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Translating JAKs to Jakinibs Massimo Gadina, Danielle A. Chisolm, Rachael L. Philips, Iain B. McInness, Paul S. Changelian and John J. O'Shea This information is current as J Immunol 2020; 204:2011-2020; ; of September 29, 2021. doi: 10.4049/jimmunol.1901477 http://www.jimmunol.org/content/204/8/2011 Downloaded from References This article cites 127 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/204/8/2011.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Translating JAKs to Jakinibs † † ‡ Massimo Gadina,* Daniellex A. Chisolm, Rachael L. Philips, Iain B. McInness, Paul S. Changelian, and John J. O’Shea† The discovery of JAKs and STATs and their roles in a safe and effective alternative. In this short review, our goal is and IFN action represented a significant basic to tell the story of the discovery of JAKs, how their role in advance and a new paradigm in cell signaling. This was cytokine signaling was elucidated, and how a new class of quickly followed by discoveries pointing to their essen- drugs was conceived and developed. We will discuss drugs tial functions, including identification of JAK3 muta- that are approved and in development and how we expect this tions as a cause of SCID. This and other findings class of drugs will be used in the future. We would also be predicted the use of therapeutically targeting JAKs as remiss if we did not point out the basic science gaps and what is needed to understand cytokine signaling more completely a new strategy for treating immune and inflammatory Downloaded from diseases. This now is a reality with seven approved for even more therapeutic opportunities. As a caveat, this is a jakinibs being used to treat multiple forms of arthritis, fast-moving field. We have tried our best to be as current as inflammatory bowel disease and myeloproliferative possible; however, for clinical issues, be sure to check the research yourself. neoplasms, and numerous ongoing clinical trials in other settings. This story provides interesting insights Discovery of Janus kinases and their role in cytokine signaling into the process of translating basic discoveries and also http://www.jimmunol.org/ reveals the need to return to basic work to fill gaps that The elucidation of the function of JAKs began with the dis- now become apparent. The Journal of Immunology, covery of IFNs by Isaacs and Lindenmann (6) and the rec- 2020, 204: 2011–2020. ognition that IFNs induced rapid transcriptional programs in the antiviral response (7). This area attracted the attention of a number of investigators, as it provoked the corollary that nterferons, , and growth factors were first rapid membrane-to-nucleus signaling occurred to engage identified more than half a century ago; however, with the the transcriptional apparatus. George Stark and colleagues

I advances in molecular biology techniques, the pace of (8) tackled this problem by generating a series of mutant cell by guest on September 29, 2021 discovery in this field exploded in the 1980s (1). The eluci- lines resistant to the actions of IFNs. A key finding came from dation of the diversity of these factors provided enormous George’s colleague, Sandra Pellegrini (9), who showed that one insights into hematopoiesis and immunoregulation, making it IFN-resistant line was overcome by complementation with a hard to overstate the clinical significance of these advances. encoding a structurally distinct kinase, 2 Immunologists can be appropriately very proud of the effi- (TYK2), which had been cloned by Krolewski and colleagues ciency by which the avalanche of their basic discoveries was shortly before (10). Fortunately, right around this time, the broad quickly translated into many new, effective, and safe drugs. importance of tyrosine kinases in was Cytokines themselves were quickly used to treat hematologic, becoming increasingly clear, and the race was on to discover oncologic, and infectious diseases. This was quickly followed new kinases using different screening strategies. Shortly after by targeting cytokines using mAbs to treat autoimmune dis- the discovery of TYK2 came the discovery of two other kinases, ease. Indeed, the era of “biologics” undeniably revolutionized termed JAK1 and JAK2 (11). These kinases were named by the treatment of autoimmune diseases, from rheumatoid ar- Andrew Wilks for the Roman god Janus, the two-faced god of thritis (RA) and other inflammatory arthropathies to in- doorways, based on the presence of tandem kinase-like and flammatory bowel disease (IBD) and (2–5). Despite kinase domains (a remarkably prescient designation, as it turns the success of biologics, not all patients respond to these out). Using the different Stark lines, it became clear that TYK2 drugs, and others do not respond completely. This necessi- and JAK1 were both required for type I IFN signaling, and tated consideration of newer strategies, including investiga- IFN-g signaling used JAK1 and JAK2 (9–12). Later, we and tions into whether targeting cytokine signaling might provide others discovered a fourth member of the family, JAK3, which

