based treatment. Although some randomized controlled trials (RCTs) have shown that adding immunomodulators (IMs), such as the thiopurines azathioprine and 6-mercaptopurine, may reduce the immunogenicity of anti-TNF agents, and then improve the efficacy of anti-TNF therapy, only a minority of patients will benefit from this strategy[9,10]. Gut-selective anti-TNF agents might overcome these defects. An oral anti-TNF agent is currently in development. Since the antibodies comprising this therapy are derived from cow colostrum, this agent can act on the small intestine and colon in a delayed-release manner. A preclinical study that assessed the efficacy of AVX-470 showed a higher clinical response rate in the treatment group at week 4 than in the control group (25.9% vs 11.1%)[11]. Additionally, serious systemic side effects and formation of anti-drug antibodies were not observed. The current new oral formulation of anti-TNF agents might bring gut specificity to anti-TNF treatments. However, many more clinical studies are needed to confirm the efficacy of this novel formulation.

Anti-IL-12/23 agents

IL-12/23 signalling pathways are the key in regulating the differentiation and maturation of Th17 cells, which results in intestinal inflammation in IBD[12]. The conventional anti-IL-12/23 agent, UST, prevents activation of the IL-12/23 signalling pathway by targeting the shared subunit of cytokine p40 of IL-23 and IL-12[13,14]. At present, several monoclonal antibodies are in development that targets other subunits of IL-12/23.

Briakinumab is a human monoclonal antibody that acts specifically against the p19 subunit of IL-23 and exerts no effect on IL-12. In a clinical phase II study, 119 CD patients who failed anti-TNF therapy received brazikumab or placebo randomly at the beginning of the trial and 4 wk later. A higher clinical response rate was observed in brazikumab-treated patients than for those in the placebo group (49% vs 27%, P = 0.01)[15]. Guselkumab is another anti-p19 human mAb that was assessed in a phase II study in 250 patients with moderate-to-severe CD. Patients in all guselkumab groups treated with different doses exhibited a significant reduction in inflammatory activity at week 12. In addition, more patients in guselkumab treatments achieved clinical response [200 mg: 54%, 600 mg: 65%, 1200 mg: 50% vs 15.7% placebo (P < 0.001, respectively)] and safety events were similar between the groups[16]. Risankizumab, another anti-p19 monoclonal antibody, resulted in a 31% remission rate in treated CD patients in a phase III study, which was much higher than that in the control group (15%)[17]. Similarly, another anti-p19 antibody, mirikizumab, seemed to be effective in inducing remission in patients with moderate to severe UC[18]. Inhibition of the IL-12/23 signalling pathway is a promising therapeutic option for IBD, especially if the safety of the new anti-IL-12/23 agents targeting the p19 subunit can be confirmed.

Anti-lymphocyte trafficking agents

Inhibition of immune cell migration to inflamed tissue has emerged as a novel therapeutic mechanism for IBD[19]. VDZ is the most commonly used antiadhesion agent with a selective blocking effect of the α4β7 integrin in the intestine[20]. In addition to this agent, etrolizumab is a newly developed monoclonal antibody that targets the β7 subunit of the α4β7 and αEβ7 integrins. In a study that included 1081 patients with moderate to severe UC, the rate of remission induction in the etrolizumab group was 18.5% compared with only 6.3% in the placebo group[21]. Etrolizumab was also reported to be effective in CD patients[22]. In addition, inhibition of the integrin-α4 subunit might also be useful for inflammation control in IBD. AJM300 is a small molecule inhibitor of the α4 subunit of integrin that led to disease remission rate of 63% compared with a 26% remission rate in the placebo group among 102 UC patients in a randomized controlled study[23]. Another mechanism that limits immune cell migration is the inhibition of the sphingosine-1-phosphate receptor (S1PR). The S1P signalling network is mediated by 5 S1P G-protein coupled receptors (S1PR1-5). Ozanimod is a new class of S1PR modulators that shows activity against S1PR1 and S1PR5. In the TOUCHSTONE study, ozanimod therapy showed excellent efficacy in remission induction and maintenance in moderate to severe UC, and mucosal healing was better (34% with ozanimod vs 12% with placebo)[24]. Anti-lymphocyte migration might be an attractive therapeutic strategy in some situations, and these drugs may be promising and powerful in IBD management.

