IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy

1Interleukin (IL)-23 is a member of the IL-12 cytokine family and is implicated in a cluster of immune-mediated inflammatory diseases (IMIDs) that includes psoriasis (PsO), psoriatic arthritis (PsA), and inflammatory bowel disease (IBD; namely Crohn’s disease [CD] and ulcerative colitis [UC]). Because of its ability to reprogram immune cells in inducing and maintaining a highly proinflammatory state, IL-23 can be considered a dominant regulatory cytokine that acts as a rheostat, or a master switch, for initiating development and maintenance of these IMIDs.

2In response to tissue injury or pathogenic insults, IL-23 is produced by tissue-resident myeloid cells and promotes expansion and survival of a subset of T lymphocytes, known as T helper (Th)17 cells, that produce and secrete IL-17A and other inflammatory mediators ( Figure 1 ). Besides promoting proliferation and maintenance of Th17 cells, the cell type that has been studied most extensively with regard to IL-23 function, IL-23 can stimulate “natural” Th17 cells and IL-17+CD8+ T (Tc17) cells, as well as innate immune cells, such as γδ T cells, natural killer T cells (NKTs), mucosal-associated invariant T cells (MAITs), and IL-17–secreting innate lymphoid cells (ILC3s), all of which may be collectively termed type 3 immune cells or type-17 cells. This set of innate immune cells express the IL-23 receptor and retinoic acid receptor–related orphan receptor-γt (RORγt). The IL-23 receptor is also expressed on a small subset of interferon-γ (IFN-γ)–producing Th1 cells, where it also plays a critical role in inducing a colitogenic phenotype with induction of genes that have been implicated with human IBD by genome-wide association study (GWAS). IL-23 stimulation of Th17 and type-17 cells induces local tissue inflammation via release of proinflammatory cytokines, such as IL-17A, IL-17F, IL-22, human granulocyte macrophage colony-stimulating factor (GM-CSF), IFN-γ, and tumor necrosis factor (TNF)-α. IL-23 can also suppress regulatory T (Treg) cell differentiation and promote expansion of tissue-resident memory T (TRM) cells, which have been linked to the chronicity of autoimmune and inflammatory diseases. IL-23 promotes programming of pathogenic Th17 cells that drive immune-mediated disease through the induction of genes encoding IL-23–dependent transcription factors, including the RORγt gene and the IL-23 receptor gene (IL23R), thus amplifying IL-23 signaling in a positive feedback loop and stabilizing production of proinflammatory effector molecules.

3Th17 effector cytokines drive inflammation in psoriatic disease (ie, PsO and PsA) and contribute to the development of spondyloarthritis. In IBD, IL-23 is one of the primary drivers of inflammation, although patients with CD and UC may have different cytokine expression profiles. Targeting IL-23 for the treatment of psoriatic disease and IBD may restore immune homeostasis and could have significant long-term anti-inflammatory effects. Inhibition of IL-23 reduces levels of IL-17A, IL-17F, and IL-22, and markedly improves clinical outcomes for patients with these IMIDs. Moreover, robust joint and skin responses have been sustained long-term in patients with psoriatic disease receiving anti–IL-23 therapy. Although most patients respond to treatment, some show only a partial response. Furthermore, the therapeutic benefit of IL-23 inhibition beyond this immediate cluster of IMIDs is unclear. An attenuated effect with IL-23 inhibition in some cases may be due, in part, to the timing of therapeutic intervention over the course of disease and/or limitations of currently available anti–IL-23 therapies. Also, IL-23 may be a dominant regulatory cytokine in only type 3 IMIDs driven primarily by type 3 immune cells, pathogenic type-17 cells, and/or dysregulation of the IL-23/IL-17 axis. Additional studies are needed to establish a novel molecular ontology centered around IL-23–driven disease, advance new approaches to treating inflammatory diseases with IL-23 inhibition, and ultimately identify IMID patients who represent optimal candidates to receive treatment with anti–IL-23 therapy.