*Translational Immunology Section, National Institute of Arthritis and Musculoskeletal This work was supported by the National Institute of Arthritis and Musculoskeletal and and Diseases, National Institutes of Health, Bethesda, MD 20892; †Molecular Skin Diseases Intramural Research Program. Immunology and Inflammation Branch, National Institute of Arthritis and Musculo- Address correspondence and reprint requests to Dr. John J. O’Shea, Molecular Immu- skeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; nology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal ‡Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow x and Skin Diseases, National Institutes of Health, Building 10, Room 13C103C, 10 G12 8TA, United Kingdom; and Aclaris Therapeutics, Inc., Wayne, PA 19087 Center Drive, Bethesda, MD 20892. E-mail address: [email protected] ORCIDs: 0000-0001-9084-6736 (M.G.); 0000-0002-2957-6412 (P.S.C.). Abbreviations used in this article: ATC, Anatomical Therapeutic Chemical; Btk, Bruton Received for publication December 16, 2019. Accepted for publication February 11, tyrosine kinase; EPO, ; GVHD, graft-versus-host disease; IBD, inflamma- 2020. tory bowel disease; MPN, myeloproliferative neoplasm; RA, ; SLE, systemic lupus erythematosus; TYK2, ; UC, . www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901477 2012 TRANSLATING IMMUNOLOGY: FROM JAKs TO JAKINIBS was found to be activated by IL-2 (13). Later, IL-12 was also found to signal via TYK2 (14). The completion of the ultimately revealed that out of a total of 518 kinases, only these four kinases had the characteristic tandem kinase/ kinase-like domains. JAKs play a critical role in cytokine signaling (Fig. 1). JAKs bind to a subset of cytokine receptors (bc cytokines, gc cy- tokines, IFNs, gp130 cytokines, IL-10 family, TSLP, IL-12, IL-13, and IL-17), and upon cytokine-activation, JAKs use ATP to phosphorylate themselves as well as the intracellular tail of the receptor subunits. This creates docking sites for the recruitment of downstream signaling molecules. A crit- ical discovery in understanding cytokine signaling was the identification of another class of JAK substrates by members of Jim Darnell’s laboratory (15, 16), the tyrosine-phosphorylated STAT family of DNA binding . These transcription factors carry out the rapid transcriptional programs, thus solving a large part of the mystery of how IFNs could so Downloaded from quickly mediate changes in .

In vivo function of JAKs: Mendelian disorders, mutations, and knockouts The efforts of Stark, Darnell, and colleagues provided striking and tantalizing evidence for a new paradigm in cell signaling: a direct membrane-to-nucleus scheme that explained how http://www.jimmunol.org/ cytokines could rapidly and directly impact gene transcrip- tion. What was less clear was the role of the four JAKs in vivo. During this time, new cytokines continued to be discovered, and the question was how important were JAKs for all these factors. Spoiler alert — we now know that there are 57 cytokines that signal by the four JAKs (Table I; more on this later). The first in vivo proof of the criticality of JAKs came from the recognition of humans with a primary immunodeficiency. by guest on September 29, 2021 This appreciation began with the discovery that mutations of FIGURE 1. Jakinibs target JAK family proteins to therapeutically inhibit cytokine signaling. JAKs associate with subunits and are the common g-chain, gc (encoded by IL2RG), a shared re- ceptor subunit that pairs with ligand-specific subunits to form activated upon cytokine binding. JAKs auto- and transphosphorylate and receptors for IL-2, 4, 7, 9, 15, and 21, underlies the disorder phosphorylate cytokine receptors. Phosphorylated receptors are bound by STATs, which are themselves phosphorylated by JAKs. Activated STATs X-linked SCID (17). The absence of signaling by all these accumulate in the nucleus, bind DNA, and