JAK inhibitors

The JAK family comprises important intracellular signalling molecules consisting of 3 subtypes (e.g., JAK1, JAK2, and JAK3). Tofacitinib is the only SMD targeting JAK1 and JAK3 for moderate to severe UC that is approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA)[25]. However, some studies have revealed an association between tofacitinib and systemic side effects, such as malignancies, cardiovascular events, and venous thromboembolism, in patients with rheumatoid arthritis[26]. Thus, more selective JAK inhibitors are needed for IBD. Currently, filgotinib is a selective JAK1 inhibitor that has shown promising effects in the induction of disease remission in CD patients in the phase II FITZROY study[27]. More patients treated with filgotinib achieved endoscopic response, remission and healing compared with those who received placebo (47% vs 23%, P = 0.0077). However, data from that study showed that patients in the filgotinib group experienced more serious adverse events (9% vs 4%) and more serious infections (3% vs 0%) than those in the placebo group. Upadacitinib is another oral selective JAK1 inhibitor. The CELEST trial recently assessed upadacitinib in patients with moderate to-severe CD. At week 16, clinical remission was notable in the 6 mg group (upadacitinib 27% vs 11% placebo, P < 0.1). However, at week 52, patients in the upadacitinib groups had a higher incidence of serious infections. In addition, patients treated with 12 or 24 mg twice daily had increased serum lipids[28]. Generally, these new selective JAK inhibitors provide a promising prospects in IBD treatments, but their safety profiles should not be ignored.

Phosphodiesterase 4 inhibitors

Phosphodiesterase 4 (PDE4) is involved in intracellular cAMP transformation and activation of the nuclear transcription factor kappaB and promotes inflammation in the intestine[29]. Thus, PDE4 inhibition may reduce cytokine release syndrome. A phase II RCT assessed the efficacy of the PDE4 inhibitor apremilast in 170 adult UC patients. The results showed a higher clinical remission rate in patients treated with apremilast vs placebo[30]. In addition, significant decreases in inflammatory markers, such as C-reactive protein (CRP) and faecal calprotectin, were observed in this study.

Taken together, although the understanding of the pathogenesis of IBD is rapidly evolving and increasing numbers of new biologics and SMDs that have been developed, none of these drugs is effective in all patients. Thus, there is increasing interest in the therapeutic potential of the combination of biologics and/or SMDs with different mechanisms of action in patients with refractory IBD.

THE CURRENT STATUS OF BIOLOGICAL COMBINATIONS IN IBD

The immune response in IBD is multifaceted and accompanied by multiple activated inflammatory pathways in the intestinal mucosa. Single-targeted therapy consisting of biological monotherapy blocks only one inflammatory pathway, which is inadequate to control inflammation completely. Combinations of biologics with different mechanisms may have synergistic effects and contribute to the control of refractory IBD[3,31]. Currently, an emerging strategy, DTT, which is a combination of two biologics or a biologic and tofacitinib has been applied in patients with refractory disease. However, most studies on DTT are case reports and case series, and therefore, we could not summarize data to provide a comprehensive understanding of experiences with this strategy. From the limited evidence available, we briefly discuss the current paradigms of DTT in treating patients with refractory IBD who have failed multiple biologics.