4In 2000, Oppmann and colleagues identified IL-23, a novel member of the IL-12 family of cytokines comprising p19 and p40 subunits ( Figure 2 ). Although the p40 subunit is common to both, IL-23 (p19/p40) and IL-12 (p35/p40) are functionally distinct, with divergent roles in driving differentiation and maintenance of Th17 and Th1 cells, respectively ( Figure 3 ). While early studies using p40-/- mice and anti-p40 antibodies could not discriminate between IL-12 and IL-23, later studies in p19-/- (IL-23 deficient), p35-/- (IL-12 deficient), and p40-/- (IL-12 and IL-23 deficient) mice revealed that IL-23 was a critical cytokine driving inflammation in several models of IMIDs and exhibited functions that were pathogenetically discrete from IL-12. In contrast to the role of IL-23 in driving inflammation in the skin, IL-12 receptor–mediated signaling appears protective in PsO. In some models of gastrointestinal inflammation, IL-12 has been shown to have a limited role, whereas other models suggest IL-12 is necessary to trigger inflammation, with IL-23 driving disease chronicity. The roles of p19 heterodimeric cytokines paired with other subunits are not fully understood in IMIDs.

5The IL-23/IL-17 axis is also involved in host defense against certain bacterial and fungal pathogens and also plays a key role in gut tissue homeostasis by supporting barrier function, tissue repair, and maintenance. IL-17A signaling contributes to maintenance of gut epithelial homeostasis and promotes neutrophil effector function to protect against certain mucosal infections. By corollary, IL-17A inhibition has been shown to have paradoxical effects in the gut and may induce or worsen bowel inflammation.

6The role of IL-23 in maintaining barrier homeostasis in the skin and joints is less well understood. Keratinocytes from normal skin express low levels of IL-23, but it is only in the context of inflammatory skin disease that IL-23 can stimulate IL-20 family members, resulting in TNF-regulated epidermal thickening. In the gut, epithelial-like C-X3-C motif chemokine receptor 1(CX3CR1)+ macrophages are an important source of IL-23 and protect from effacing bacteria, likely via modification of gastrointestinal barrier function. In joints, CX3CR1+ macrophages play a role in maintaining tight junction-mediated barriers at the synovium lining, but how IL-23 may contribute to maintaining barrier function has not yet been elucidated. Only a small number of IL-23–responsive cells appear to be present in entheseal tissue from mice and humans. In response to endogenous (eg, IL-6, TGF-β) or exogenous (eg, microbial-component lipopolysaccharides, bacterial infection) stimuli, IL-23 expression increases and activates IL-23 receptor–expressing cells to produce downstream effector cytokines, contributing to local tissue inflammation that plays a role in barrier homeostasis.

7The IL-23 receptor ( Figure 3 ) is constitutively expressed on the surface of NKTs, ILCs, γδ T cells and MAITs, all of which recognize antigens via invariant T-cell receptors or other motifs. Engagement of the IL-23 receptor results in formation of a cytokine-receptor ternary complex that includes IL-23, IL-23R, and IL-12Rβ1, and activates a range of Janus kinases (JAKs; eg, JAK2, TYK2) and signal transducers and activators of transcription (STATs; eg, STAT3, STAT4). In particular, TYK2 and STAT3 activation represent key proximal signaling events for upregulating production of cytokines (eg, TNF-α, IL-17, IL-6, IL-23) implicated in IMIDs. Therefore, blockade of JAKs, including TYK2, has emerged as a therapeutic target in IMIDs. However, JAK inhibitors broadly inhibit the signaling of multiple cytokines and are not specific to IL-23 activation.