regulate gene expression. JAKs cytokines has dramatic effects on lymphocyte development associate with receptors via their N-terminal band 4.1 (F), ezrin (E), radixin and function. With the recognition that JAK3 specifically (R), and moesin (M) (FERM) domains. The JAK catalytic domain (JH1) is the associates with gc, it was predicted that mutations of JAK3 target of most jakinibs, which are competitive ATP inhibitors. The kinase-like might be a cause of autosomal recessive SCID. In fact, this (JH2) domain regulates kinase activity and the JAK2 JH2 is mutated in MPNs. turned out to be the case; patients with mutations of IL2RG Some jakinibs (e.g., BMS-986165) target the JH2 domain instead of the JH1 domain. and JAK3 phenocopy one another in that T and NK cells are lacking and B cells are dysfunctional in both diseases (Table I) (18, 19). Of note, patients with immunodeficiency due to JAK3 megakaryocytes does not cause but rather or IL2RG mutations do not have clinical problems beyond im- causes thrombocytosis and increased circulating thrombo- munodeficiency, and stem cell transplantation is curative. This poietin (25). Conversely, somatic GOF mutations in the points to selective functions of JAK3 and was the rationale for JAK2 kinase-like domain are associated with myeloprolifera- efforts to therapeutically target this kinase. Of note, somatic JAK3 tive neoplasms (MPN), including polycythemia rubra vera, mutations were recently identified in NK cell enteropathy (20). essential thrombocytopenia, and myelofibrosis, the most Shortly after the discovery of JAK3–SCID, knockout mice common being the V617F mutation (26). Of note, the im- targeting Jak3, Jak2, Jak1, and Tyk2 were reported. Deletion portance of activating mutations in the JAK kinase-like do- of Jak3 in mice results in a phenotype mirroring human au- main in flies anticipated disease in humans, as a mutation tosomal SCID, with immune deficits but not global abnor- termed tumorous lethal of the Drosophila JAK, Hopscotch, malities beyond immune cells (21). In contrast to Jak3 knockout caused (27). Germline deletion of Jak1 causes mice, germline deletion of Jak2 in mice has embryonically lethal perinatal lethality, as JAK1 is essential for signaling by all class results because of impaired definitive hematopoiesis and the II cytokine receptors, gc using cytokines, and gp130 using essential function of JAK2 in erythropoietin (EPO) signaling cytokines (Table I). Biallelic germline mutations identified in (22, 23). Conditional Jak2 deletion in young adult mice also a single patient were associated with atypical mycobacterial severely affects thrombopoiesis, granulopoiesis, and mono- infection and early onset metastatic bladder cancer, although cytopoiesis (24). Selective deletion of Jak2 in platelets and the patient had normal numbers of T, B, and NK cells (28). The Journal of Immunology 2013

Table I. Summary of usage of JAKs by various cytokines

JAK Cytokine Mouse Knockout Human LOF Human GOF

JAK1 gc cytokines: (IL-2, IL-4, IL-7, IL-9, IL-15, IL-13, Perinatal lethality, Atypical mycobacterial Systemic immune 2 2 and IL-21) T B+NK SCID infection, metastatic dysregulation TSLP gp130 cytokine family: (IL-6, IL-11, bladder cancer IL-31, OSM, CNTF, LIF, CT-1, and NNT-1) IFN-g, IFN-a, IFN-b, and IFN-l IL-10–like cytokines: (IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26) JAK2 bc cytokines: (IL-3, IL-5, and GM-CSF) Embryonic Not reported MPN leukemia, TSLP gp130 cytokine family: lethal, (IL-6, IL-11, IL-31, OSM, CNTF, LIF, CT-1, and NNT-1) Leptin, GH, prolactin, EPO, TPO, IFN-g, and IL-13 IL-12, IL-23 2 + 2 2 + 2 JAK3 gc cytokines: (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) T B NK SCID T B NK SCID leukemia TYK2 IFN-as, IFN-b, and IFN-l Viral susceptibility, Primary immunodeficiency, gp 130 cytokinesa diminished responses variants protect against IL-10-like cytokines (L-10, IL-19, to type I IFNs, IL-12, autoimmunity IL-20, IL-22, IL-24, and IL-26) and IL-23 Downloaded from IL-13 IL-12, IL-23, and IL-27 aSome evidence points to a role for TYK2 in signaling by gp130 and other cytokines; however, the cell, cell-state, and species-specific requirements for gp130 cytokines and likely many other cytokines are incompletely understood. CNTF, ciliary neurotrophic factor; CT-1, cardiotropin-1; G-CSF, G-CSF (encoded by CSF3); GH, growth hormone; LIF, leukemia inhibitor factor; NNT-1, neurotrophin-1 (encoded by CLCF1 gene); OSM, ; TPO, ; TSLP, thymic stromal lymphopoietin. http://www.jimmunol.org/