As a prominent anti-TNF biologic, IFX was the first biologic agent used in IBD and has achieved great success[20]. In the last decade, several RCTs have demonstrated the efficacy of IFX combined with immunosuppressive agents[9,32,33]. However, approximately one-third of IBD patients exhibit no response to anti-TNF biologics, and another third need to switch to different agents within one year due to the secondary loss of response[20,34]. With the permission of the FDA and EMA, VDZ has become the first choice among second-line biologics for moderate to severe CD and UC patients who have experienced failure with conventional medications or anti-TNF agents[31]. Thus, in clinical practice, anti-TNF + VDZ is the most common combination paradigm used in DTT. A meta-analysis consisting of 30 studies of dual biologics or SMDs in IBD management revealed that the proportion of anti-TNF + VDZ algorithms ranked first among the various DTT paradigms and accounted for 48% of all algorithms used. The combination of UST + VDZ was the second most popular paradigm and accounted for 19%. The clinical response rates and endoscopic response rates were comparable for different DTT groups in this meta-analysis[35]. Yang et al[36] reported that the rates of endoscopic improvement [reduction of simple endoscopic score for CD (SES-CD) > 50%] for anti-TNF + VDZ and anti-TNF + UST were both 33%. Additionally, VDZ + UST had the highest rates of endoscopic improvement (63%) compared with other combinations, but all DTT paradigms had similar efficacy in terms of endoscopic remission (SES-CD < 3). To date, the broadest experience with IBD patients treated with various DTTs is reported by a retrospective study[37]. Fifty patients with IBD [31 CD, 18 UC and 1 IBD-unclassified (IBD-U)] were included in this study. VDZ + UST was the most used combination paradigm (25/50), followed by VDZ + ADA (3/50), VDZ + GOL (2/50), and VDZ + CZP (2/50). Notably, 20 patients received tofacitinib combined with biologic treatment, but no specific data on this subgroup were provided in this report. The results from this study showed that CRP levels were significantly reduced from baseline (2.35 mg/dL vs 5.00 mg/dL, P = 0.002), 56% (18/32) of patients treated with dual biologic therapy maintained clinical remission after 3 mo, and that 11 of 32 patients were still in endoscopic remission after 8 mo[37]. Currently, growing numbers of newer biologics and SMDs are included in the candidate pools for DTTs, including anti-IL-23 agents such as mirikizumab, risankizumab, brazikumab and guselkumab, anti-integrin agents such as etrolizumab and ontamalimab[38], new SMDs such as PDE-4 inhibitors, as well as IL-6 inhibitors and S1PR agonists[4,39,40].

Although the use of DTTs that address different targets is increasingly applied to treat patients with refractory CD or UC, no strong evidence has shown that DTT might be effective in all patients. An early RCT included 79 patients with active CD who failed to respond to IFX treatment and did not report a statistically significant difference in efficacy between the IFX + NAT group and the IFX + placebo group[41]. Another observational study conducted on 16 paediatric patients with refractory IBD (7 CD, 9 UC, 1 IBD-U) showed that 75% achieved steroid-free clinical remission 6 mo after DTT but that 19% of patients discontinued DTT treatment because of inflammation control failure[42]. Additionally, some low-quality evidence suggested that DTT is more effective in CD patients with a penetrating phenotype[36,43]. Among the patients enrolled in a study conducted by Kwapisz et al[43], the median disease duration was 12.5 years, 86.7% (13/15) had penetrating disease, and 3.8 types of biologics were ineffective for these patients. Despite the disease severity, more than half of patients exhibited improved clinical symptoms and had less steroid use after DTT[43]. However, it is still unclear which combinations of biologics work best in specific IBD subgroups. Understanding of the pathophysiology of IBD and identifying prognostic biomarkers may significantly optimize DTT therapy.

WHAT CAN WE DO TO IMPROVE THE RESPONSE TO DTT

Heterogeneity among patients is one of the main features of IBD and is reflected by different disease behaviors and responses to therapeutics[44]. Although remarkable progress has been achieved in the development of new agents with novel mechanisms of action assisted by advanced management strategies, the current treatment pattern for IBD still relies on clinical symptoms and endoscopy examinations[45]. In addition, as mentioned above, many drugs are effective only in selected patients with IBD, and even DTT strategies cannot guarantee a response in all patients. Thus, the identification of patients who can benefit from DTT is urgent so that individualized treatment with biological agents can be provided.

Therapeutic drug monitoring enhanced the response to DTT

DTT is mainly used as an add-on therapy for patients who exhibit a partial response to monotherapy or who relapse during maintenance therapy. A major problem associated with failure of biological therapy is a loss of response, and therapeutic drug monitoring (TDM) may be a useful auxiliary tool in the management of patients treated with DTT[6,46].

TDM was originally suggested as a way to monitor the response to monotherapy and is divided into two categories: Proactive TDM (performed regularly to target an appropriate drug trough concentration) and reactive TDM (performed upon loss of response)[46]. Strong evidence indicates that TDM implementation is associated with higher rates of clinical remission, better endoscopic mucosal healing, and lower rates of secondary loss of response to biologics[47,48]. To date, TDM has achieved great success in optimizing the management of a combined biologics approach in patients treated with anti-TNF agents. The most convincing evidence comes from the management of secondary failures for IFX and ADA. The personalized anti-TNF therapy in CD study (PANTS), which included 1610 anti-TNF-naive patients with exposure to IFX or ADA, demonstrated that monitoring drug concentrations helps greatly in predicting therapeutic responses. The results showed that the only risk factor associated with primary nonresponse was low drug concentrations at week 14 [IFX: Odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.20-0.62, P = 0.00038; ADA: OR = 0.13, 95%CI: 0.06-0.28, P < 0.0001] and that ideal drug concentrations at week 14 (7 mg/L for IFX and 12 mg/L for ADA) were a strong predictor for clinical remission at week 54. With the guidance of proactive TDM, dose intensification of initial biologics or combinations with IM (thiopurine or methotrexate) therapy improved outcomes of patients with suboptimal drug concentrations at week 14[47]. Additionally, an expert consensus statement by Cheifetz et al[49] recommended a proactive TDM strategy during remission induction with anti-TNF agents and at least once during maintenance.