8Induction of IL-17A and IL-17F production by Th17 cells does not require IL-23R signaling, but activation of the IL-23 receptor is required for pathogenic effector Th17 cell responses, which include production of IL-17A, IL-17F, IL-22, GM-CSF, and IFN-γ. Type-17 cells have been shown to be important in the pathogenesis of IMIDs, with Th17 cells being major producers of IL-17A in host defense. There is growing evidence that two different types of Th17 cells exist in vivo in murine models: non-pathogenic (homeostatic) and pathogenic Th17 cells. Nonpathogenic Th17 cells regulate barrier functions and control microbial invasion at mucosal surfaces. Pathogenic Th17 cells induce tissue inflammation and autoimmunity. IL-23 receptor expression differentiates pathogenic from nonpathogenic type 17 cells, with pathogenic cells demonstrating high levels of IL-23 receptor expression. IL-21 and IL-12 were shown to stimulate IL-23 receptor expression and, therefore, promote differentiation and activation of type 17 cells in vitro. In addition, the localization pattern of IL-23 receptor–positive cells within tissues, particularly in barrier tissues that have resident type-17 cells, may determine disease-specific patterns of clinical inflammation when the IL-23 pathway is dysregulated.

9The roles of IL-17, IL-22, and other effector cytokines downstream of IL-23 vary by disease state. Cytokine expression is dynamic, and expression patterns change over the course of disease; in particular, timing and location are important. The IL-17A receptor subunit (IL-17RA), which binds IL-17A, IL-17F, IL-17A/F, and IL-25 (IL-17E), is ubiquitously expressed by a variety of cell types, including endothelial cells, keratinocytes, and gut enterocytes. Activation of these cells by IL-17A and IL-17F, usually working in synergy with other activator cytokines, promotes the expression of IL-1, IL-6, IL-8, and TNF, which may induce and sustain chronic inflammatory processes. IL-23 also regulates production of IL-22 by Th17 cells, Th22 cells, and ILC3s; furthermore, CD8+ T cells, γδ T cells, and NKTs can produce IL-22 in the presence of IL-23. In addition, a small subset of Th1 cells was shown to express IL-23R and activation of IL-23 resulted in the induction of multiple genes that are not typically expressed in Th17 cells, but which have been linked to IBD by GWAS analysis. IL-17 upregulates expression of genes encoding immune chemoattractants whereas IL-22 downregulates expression of genes needed for keratinocyte differentiation; both IL-17 and IL-22 can induce expression of antimicrobial protein-encoding genes. IL-22 has been implicated in promoting inflammation and the pathogenesis of several diseases (eg, PsO and select cancers) but plays a protective role in other conditions (eg, asthma and pancreatitis). The potentially conflicting roles for IL-22, coupled with a lack of efficacy for IL-22 inhibition in studies in some disease states, raise questions about the therapeutic utility of targeting this cytokine.

10In Tables 1, 2, we summarize the extensive experimental and clinical data characterizing the role of IL-23 and the therapeutic effect of targeting the IL-23p19 subunit in PsO and PsA. IL-23 plays an important role in the pathogenesis of psoriatic disease, in part, by contributing to recurrence of skin lesions and inducing enthesitis in PsO and PsA, respectively. Clinical data suggest that selective IL-23p19 subunit inhibitors are effective in psoriatic disease. In PsO, targeting the IL-23p19 subunit can restore favorable ratios of T-cell populations in lesional skin compared with IL-17A inhibition. In PsA, targeting the IL-23p19 subunit can modulate expression of disease-associated genes, with directionality toward normalization of whole blood transcriptomes towards those found in healthy volunteers. Selective blockade targeting of the IL-23p19 subunit has not elicited specific safety signals in either PsO or PsA. The clinical efficacy of selective IL-23 inhibition has been established, with anti–IL-23 therapy approved for use in both PsO and PsA. In addition, head‐to‐head comparative data from clinical trials of patients with PsO suggest that IL-23p19 subunit inhibitors (ie, guselkumab, risankizumab) have superior efficacy over the TNF inhibitor adalimumab, the IL-17A inhibitor secukinumab, and the IL-12/IL-23 inhibitor ustekinumab. Nevertheless, onset of efficacy with IL-23p19 subunit inhibitors has been shown to be less rapid than with IL-17A inhibitors, as observed in the head-to-head comparison of guselkumab and ixekizumab for PsO. In PsA, there are no head-to-head comparisons of IL-23p19 subunit inhibitors versus other targeted PsA therapies. A systematic literature review and network meta-analysis of clinical trials in patients with PsA showed that IL-23p19 subunit inhibition with guselkumab provided better skin efficacy than most TNF and JAK inhibitors, while demonstrating joint efficacy comparable to IL-17A, JAK, and TNF inhibitors administered by subcutaneous injection.