Gain-of-function mutations of JAK1 in humans cause mul- whether they would be safe. Today, seven jakinibs are approved tiple system immune disease (29), and polymorphisms of for various indications, including RA, psoriatic arthritis, UC, JAK1 are associated with juvenile idiopathic arthritis (30). MPN, acute GVHD and (canine) allergic . Six Consistent with Pellegrini’s seminal work using the Stark cell jakinibs are approved for humans (, 2 2 lines, Tyk2 / mice have impaired responses of IFNs and [ATC code: L01XE18], [ATC code: L04AA37], IL-12 (31, 32). Humans with TYK2 deficiency have severe peficitinib, [ATC code: L01XE57], and upadaci-

infections with bacterial, viral, and fungal pathogens (33–35). tinib [ATC code: L04AA44]) and one is approved for dogs by guest on September 29, 2021 In addition, these patients have variable allergic disease and (; ATCvet code: QD11AH90) (Fig. 1). The safety elevation of IgE and variable impairment of IL-6 signaling. and efficacy of first-generation nonselective jakinibs have been Genome-wide association studies have implicated TYK2 in established in numerous clinical studies, and numerous clin- susceptibility to autoimmune diseases, including systemic ical trials are ongoing for the treatment of many other dis- lupus erythematosus (SLE), Crohn’s disease, ulcerative colitis eases. Notably, the first selective jakinib, , was (UC), psoriasis, , systemic sclerosis, inflam- recently approved for the treatment of RA (discussed in next matory myopathies, primary biliary cirrhosis, and type 1 di- section). abetes (36). Importantly, some -coding variants in Arthritis. Tofacitinib and baricitinib are approved for the treat- TYK2 have been reported to provide protection against vari- ment of patients with RA with inadequate response to conven- ous autoimmune diseases, including multiple sclerosis, RA, tional therapies. Tofacitinib and baricitinib can be used as psoriasis, and SLE (37–39). monotherapy or with , and the combination is equivalent to or even statistically superior to anti-TNF mAb Jakinibs as a new class of drugs for autoimmune disease comparators. Jakinibs are also effective in patients who have The dramatic impact of JAK3 mutations in humans led to the had an inadequate response to biologicals other than TNF proposal that targeting JAKs with small-molecule kinase in- inhibitors. Peficitinib was approved in Japan for the treatment hibitors could represent a new strategy in the treatment of of RA. Tofacitinib has also been approved for the treatment immune-mediated diseases (19) (Fig. 1). The verification of of psoriatic arthritis. The longstanding efficacy and safety of the critical but distinct role of JAKs in different mouse models tofacitinib has been documented for 9.5 y (41), and recent provided a strong rationale for pursuing the development of long-term extension studies suggest that baricitinib enjoys similar jakinibs. The first reported in vivo use of a jakinib showed tolerance. Whereas jakinibs clearly affect inflammation, jakinibs that tofacitinib (also known as CP 690,550; Anatomical also appear to control pain independent of inflammation (42). Therapeutic Chemical [ATC] code: L04AA29) effectively How cytokines influence pain and inflammation as distinct blocked allograft rejection (40). Later, tofacitinib and other but related parameters is clearly an area in need of further jakinibs were tested in an array of preclinical models of investigation. Preclinical models support the use of jakinibs immune-mediated diseases, including arthritis, allergy, graft- in spondyloarthritis (43), and recently, tofacitinib was shown versus-host disease (GVHD), psoriasis, and lupus. First-generation to offer benefit in axial spondyloarthritis (43–45). jakinibs were all found to inhibit more than one JAK. Inflammatory bowel disease. Tofacitinib is approved for moderate- Based on genetic and preclinical data, the expectation was to-severe UC, showing an increase in the likelihood of a that such drugs would be efficacious; what was less clear was free remission. However, tofacitinib was not effective in Crohn’s 2014 TRANSLATING IMMUNOLOGY: FROM JAKs TO JAKINIBS disease, but other jakinibs are being studied in this disease this disease. Only the 10 mg, twice daily dosage of tofacitinib (see below). In a phase 2 study, peficitinib showed no dose showed noninferiority to TNF inhibitors, and the Food and response in patients with moderate-to-severe UC, but Drug Administration issued a complete response letter indi- evidence of efficacy was suggested at