Reactive TDM could help distinguish patients who need to switch or combine with another class of biologic due to anti-drug antibodies (immunogenicity) from those who might benefit from dose escalation of monotherapy[50]. Actually, identifying patients with pharmacokinetic failure in biologics therapy is extremely useful in the guidance of biologics regimens, especially in DTT. Inadequate trough concentrations of drugs can not only lead to an insufficient efficacy of biologics, but patients may also become insensitive to the mechanism of action. For example, it was recently found that anti-TNF resistance in CD patients may be related to increased numbers of CD4+ T cells that overexpress the IL-23 receptor. Thus, it is possible that combinations with IL-23 inhibitors may help restore the sensitivity to the mechanism of action of anti-TNFs in such patients[51].

At present, there is little research focusing on the role of TDM for biologics other than anti-TNF agents, such as VDZ (anti-α4β7 integrin) or UST (anti-IL-12/23)[52]. Although the relationship between drug concentrations and clinical outcomes has been demonstrated, the value and cost-effectiveness of TDM in optimizing these biologic therapies are uncertain, and all the information given regarding TDM is derived from studies performed in patients treated with monotherapy. Therefore, relevant guidelines about TDM implementation in DTT have not been recommended by any academic association. Overall, TDM has great value in optimizing biologics therapy and providing individualized treatment for IBD but still has very significant problems and challenges in clinical practice.

Biomarkers help predict responses to biological therapies

IBD treatments are a long-term process, and disease monitoring is essential once treatment has started. A growing number of studies have put great effort into identifying prognostic and predictive biomarkers[53,54]. To date, various biomarkers have been proposed as clinical predictors of the response to biologics, including serological and faecal proteins, cytokines, proteomic-related and microbiome-related factors as well as metabolomic and genetic factors[55].

Serum and faecal markers have been widely applied in evaluating the efficacy of biologics. Serum CRP and fecal calprotectin, as inflammatory markers, have been shown helpful in response detection of anti-TNF agents. Although fecal markers are more sensitive than serum markers, such as CRP, in monitoring intestinal inflammation, there is no solid evidence demonstrating the association between fecal biomarkers and the response to anti-TNF agents[56,57]. Some proteins in the intestinal mucosa can also play a predictive role in response to biologics, such as Piwi-like protein 1, MYCBP associated and testis expressed 1, regulators of G-protein signaling 13 and Dachsous 2. Elevated expressions of these cytokines or proteins are beneficial for achieving a stable response to anti-TNF therapy[58,59].

Exploration of the genetic factors that predict the responses to anti-TNF therapy has also made great progress. The genetic polymorphisms in TNFRSF1A (rs4149570), IL-6 (rs10499563), IL-1β (rs4848306), toll-like receptors 2 (TLR2) (rs3804099), and TLR4 (rs5030728) are associated with the response to anti-TNF agents[60]. In addition, an observational study including 1240 European patients with CD found that the human leukocyte antigen-DQA1*05 mutation increased the risk of developing anti-TNF antibodies[61]. Single-cell sequencing revealed that some activated cells [e.g., macrophages, immunoglobulin G (IgG) cells, T cells, and dendritic cells] in patients with failure to receive anti-TNF therapy are dysfunctional with genetic variation[62].

Many studies have suggested that the composition of the gut microbiota is related to the response to therapies. In the STORI study, Rajca et al[63] found that lower levels of Faecalibacterium prausnitzii (F. prausnitzii) were associated with early recurrence of CD after IFX withdrawal. Additionally, higher abundances of F. prausnitzii were associated with better responses to anti-TNF treatments[64,65]. Nevertheless, this relationship could not be confirmed in other studies[66], and when we examine the effects of other bacteria, studies with conflicting results are common[65,67]. To date, the microbiome has not been shown to be a predictive indicator of the response to biologics due to the very high heterogeneity in different individuals.