11Despite experimental evidence from animal models that suggests a pathogenic role for IL-23 in axial spondyloarthritis, clinical trials of IL-23p19 subunit and IL-12/IL-23p40 subunit inhibitors in patients with axial spondyloarthritis failed. The lack of efficacy of IL-23 blockade in axial (axial spondyloarthritis) but not peripheral (PsA) spondyloarthritis may be due to differences in IL-23 responsive cell types involved in disease pathogenesis and the timing of therapeutic intervention in the course of these diseases. Limited penetration of large molecule therapeutic antibodies into joint tissues, such as synovium, may also limit efficacy. In contrast to trials in axial spondyloarthritis, post hoc analyses of selective IL-23p19 subunit inhibition with guselkumab in patients with axial PsA showed significant improvement in symptoms of axial involvement versus placebo. A prospective, controlled trial of guselkumab in patients with PsA with magnetic resonance imaging–confirmed axial involvement is ongoing to further expand upon this finding (ClinicalTrials.gov Identifier: NCT04929210).

12In Table 3, the genetic, experimental, and clinical evidence supporting a role for IL-23 inhibition in IBD is summarized. In inflamed tissue, overexpression of IL-23 converts nonpathogenic Th17 cells into pathogenic effectors, resulting in impaired barrier function, and drives continued inflammation via downstream pathways, leading to survival and expansion of Th17 cells. Moreover, IL-23 signaling can suppress Treg cell differentiation, a cell population that is important in regulation and suppression of chronic gut inflammation. Risankizumab is an IL-23p19 subunit inhibitor approved for use in many countries for CD, while mirikizumab is an IL-23p19 inhibitor approved for treatment of UC in Japan and by the European Medicines Agency. IL-23p19 subunit inhibitors have generally demonstrated efficacy in clinical and/or endoscopic outcomes, with evidence to support maintenance of long-term clinical responses and a favorable safety profile. One systematic review and network meta-analysis of clinical trials for biologic therapies for CD suggested that IL-23p19 subunit inhibition with risankizumab may yield better outcomes compared to other biologics and be preferred as second-line therapy for induction of clinical remission. However, head-to-head comparative studies of IL-23p19 subunit inhibitors versus other biologics for IBD are warranted to evaluate the relative efficacy of IL-23p19 subunit inhibitors versus other biologics.

13Other IMIDs in which IL-23 has been implicated through genetic association, tissue expression, animal models, and plausible biological profile include palmoplantar pustulosis, pityriasis rubra pilaris, rheumatoid arthritis, multiple sclerosis, giant cell arteritis, and type 1 diabetes. Guselkumab is an IL-23p19 subunit inhibitor approved for treatment of palmoplantar pustulosis in Japan and other Asian countries. Selective targeting of the IL-23p19 subunit improved clinical outcomes for patients with palmoplantar pustulosis and a small number of patients with pityriasis rubra pilaris.