dosages $75 mg/d (47). cating that it would not be able to approve tofacitinib for Primary biliary cholangitis is an autoimmune disease psoriasis. Baricitinib, was found to be efficacious in a phase II affecting the , and baricitinib is being tested in this study that tested patients with moderate-to-severe psoriasis, disease (NCT03742973). but only at dosages $8 mg/d (60). Dermatological diseases. Allergic dermatitis (eczema) is a com- GVHD is a critical complication of allogenic stem cell trans- mon disorder affecting humans (and dogs), but at present, the plant for patients with cancer or hematologic/immunologic only jakinib approved for this indication, oclacitinib, is ap- genetic disorders; in fact, ruxolitinib is approved for acute proved for dogs. However, a phase 2 trial has been conducted GVHD. Skin disease is one manifestation of GVHD, and showing that significantly more patients with are the standard first-line treatment for GVHD who received baricitinib (4 mg/d) improved compared with (61). However, some patients become steroid-refractory or controls (48). A phase 3 trial with baricitinib is currently steroid-dependent. Therefore, some trials found jakinibs as a underway (NCT03334422) (Table II). In addition, topical promising new treatment option for GVHD (62). Other tofacitinib and delgocitinib (JTE-052) have been tested in immune diseases with prominent skin involvement for allergic dermatitis with promising results (JapicCTI-152887) which jakinibs are being studied include the following:

(49–52). One prominent feature of allergic dermatitis is systemic sclerosis (63), vitiligo (62), actinic dermatitis (62), Downloaded from pruritus, resulting in an –scratch cycle. Cytokines have sarcoidosis (64), palmoplantar pustulosis (65), and amyopathic also been linked to the molecular pathogenesis of pruritus dermatomyositis-associated lung disease (66). through expression of IL-4Rs on neurons (53), as such Interferonopathies. SLE is a disorder in which IFNs and other treatment with jakinibs has the potential to break the cytokines appear to be important contributors to pathogenesis. scratch–itch cycle. In a randomized double-blind placebo-controlled trial, 314 is an autoimmune disease manifested by hair patients who received baricitinib at 4 mg/d (not the 2 mg/d http://www.jimmunol.org/ loss that affects roughly 2% of the population. Preclinical and dosage) had significant improvement in signs and symptoms small open-label studies have shown jakinibs to be useful in this of active SLE (67). In a small study in patients with familial disorder (54–56). Both ruxolitinib and tofacitinib were found chilblain lupus due to TREX1 mutations, baricitinib showed to be safe and efficacious for the treatment of moderate-to- efficacy (68). Dermatomyositis has also been shown to be severe and severe alopecia areata, respectively (55, 56). This is associated with an “IFN signature,” and tofacitinib is being another setting in which topical jakinibs may be useful (57). studied for this indication (NCT03002649). One of the most striking findings is that JAK inhibition Autoinflammatory diseases, such as chronic atypical neu-

not only limits immune responses but may also promote trophilic dermatosis with lipodystrophy and elevated tem- by guest on September 29, 2021 hair growth (58). If this is the case, jakinibs might be useful perature and stimulator of IFN (STING)–associated for treating hair loss beyond loss caused by autoimmune vasculopathy with onset in infancy are monogenic interfer- mechanisms. onopathies and have been treated with jakinibs (69–72). A trial Psoriasis is another dermatological disease in which cyto- is ongoing in Aicardi–Goutie`res syndrome (NCT03921554). kines are known to play a prominent role (59). Tofacitinib has Down syndrome has also been argued to be an interferonopathy, shown efficacy in late-phase clinical trials for the treatment of and jakinibs have been suggested as a possible therapy

Table II. Selected ongoing clinical trials of new jakinibs