Metabolomics is a novel method that can quantify small metabolite sugars, such as lipids and amino acids, and thus offers a promising opportunity to identify candidate markers. Through metabolomic analysis, Nikolaus et al[68] found that the serum tryptophan levels increased in IBD patients who responded to IFX therapy but were unchanged in patients who did not respond to IFX or VDZ therapy. In addition, another study including 76 CD patients found that responders and non-responders have distinctive patterns of bile acids derived from feces, serum, and urine. By combining these representative markers, the responses to anti-TNFs may be predicted[69]. The biomarkers mentioned above could assist only with the accuracy of disease monitoring and response to biologics in IBD, and more studies are needed to identify a gold standard in the DTT strategy of IBD.

BISPECIFIC ANTIBODIES: THE NEXT GENERATION OF DTT

It has been proven that targeting multiple inflammatory signaling pathways by combining different biologics has better outcomes for IBD patients than monotherapies[41,70]. However, the doses used in the DTT strategy are based on those for individual therapies, which might have unfavorable benefit-risk ratios, such as placing patients at greater risk of serious infections or malignancies[6,35]. The advent of bispecific antibodies (BsAbs) may provide new insights to help avoid some of these problems in DTT.

BsAbs are antibody formats that can bind to two different antigens or two different epitopes of the same antigen. Broadly, they can be classified as a special type of DTT. To date, BsAbs are divided into two major structural classes: IgG-like BsAbs carrying an Fc domain and non-IgG-like formats, which rely entirely on their antigen-binding capacity to exert therapeutic effects[71]. BsAbs can function by: (1) Impacting specific cell types by targeting multiple receptors; (2) Activating novel signaling via receptor colocalization or hyper crosslinking; and (3) Destroying pathogenic T cells through redirection[72]. Currently, different BsAbs are in different stages of clinical trials, and three BsAbs have been approved for clinical practice globally, namely, catumaxomab (for malignant ascites), blinatumomab (for leukemia) and emicizumab (for hemophilia)[71].

Although there are currently no BsAbs approved for IBD patients in clinical practice, several promising BsAbs are under investigation. For instance, BsAb drugs targeting both TNF and IL-23 are in the preclinical stage for autoimmune diseases, including IBD[72]. These BsAbs showed synergistic efficacy in alleviating colitis in a CD40-induced colitis model compared with anti-TNF and anti-IL-23 agents alone. Another ongoing phase I trial is investigating the effects of APVO210 in treating UC. These BsAbs are composed of an anti-CD86-IL-10 fusion protein and selectively deliver IL10 to CD68+ antigen-presenting cells, in which they have been demonstrated to induce a tolerogenic phenotype to relieve inflammation[73].

The unique mechanism of BsAbs provides an opportunity to target multiple molecular pathways with a single therapeutic agent. With careful dose adjustments, IBD patients can achieve maximal benefits from BsAbs and also good benefit-risk ratio[72]. However, this therapeutic approach is not without defects. On the one hand, the formulation of the two antibody binding domains of BsAbs is fixed, so it is impossible to change the single administration dose of different monoclonal antibodies according to patient needs, as we usually do in traditional dual biologic combination paradigms[74,75]. On the other hand, immunogenicity is an ever-present concern during the development of biological medication in IBD, especially in BsAbs. The large antibody complexes on the surface of BsAbs could act as “danger signals” that induce immunogenicity and eventually lead to loss of response[76].

CONCLUSION

Medical treatment patterns for IBD are rapidly evolving with the increased understanding of disease pathogenesis and development of new drugs that target various pathways. This review describes novel biological agents and SMDs that are in development and highlights the current status of DTT strategies in IBD management. Although drugs and therapeutic strategies that can cure all patients have not yet emerged, the efficacy of DTT in inducing and maintaining disease remission has been dramatically improved by taking advantage of new biological combination paradigms, modern TDM strategies, and novel predictive biomarkers. In future work, the identification of biomarkers that can predict subsets of patients and a more profound comprehension of the immunological landscape with IBD would help to enable more specific individualized medicine.

ACKNOWLEDGEMENTS

We sincerely appreciate Prof Yi Li (Jinling Hospital, Medical School of Nanjing University) for the help and suggestion in this article.