14In contrast, IL-12/IL-23p40 subunit inhibition failed to show clinical benefit in multiple sclerosis, and IL-12/IL-23p40 or IL-23p19 subunit-targeted therapy failed to improve clinical outcomes in studies of patients with active rheumatoid arthritis, despite strong scientific rationale for this approach derived from animal models. The IL-23/IL-17 axis has been implicated in driving intrinsic inflammatory activity and triggering the clinical onset of rheumatoid arthritis, primarily in animal models, suggesting that early intervention in the pre–rheumatoid arthritis phase could potentially lead to clinical improvement. Observations in animal models of multiple sclerosis suggest that IL−23 is necessary for the induction of disease but not disease maintenance, and that lack of IL−23 is not protective once encephalitogenic T cells have developed. Patients with multiple sclerosis may therefore potentially benefit from targeting the IL-23/IL-17 axis at an earlier stage of disease. Treatment of multiple sclerosis is further complicated by the need for therapeutic agents that cross the blood-brain barrier. Nevertheless, IL12/23p40–targeted therapy in patients with established multiple sclerosis was ineffective, whereas the impact of IL-23p19 subunit inhibition in this patient population has yet to be determined. However, the anti–IL-17A therapeutic antibody secukinumab was shown to decrease the development of new lesions in a small, double-blind clinical trial of patients with multiple sclerosis.

15Conflicting results regarding the efficacy of IL-12/IL-23p40–targeted therapy in patients with giant cell arteritis have been observed across trials, and further studies are needed for more definitive evidence. A proof-of-concept study to evaluate targeting the IL-23p19 subunit with guselkumab in patients with new-onset or relapsing giant cell arteritis is ongoing (NCT04633447). IL-12/IL-23p40 inhibition is currently being assessed for treatment of new-onset type 1 diabetes in clinical studies. IL-23 gene expression was shown to be increased in the pancreatic islet cells of a patient with type 1 diabetes, and targeting both the IL-23p19 and IL-12/IL-23p40 subunits has been shown to suppress the incidence of diabetes in nonobese diabetic mice.

16The pleiotropic nature of the biology of IL-23 also predicts its potentially important role in other diseases beyond IMIDs, such as obesity, atherosclerosis, stroke, cancer, mood disorders, and neurodegenerative diseases. Although IL-23 could be involved in the pathogenesis of multiple disease states, it may act on different cell types or at different stages of disease in each, yielding nuanced effects, a wide range of clinical manifestations of disease, and varied implications of IL-23p19 subunit-targeted therapy.

17Further investigation is needed to better understand the molecular biology of IL-23 to properly adapt anti–IL-23 therapy across the breadth of IMIDs. Herein, we propose a multiomics approach to advance the science of IL-23, including comprehensive studies to identify the spectrum of IL-23 receptor–expressing cells, and to provide insights into the role of IL-23 in driving IMIDs. Moreover, we identify gaps in the understanding of IL-23 signaling and cellular activity and discuss durability of treatment response and future prospects for anti–IL-23 therapeutic intervention, including potential approaches for combination therapy ( Box 1 ).

18The emergence of high-throughput technologies over the past 30 years has revolutionized medical research. The “omic” technologies provide a comprehensive assessment of genomics, epigenomics, transcriptomics (including single cell RNA-seq and spatial transcriptomics), proteomics, metabolomics, and microbiomics. Each of these “omic” technologies provides a global pattern of molecular signatures (genes, epigenetic factors, RNA transcripts, proteins, or metabolites) that are altered in disease, providing insight into biomarkers, pathways, or cell types involved in disease pathogenesis. Combining these “omic” technologies can provide a more complete picture of the molecular factors that drive functional consequences and interactions of IL-23 signaling underlying the pathogenesis and phenotypic manifestations of IMIDs. For instance, a recent genome-wide study identified allelic variants of the HLA-C upstream region (which includes PSORS1C3, MICA, and TNFA) that were associated with clinical response to anti-IL-12/IL-23 therapy. In addition, an interaction between gut microbiota composition and responsiveness to IL-17 and IL-23 inhibitors has been observed in patients with PsO. Another example derives from a multiomics study that used matched colonic biopsy tissue and serum samples at multiple time points from IBD patients treated with guselkumab or placebo. This application of a multiomics approach allowed deeper understanding of local (gastrointestinal tissues) versus systemic (serum protein) immune responses driven by IL-23 in IBD patients and revealed that guselkumab mainly suppressed local gastrointestinal tissue inflammation by normalization of gut epithelial cell-injury responses (manuscript in preparation).