Agent Specificity Disease JAK1 RA (NCT03926195), Crohn’s disease (NCT03077412, NCT03046056, NCT02914600, and NCT02914561), UC (NCT02914535), (NCT03926195), psoriatic arthritis (NCT04115839, NCT03926195), cutaneous lupus, membranous lupus (NCT03285711) JAK1 Atopic dermatitis (NCT03422822; NCT03915496) Itacitinib JAK1 GVHD (NCT04070781, NCT03846479, NCT03584516, and NCT03497273), MPN (NCT03144687), non–small cell lung cancer (NCT03425006), Hodgkin lymphoma (NCT03697408), hematologic malignancies (NCT03320642), UC (NCT03425006), cytokine release syndrome (NCT04071366), sarcomas (NCT03670069), prolymphocytic leukemia (NCT03989466) PF-06651600 JAK3/Tec Crohn’s disease (NCT03395184), UC (NCT02958865), alopecia areata (NCT04006457, NCT03732807), vitiligo (NCT03715829) BMS-986165 TYK2 SLE (NCT03920267), psoriasis (NCT04036435, NCT03924427), psoriatic arthritis (NCT03881059), plaque psoriasis (NCT03624127, NCT03611751), UC (NCT03934216), Crohn’s disease (NCT03599622), lupus nephritis (NCT03943147) PF-06700841 TYK2, JAK1 Atopic dermatitis (NCT03903822), SLE (NCT03845517), psoriasis (NCT03850483), psoriatic arthritis (NCT03963401), vitiligo (NCT03715829), IBD (NCT03395184, NCT02958865), hydradenitis suppurativa (NCT04092452) JAK1, JAK2 Primary myelofibrosis (NCT02124746, NCT02101268, NCT01969838, NCT02515630, NCT03441113, NCT01236638, and NCT00935987) Gandotinib JAK2V617F MPN (NCT01520220) PF-06263276 Multiple JAKs Psoriasis (NCT02193815) (topical) The Journal of Immunology 2015

(73). More recently, JAK inhibition has been reported to be unsurprisingly, there was a higher incidence of infections efficacious in a child with interferonopathy due to USP18 and some patients developed posttransplant Epstein–Barr deficiency (74). virus–related lymphoproliferative disease (84). Myeloproliferative neoplasms and cancer. Mutations in the kinase- An infectious complication that is commonly associated like domain of JAK2 areacommonpathogeneticmechanism with jakinibs is reactivation of varicella zoster virus (herpes underlying the spectrum of diseases encompassing polycythemia zoster) (81, 85–87). Overall, the rate of zoster associated with vera, essential thrombocytosis, and myelofibrosis. Ruxolitinib tofacitinib is roughly the rate seen with biologics (88). Be- and fedratinib are approved for the treatment of these cause of the increased risk, vaccination is recommended disorders, and momelotinib (another JAK1/JAK2 inhibitor) is (88–91). There has been one case of fatal John Cunningham being studied in MPNs (75, 76) (NCT02124746, NCT02101268, virus infection with ruxolitinib (92). NCT01969838, NCT02515630, NCT03441113, NCT01236638, Anemia and other hematological effects. Treatment with first- and NCT00935987). generation jakinibs leads to a decrease of hemoglobin. In addition, many types of cancers, from and Presumably this is related to inhibition of JAK2, which to solid organ malignancies, exhibit activation of interferes with the action of EPO and related cytokines the JAK/STAT pathway (77). This can either be due to that are dependent upon JAK2 (93). Other changes include mutation of JAKs or, indirectly, by autocrine cytokine pro- decreased numbers of lymphocytes, NK cells, , and duction. Many trials are ongoing to test the efficacy of jaki- platelets (41, 94). Especially with higher doses of jakinibs, there nibs in this setting (NCT03117751 and NCT04021082). In may be an increased risk of venous thrombosis and pulmonary Downloaded from addition, preclinical data has shown that targeting JAKs embolism. can modulate the tumor microenvironment and facilitate Hyperlipidemia. Jakinibs alter and have immunotoxin access to malignant cells (78). This could be modest but statistically significant increases in high- and low- yet another strategy in which jakinibs might be useful in the density lipoproteins and triglyceride levels. However, the ratio treatment of cancer. of low density lipoprotein-C to high density lipoprotein-C is not altered, and whether these changes increase the risk of http://www.jimmunol.org/ Side effects of first-generation jakinibs cardiovascular disease is unclear (95–97). Given that first-generation jakinibs block multiple JAKs Other effects. Jakinibs also reduce creatinine clearance (a mea- and therefore block many cytokines, it is not surprising sure of function) (98), increase creatine phosphokinase that these drugs have side effects, especially when used at levels without causing muscle disease (89), and increase levels higher doses. Common side effects include infection, anemia of liver (99–101). Gastrointestinal perforations have and hematological effects, hyperlipidemia, and other effects been reported, possibly because of the blockade of IL-6 signaling, (Table III). but the cytokines involved in this adverse event have not Infection. The essential function of JAKs in host defense is well- been definitively clarified. Lymphoma and other malignancies by guest on September 29, 2021 established, so it was no surprise that infections are a common have been observed