Generation and characterization of a potent fully human monoclonal antibody against the interleukin-23 receptor

Sasaki-Iwaoka, Haruna; Ohori, Makoto; Imasato, Akira; Taguchi, K; Minoura, Kyoko; Saito, Tetsu; Kushima, Kiyoshi; Imamura, Emiko; Kubo, Satoshi; Furukawa, Shigetada; Morokata, Tatsuaki

doi:10.1016/j.ejphar.2018.03.036

Cited by 6 publications

(5 citation statements)

References 38 publications

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“…The pharmaceutical blockade strategy that delivered the next best topological alignment of GWI and HC sub-circuits consisted of jointly inhibiting MK6 (IL-6) and MK23 (IL-23) receptors. Interestingly IL-23 modulation has recently attracted interest as a potentially important therapeutic target relevant to a broad range of autoimmune illnesses (Gaffen et al, 2014;Yang et al, 2014;Sasaki-Iwaoka et al, 2018). Moreover, activation of STAT3, a key component of IL-23/IL-17 signaling has been linked to neurotoxin induced neuro-inflammatory hyper-responsiveness in a mouse model of GWI (Locker et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness

et al. 2020

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Potentially linked to the basic physiology of stress response, Gulf War Illness (GWI) is a debilitating condition presenting with complex immune, endocrine and neurological symptoms. Here we interrogate the immune response to physiological stress by measuring 16 blood-borne immune markers at 8 time points before, during and after maximum exercise challenge in n = 12 GWI veterans and n = 11 healthy veteran controls deployed to the same theater. Immune markers were combined into functional sets and the dynamics of their joint expression described as classical rate equations. These empirical networks were further informed structurally by projection onto prior knowledge networks mined from the literature. Of the 49 literature-informed immune signaling interactions, 21 were found active in the combined exercise response data. However, only 4 signals were common to both subject groups while 7 were uniquely active in GWI and 10 uniquely active in healthy veterans. Feedforward mediation of IL-23 and IL-17 by IL-6 and IL-10 emerged as distinguishing control elements that were characteristically active in GWI versus healthy subjects. Simulated restructuring of the regulatory circuitry in GWI as a result of applying an IL-6 receptor antagonist in combination with either a Th1 (IL-2, IFNγ, and TNFα) or IL-23 receptor antagonist predicted a partial rescue of immune response elements previously associated with illness severity. Overall, results suggest that pharmacologically altering the topology of the immune response circuitry identified as active in GWI can inform on strategies that while not curative, may nonetheless deliver a reduction in symptom burden. A lasting and more complete remission in GWI may therefore require manipulation of a broader physiology, namely one that includes endocrine oversight of immune function.

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Section: Discussionmentioning

confidence: 99%

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness

et al. 2020

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“…In contrast, antibodies that block IL23R have not been studied in clinical trials. A fully human monoclonal antibody targeting human IL23R that had cross reactivity for both human and cynomolgus monkey IL23 receptors has been characterized (39). This anti-human-IL23R was more effective at inhibiting IL23-induced Kit-225 cell proliferation than the anti-IL12/23p40 antibody, ustekinumab, although comparison with an anti-human IL23 antibody was not performed (39).…”

Section: Discussionmentioning

confidence: 99%

“…A fully human monoclonal antibody targeting human IL23R that had cross reactivity for both human and cynomolgus monkey IL23 receptors has been characterized (39). This anti-human-IL23R was more effective at inhibiting IL23-induced Kit-225 cell proliferation than the anti-IL12/23p40 antibody, ustekinumab, although comparison with an anti-human IL23 antibody was not performed (39). Given that IL23R expression is likely to be normally lower than IL23 expression, and our results show the value of targeting IL23R over IL23p19, blocking IL23R may offer better antitumor efficacy than neutralizing IL23 for treatment of malignancies controlled by NK cells.…”

Section: Discussionmentioning

confidence: 99%

Experimental Lung Metastases in Mice Are More Effectively Inhibited by Blockade of IL23R than IL23