19A definitive atlas of IL-23 receptor–expressing cells across different tissues and at different phases of disease activity or progression in patients would be a valuable resource to further elucidate understanding of normal physiological and pathophysiological function of IL-23. For example, the role of IL-23 receptor signaling in T cells has been most extensively studied in experimental animal models, and the effect of IL-23 on diverse T-cell targets in human patients is not well understood. Generally, the IL-23 receptor is expressed at very low levels and is difficult to detect at the protein level; therefore, a combination of spatial transcriptomic and RNA sequencing data may elucidate IL-23 receptor–expressing cell populations of interest with high resolution. Data from single cells may then be interpreted in the context of broader sequencing data to better understand the IL-23 pathway gene expression profile. In turn, a recently developed and validated panel of anti–human IL-23 receptor antibodies is being utilized to identify and characterize unique IL-23 responding populations across inflamed skin, joint, and gut tissues (Lin et al, manuscript in preparation). These studies will complement IL-23 receptor transcriptomic analyses and contribute to further elucidating the role of IL-23 during disease pathogenesis.

20Studies on IL-23 signaling and cellular activity are needed to further characterize the normal physiological function of IL-23 and to identify new targets and strategies for drug development independent of direct IL-23 engagement in order to more fully tap into the therapeutic potential of inhibiting the IL-23 pathway. Gaps currently exist with respect to the impact of therapeutic intervention at the level of downstream effectors, potential modulators of IL-23 signaling, and the molecular basis for inadequate response to IL-23 inhibition in some cases.

21Inhibiting IL-23 directly may have broader utility than targeting downstream effectors of the IL-23 pathway. For example, targeting members of the IL-17 family of cytokines may not sufficiently or uniformly suppress inflammatory pathways owing to the functional redundancy of IL-17 family cytokines in promoting inflammation. However, not all inflammatory diseases in which IL-17A or IL-17F are considered pathogenic drivers are necessarily IL-23–dependent (eg, hidradenitis suppurativa). As aforementioned, the effect of IL-23 on diverse T-cell targets in patients is not yet well understood. Comparing and contrasting effector and regulatory pathway mediators across diseases in patients will better describe the impact of IL-23 and, in turn, IL-23 inhibition on broader T-cell populations. Although IL-23 signaling is generally highly conserved across species, experiments using human cells or tissues are essential to ensure relevance to human disease. Approaches to characterize IL-23–producing and IL-23–responsive cells from clinical tissue samples, such as single-cell transcriptomics, will better refine understanding of IL-23 signaling pathways and provide temporal and spatial maps of IL-23 pathway dysregulation in tissues.

22Even within the cluster of IMIDs that is sensitive to selective IL-23p19 subunit targeting, not all patients respond adequately. Additional research on signaling pathways downstream of IL-23 may determine why some patients experience inadequate response and identify potential complementary therapeutic targets. In turn, it will be important to understand synergistic and antagonistic mediators of IL-23 receptor signaling, and how they are dependent on the local tissue microenvironment. For example, in a recent study, quantitative phospho-proteomic analysis of Th17 cells was used to identify potential targets downstream of IL-23 signaling. Similar approaches may be used to address questions such as whether there are nuances to IL-23 signaling in different cell types or tissues that may impact responses to therapeutics targeting the IL-23p19 subunit. Furthermore, signaling crosstalk between IL-23 and other cytokines, such as IL-1β, can augment and sustain IL-23 signaling; study of such interactions is now feasible given the availability of high-fidelity resolution techniques. In this context, other pathogenetic components, such as the skin and gut microbiomes, may influence IL-23 receptor signaling, given its critical roles in protecting against invading pathogens, educating the immune system, and metabolizing natural products in these tissues.