in patients treated with jakinibs, but adverse event in patients treated with jakinibs. In fact, serious autoimmune diseases, such as RA, are themselves associated infections, such as , fungal, and opportunistic with an increased incidence of cancers, especially lymphoma. infections, are more frequently seen in patients on jakinibs. Next-generation, selective jakinibs Generally though, the incidence of infections in jakinib- Whereas first-generation jakinibs have been shown to be treated patients is equivalent to that observed in patients on efficacious and reasonably safe, they inhibit many cytokines. TNF-blockers and other biological therapies (79–82). One This raises the obvious question as to whether targeting a reason why infections are not more common in patients single JAK might provide efficacy with fewer side effects taking jakinibs versus biologics is that not all cytokines are because a narrower spectrum of cytokines would be inhibited. JAK dependent (e.g., TNF, IL-1, IL-17, and IL-8). The Of course, this presupposes that we are aware of the essen- second reason relates to dose. In some patients with inherited tial cytokine profiles that mediate the core effector biology autoinflammatory disease, the doses required to control symptoms of the major immune-mediated diseases and, moreover, that were high, and treatment was associated with BK viremia this will translate across to tractable JAK selectivity. Mul- (83). A third consideration is that in some settings multiple tiple second-generation jakinibs have been developed, with immunosuppressive drugs are used, thus increasing the incidence one approved (upadacitinib) and others at various phases of of infection (84). In transplant trials, tofacitinb was found clinical trials. effective compared with cyclosporin A; however, these patients werealsotreatedwithmycophenolateandsteroids.Perhaps JAK1 inhibitors. Whereas many cytokines signal via JAK1, the spectrum of cytokines blocked with a JAK1 antagonist is narrower than first-generation jakinibs, and avoidance of JAK2 Table III. Major side effects of jakinibs inhibition in particular could be advantageous. Upadacitinib, filgotinib (ATC code: L04AA45), and abrocitinib are selective Infection Serious and opportunistic infections JAK1 inhibitors in which results of phase 3 clinical trials have Herpes zoster been completed (102–106). As indicated, upadacitinib has Hematologic been approved for RA. In patients with inadequate response Anemia to methotrexate, upadacitinib was statistically superior to Thrombocytopenia the TNF inhibitor adulimumab (103). Filgotinib showed Venous thrombosis efficacy in RA patients with inadequate responses to biologics Hyperlipidemia (106) and showed efficacy in a phase 2 trials in ankylosing 2016 TRANSLATING IMMUNOLOGY: FROM JAKs TO JAKINIBS spondylitis and psoriatic arthritis (46, 107). In a phase 2 Tec family of tyrosine kinases encompasses Itk, Bruton tyrosine dose-ranging study, abrocitinib was found to improve kinase (Btk), Rlk, and Bmx, which have important immunological psoriasis and atopic dermatitis (108, 109). Itacitinib is functions. Btk has been widely studied because of its critical role being studied in phase 3 trials in GVHD (NCT03139604) in B cell development and evidence showing that pharmacologic and malignancies (hematologic and solid tumor) as well as blockade Btk is effective in ameliorating lymphoma progression RA, UC, and psoriasis (NCT01634087). Other JAK1- and arthritis models. PF-06651600 is being studied in RA, alopecia selective drugs being tested include SHR0302 for IBD areata, Crohn’s disease, and UC (122, 123) (NCT02974868, (NCT03675477 and NCT03677648) and INCB054707 NCT02958865, NCT02969044, NCT03395184, and for hydradenitis suprativa (NCT03569371 and NCT03607487). NCT03978520). SYK is a nonreceptor tyrosine kinase highly Overall, a substantial number of JAK1-selective inhibitors expressed in hematopoietic cells and plays important roles in have been generated and are being studied in a wide range immune cell differentiation and signaling. Targeting SYK of diseases. alongside JAKs may also extend the range of cytokines targeted Adverse events found with JAK1-selective inhibitors are for therapies. Gusacitinib (ASN002) is an oral dual JAK/SYK increased lipids and infections, including herpes zoster and inhibitor shown to have effects on the treatment of moderate- dyslipidemia. Upadacitinib was also associated with anemia to-severe atopic dermatitis by diminishing cellular infiltrates, and thromboembolic