Yan

Allen

Vijayan

et al. 2018

Cancer Immunology Research

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Tumor-induced immunosuppression is mediated through various mechanisms including engagement of immune checkpoint receptors on effector cells, function of immunoregulatory cells such as regulatory T cells and myeloid-derived suppressor cells, and deployment of immunosuppressive cytokines such as TGFβ and IL10. IL23 is a cytokine that negatively affects antitumor immunity. In this study, we investigated whether IL23-deficient (IL23p19) and IL23R-deficient (IL23R) mice phenocopied each other, with respect to their tumor control. We found that IL23R mice had significantly fewer lung metastases compared with IL23p19 mice across three different experimental lung metastasis models (B16F10, LWT1, and RM-1). Similarly, IL23R blocking antibodies were more effective than antibodies neutralizing IL23 in suppressing experimental lung metastases. The antimetastatic activity of anti-IL23R was dependent on NK cells and IFNγ but independent of CD8 T cells, CD4 T cells, activating Fc receptors, and IL12. Furthermore, our data suggest this increased antitumor efficacy was due to an increase in the proportion of IFNγ-producing NK cells in the lungs of B16F10 tumor-bearing mice. Anti-IL23R, but not anti-IL23p19, partially suppressed lung metastases in tumor-bearing mice neutralized for IL12p40. Collectively, our data imply that IL23R has tumor-promoting effects that are partially independent of IL23p19. Blocking IL23R may be more effective than neutralizing IL23 in the suppression of tumor metastases. .

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“…The human Kit225 T-cell line was kindly provided by Dr. Toshiyuki Hori (Ritsumeikan University, Kyoto, Japan) and cultured in complete Roswell Park Memorial Institute (RPMI) in the presence of human interleukin 2 (IL2, R&D systems, #202-IL) following an established protocol as described in the previous literature (60,61). Kit225 cells were seeded in 384-well plate at a density of 1×10 5 cells/well in 4 µL Hank's Balanced Salt Solution (HBSS), and incubated for 2 hours in a humidified, 5% CO2 cell culture incubator at 37°C.…”

Section: Kit225 T Cell Assay For Ifna-induced Tyk2/phosphostat1 Activitymentioning

confidence: 99%

Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways

Zhou

Shen

et al. 2022

Front. Immunol.

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A member of the Janus kinase (JAK) family, Tyrosine Kinase 2 (TYK2), is crucial in mediating various cytokine-signaling pathways such as interleukin-23 (IL23), interleukin-12 (IL12) and type I Interferons (IFN) which contribute to autoimmune disorders (e.g., psoriasis, lupus, and inflammatory bowel disease). Thus, TYK2 represents an attractive target to develop small-molecule therapeutics for the treatment of cytokine-driven inflammatory diseases. Selective inhibition of TYK2 over other JAK isoforms is critical to achieve a favorable therapeutic index in the development of TYK2 inhibitors. However, designing small molecule inhibitors to target the adenosine triphosphate (ATP) binding site of TYK2 kinase has been challenging due to the substantial structural homology of the JAK family catalytic domains. Here, we employed an approach to target the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein. We developed a series of small-molecule TYK2 pseudokinase ligands, which suppress the TYK2 catalytic activity through allosteric regulation. The TYK2 pseudokinase-binding small molecules in this study simultaneously achieve high affinity-binding for the TYK2 JH2 domain while also affording significantly reduced affinity for the TYK2 JAK homology 1 (JH1) kinase domain. These TYK2 JH2 selective molecules, although possessing little effect on suppressing the catalytic activity of the isolated TYK2 JH1 catalytic domain in the kinase assays, can still significantly block the TYK2-mediated receptor-stimulated pathways by binding to the TYK2 JH2 domain and allosterically regulating the TYK2 JH1 kinase. These compounds are potent towards human T-cell lines and primary immune cells as well as in human whole-blood specimens. Moreover, TYK2 JH2-binding ligands exhibit remarkable selectivity of TYK2 over JAK isoforms not only biochemically but also in a panel of receptor-stimulated JAK1/JAK2/JAK3-driven cellular functional assays. In addition, the TYK2 JH2-targeting ligands also demonstrate high selectivity in a multi-kinase screening panel. The data in the current study underscores that the TYK2 JH2 pseudokinase is a promising therapeutic target for achieving a high degree of biological selectivity. Meanwhile, targeting the JH2 domain represents an appealing strategy for the development of clinically well-tolerated TYK2 inhibitors that would have superior efficacy and a favorable safety profile compared to the existing Janus kinase inhibitors against autoimmune diseases.

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Generation and characterization of a potent fully human monoclonal antibody against the interleukin-23 receptor

Cited by 6 publications

References 38 publications

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness

Experimental Lung Metastases in Mice Are More Effectively Inhibited by Blockade of IL23R than IL23

Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways

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