23TRM cells are a subset of noncirculating memory T cells that persist over the long-term in peripheral tissues. TRM cells provide rapid, local immune responses on re-exposure to pathogens under healthy conditions, but also develop after sensitization to self-antigens and are involved in the pathogenesis of autoimmune disorders. TRM cells are a key reason for why some IMIDs, such as PsO, are chronic, life-long diseases, and why skin lesions in PsO tend to recur at the same sites upon relapse of disease. Treg cells help to maintain immune homeostasis and self-tolerance by suppressing inflammation and effector T cells. IL-23 has been shown to suppress the differentiation of Treg cells, and promote differentiation, survival, and expansion of pathogenic Th17 cells.

24The durable, long-lasting therapeutic effect observed with selective targeting of IL-23p19 subunit is hypothesized to derive from suppression of TRM cells. IL-23 inhibition has been shown to favorably shift the relative ratio of CD8+ TRM cells and Treg cells in PsO lesions compared with IL-17A inhibition. Moreover, clinical studies have shown superior long-term maintenance of response with IL-23 inhibition over IL-17A blockade; IL-17A inhibitors, in essence targeting an effector cytokine, have less impact on the relative numbers of proinflammatory and anti-inflammatory T cells compared to IL-23 inhibitors. Nonetheless, further studies with larger numbers of samples over long-term duration of follow-up are needed to confirm these findings. Future studies are needed to determine whether selective IL-23 inhibition, if initiated in the optimal context, can result in the reduction or even elimination of pathogenic TRM cells and ultimately drive PsO and other IMIDs into long-term remission. The intriguing possibility of prolonged drug-free remission is particularly enticing in this context. The ongoing GUIDE study is evaluating the implications of early intervention with guselkumab in patients with PsO and short disease duration to achieve a super-response, extend dosing interval, and maintain disease control after treatment withdrawal, and is further exploring the impact of guselkumab treatment on the balance of TRM/Treg cell populations in patients with PsO over time.

25Specific attributes of currently available and future IL-23 inhibitors may enhance blockade of IL-23 signaling and further improve clinical outcomes. The in vitro binding affinity for IL-23 and potency for blocking IL-23 signaling of available antibodies targeting the IL-23p19 subunit may be different, potentially driving differences in clinical performance of these drugs. However, the relevance of bioavailability and serum levels of IL-23 inhibitors to clinical efficacy is unclear given that IL-23 is produced and drives inflammation within the local tissue microenvironment. It is important to note, however, that IL-23–producing cells are also capable of trafficking to other tissue sites to extend or propagate disease pathogenesis. The mechanism by which an anti–IL-23 antibody localizes to inflamed tissue(s) to sequester and neutralize IL-23 at the site of its production and activity may represent an important attribute for consideration. For example, myeloid cells that express FcγRI/CD64 have been identified as major IL-23–producing cells in preclinical models as well as in lesional tissue from human patients with psoriatic disease and IBD. Thus, anti–IL-23 monoclonal antibodies that can also bind to FcγRI/CD64 via their Fc region may be optimally localized within the inflamed tissue microenvironment to neutralize IL-23 at its cellular source and potentially provide a therapeutic advantage.

26A potential alternative to directly targeting the IL-23p19 subunit is to target the IL-23 receptor itself. Orally bioavailable therapeutic peptides that bind the IL-23 receptor with high specificity and affinity offer promise. Small molecules and peptides may have an advantage over therapeutic antibodies by virtue of better tissue penetration, which could potentially improve outcomes for and expand the scope of IMIDs that are treatable through inhibition of IL-23 receptor signaling. An oral IL-23 receptor antagonist peptide is currently being studied in PsO and UC in clinical trials, and future studies in other IMIDs may be warranted.

27Although monotherapy with selective anti–IL-23 antibodies has been shown to be therapeutically effective across a variety of IMIDs, some patients fail to achieve adequate or durable responses. One approach to addressing remaining unmet needs across IMIDs is to also target complementary pathogenic pathways through combination therapy. IL-23 inhibitors may be useful in the context of combination therapy because of their potent ability to target a dominant, regulatory cytokine that serves as a rheostat to control the stream of inflammatory signals that can drive IMID pathogenesis. Moreover, the safety profile of IL-23 inhibitors has been thus far reassuring, which further supports pairing IL-23 inhibition with a second mechanism in a combination therapy approach. In turn, IL-23 blockade may synergize with inhibition of a pathway with a complementary mechanism of action, such as the TNF pathway, to achieve even higher levels of efficacy than those achievable using either approach alone, and potentially with minimal risk of compounding safety concerns, a problem that has beset prior combination therapeutic approaches for cytokine blockade.