events, suggesting that at higher doses ameliorating epidermal barrier abnormalities, and suppressing upadacitinib might inhibit JAK2. Abrocitinib is associated inflammation (124). with neutropenia, possibly related to inhibition of IL-6 sig- Cancers are one circumstance in which multikinase inhib- Downloaded from naling, and thrombocytopenia, also possibly related to JAK2 itors might be especially attractive. Cerdulatinib is another inhibition. SYK/JAK inhibitor being studied in lymphoma and leukemia Inhaled jakinibs are in development and testing (e.g., (125) (NCT04021082) but could also be useful for immune AZD0449 and NCT03766399). For example, a selective and inflammatory disorders. is a JAK2/FLT3 in- JAK1 inhibitor has been optimized for inhaled delivery and hibitor being investigated in myelofibrosis, leukemia, small reverses pathology in a rodent model (110). cell lung cancer, and GVHD. http://www.jimmunol.org/ TYK2 inhibitors. TYK2 is used by a relatively narrow spectrum An alternative strategy is to use jakinibs with other kinase of cytokines, including IL-12, IL-23, and type I and type III inhibitors. Itacitinib (ATC code: L04AA46) is being tested in d IFNs (Table I). The demonstrated role of these cytokines in combination with the PI3K inhibitor parsaclisib (64, 126) and (ATC code: L01XE27; NCT02760485). autoimmunity, along with data pointing to the protective AZD4205, a JAK1-selective inhibitor, is being studied with effect of inactivating TYK2 coding variants, provides a rationale the EGFR inhibitor (ATC code: L01XE35) for for selectively targeting TYK2 (111). BMS-986165 is a selective cancer (NCT03450330). Still another strategy is to use se- TYK2 inhibitor, and its efficacy has been documented in a

lective jakinibs in combination; for instance, itacitinib is being by guest on September 29, 2021 dose-ranging phase 2 trial in psoriasis (112). Adverse events tested with low-dose ruxolitinib (NCT03144687). included upper respiratory tract infection, acne, and one case In cancer, one could imagine that jakinibs could represent a of melanoma; no anemia, neutropenia, or thrombocytopenia double-edged sword, as they could antagonize the production were reported (113). Of note, BMS-986165 does not target and actions of IFN-g, which helps eliminate tumors. Indeed, the catalytic domain; rather, it targets the kinase-like domain somatic LOF mutations of JAK1 can arise in tumor cells and (Fig. 1) (113). It is being studied in SLE, psoriasis, psoriatic are associated with resistance to IFN-g and cancer evasion. arthritis, and IBD. Brepocitinib (PF-06700841) is a TYK2/ However, blocking IFN signaling with jakinibs also has the JAK1 inhibitor being tested in psoriasis, IBD, and alopecia capacity to reverse expression of inhibitory receptors and in this areata. way can promote responsiveness to checkpoint blockade ther- JAK3 inhibitors. Based on genetic data, a selective JAK3 in- apy (127). A phase 2 study is ongoing in hematological ma- hibitor would be expected to only inhibit the six gc cyto- lignancies using anti-PD1 () kines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), a much and ruxolitinib (NCT04016116) (128). narrower spectrum of action compared with other jakinibs. was reported to be a selective inhibitor of JAK3 Conclusions and phase 2 trials showed efficacy in RA; however, drug-drug Targeting cytokines both inside and outside the cell is now a interactions were found, limiting the use of decernotinib reality. Both strategies have generated remarkably effective (114–117). Decernotinib was associated with neutropenia, and reasonably safe drugs that represent extraordinary ad- suggesting the possibility of activity toward JAK1 or JAK2 vances in the treatment of autoimmune diseases. The drugs and incomplete selectivity for JAK3 (118). are highly efficacious but are not without side effects. There JAK2 inhibitors. Inhibitors, like fedratinib, with greater se- is clearly a great deal of work to be done to identify the lectivity for JAK2 have been developed primarily for the best drug or combination of drugs and the best route of ad- treatment of MPN [NCT03755518 (119)]. Gandotinib ministration for the right disease at the right time. Aside (LY2784544) is a potent inhibitor of JAK2 activity that also from topical and inhaled jakinibs, TD-1473 is a nonabsorb- V617F shows increased potency for the JAK2 mutant kinase able pan-jakinib being studied in IBD (NCT03758443, (120). NCT03920254). Combination therapy. 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