28Recently, the combination of IL-23 and TNF inhibition was shown to have a synergistic effect on preventing loss of body weight and reducing local colonic tissue inflammation in an anti-CD40 antibody–induced colitis mouse model. In that preclinical study, improvements in disease features were accompanied by normalization of gene expression patterns in shared molecular pathways for either treatment when used as monotherapy and when used in combination; however, normalization of expression of gene networks that were uniquely impacted in response to combination therapy was also observed. In the phase 2 VEGA study for UC, combination induction treatment with both an IL-23 inhibitor and a TNF inhibitor more effectively induced clinical response, remission, and endoscopic improvement than monotherapy with either agent alone. Further still, combination therapy was also shown to reverse the disease transcriptomic profile to a greater extent than either monotherapy alone. An additional ongoing clinical trial is studying the impact of IL-23 inhibition in combination with TNF inhibition in PsA (NCT05071664).

29Remarkable progress over the last 20 years has advanced our understanding of the science of IL-23, leading to the development of transformational therapies that selectively block IL-23. IL-23 may represent a dominant regulatory cytokine in the context of type 3 IMIDs, with broad effects mediated by regulation of Th17 cells, other IL-23 receptor+ type-17 cells, and/or the IL-23/IL-17 axis. Extensive experimental and clinical evidence supports a role for IL-23 as a critical regulatory cytokine in a class of IMIDs that includes PsO, PsA, and IBD. The use of IL-23 inhibitors has been very successful in treating these IMIDs. However, not all patients respond adequately to currently available anti–IL-23 therapies and some patients may show only a partial response to treatment. IL-23 inhibition has been unsuccessful in clinical trials for some IMIDs, despite strong a priori scientific rationale for anti–IL-23 treatment. Studies to determine the therapeutic efficacy of IL-23 inhibition in yet other inflammatory diseases are needed. Factors contributing to these observations may include the timing of therapeutic intervention over the course of disease and limitations of currently available IL-23 inhibitor therapies.

30We propose additional studies to address remaining challenges and unmet needs pertaining to anti–IL-23 therapy and to advance the science of IL-23. These include studies using a multiomics approach to: 1) further define the identities and roles of IL-23–expressing cells and IL-23 receptor–expressing cell targets in different inflammatory diseases; 2) characterize nuanced effects of IL-23 in different cell types or tissues; 3) describe changes in IL-23 receptor expression and signaling over the course of disease; and 4) characterize the mechanisms underlying tissue-specific responses and durability of response with IL-23 inhibitor therapy. Results from such studies hold strong potential to establish a novel molecular ontology centered around IL-23–driven disease, enhance and/or complement therapeutic approaches for IL-23 inhibition in treating IMIDs, further understand variability in achieving clinical responses, and ultimately better identify ideal patient candidates for anti–IL-23 therapies. The future appears promising, with the emergence of new strategies, including combination therapy, and ongoing progress in the understanding of the science of IL-23 to foster the next generation of therapeutics targeting the IL-23 pathway.

31JK: Conceptualization, Writing – review & editing. KE: Conceptualization, Writing – review & editing. VK: Conceptualization, Writing – review & editing. CR: Conceptualization, Writing – review & editing. MA: Conceptualization, Writing – review & editing. ME: Conceptualization, Writing – review & editing. AF: Conceptualization, Writing – review & editing. SF: Conceptualization, Writing – review & editing. JS: Conceptualization, Writing – review & editing. Y-WY: Conceptualization, Writing – review & editing. DC: Conceptualization, Writing – review & editing. IM: Conceptualization, Writing – review & editing.