Discovery and mechanism of ustekinumab

Benson, Jacqueline; Peritt, David; Scallon, Bernard J.; Heavner, George A.; Shealy, David J.; Giles‐Komar, Jill; Mascelli, Mary Ann

doi:10.4161/mabs.3.6.17815

Cited by 272 publications

(113 citation statements)

References 74 publications

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“…Indeed, inhibiting the Th17 pathway has been shown to be effective in the treatment of psoriasis and multiple sclerosis (47, 48). FDA has approved Ustekinumab, a human monoclonal antibody that inhibits Th17 responses by blocking the IL-23 receptor, to treat patients with severe plaque psoriasis (49). Given the essential function of RORγt in Th17 cells, many different kinds of RORγt inhibitors have been developed for therapeutic purpose (24–28).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt

Wang

Zhang

et al. 2017

The Journal of Immunology

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Transcription factor retinoid acid-related orphan receptor gamma t (RORγt) transcriptionally regulates the genes required for differentiation of T helper 17 (Th17) cells that mediate both protective and pathogenic immunity. However, little is known about the function of post-translational modifications in the regulation of RORγt activity. Mass spectrometric analysis of immunoprecipitated RORγt from Th17 cells identified multiple phosphorylation sites. Systematic mutation analysis of the identified phosphorylation sites find that phosphorylation of serine 376 (S376) enhances whereas phosphorylation of serine 484 (S484) inhibits Th17 differentiation. IKKα binds and phosphorylates RORγt at S376 but not S484. Knockdown of IKKα, dominant negative IKKα and RORγt mutants incapable of interacting with IKKα all decrease Th17 differentiation. Furthermore, nonphosophorylatable RORγt mutant (S376A) impairs whereas phosphomimetic mutant (S376E) stimulates Th17 differentiation independent of IKKα. Therefore, IKKα-dependent phosphorylation of S376 stimulated whereas IKKα-independent phosphorylation of S484 inhibited RORγt function in Th17 differentiation.

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Section: Discussionmentioning

confidence: 99%

Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt

Wang

Zhang

et al. 2017

The Journal of Immunology

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“…Ustekinumab is a human IgG1κ monoclonal antibody that binds with high affinity and specificity to the shared p40 subunit in both IL-12 and IL-23, blocking signaling by inhibiting the interactions of these cytokines with their receptors [4;14]. Ustekinumab has shown efficacy in several human autoimmune diseases, including psoriasis, psoriatic arthritis, and Crohn’s disease [8;26;37;43;56] for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis.…”

Section: 0 Cytokine Therapiesmentioning

confidence: 99%

Anti-cytokine therapies in T1D: Concepts and strategies

Nepom¹,

Ehlers

Mandrup-Poulsen

2013

Clinical Immunology

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Therapeutic targeting of proinflammatory cytokines is clinically beneficial in several autoimmune disorders. Several of these cytokines are directly implicated in the pathogenesis of type 1 diabetes, suggesting opportunities for design of clinical trials in type 1 diabetes that incorporate selective cytokine blockade as a component of preventative or interventional immunotherapy. The rationale and status of inhibitory therapy directed against IL-1, TNF, IL-12, IL-23, and IL-6 are discussed, towards a goal of using cytokine inhibition as a therapeutic platform to establish an in vivo milieu suitable for modulating the immune response in T1D.

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“…Indeed, inhibiting the Th17 pathway is effective in the treatment of psoriasis and multiple sclerosis (54, 55). For example, ustekinumab, a human monoclonal antibody that inhibits Th17 responses by blocking the IL-23 receptor, has been approved by the FDA for treatment of severe plaque psoriasis (56). Given the essential function of RORγt in Th17 cells, pharmaceutical and academic scientists are developing RORγt inhibitors for treatment of Th17-dependent autoimmunity (20–24).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitination of RORγt at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment

Wang

et al. 2016

The Journal of Immunology

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The transcription factor retinoid acid-related orphan receptor gamma t (RORγt) directs the differentiation of T helper 17 (Th17) cells. Th17 cells mediate pathological immune responses responsible for autoimmune diseases, including psoriasis and multiple sclerosis. Previous studies have focused on RORγt target genes and their function in Th17 differentiation. Here, we studied post-transcriptional regulation of RORγt and identified a functional ubiquitination site, lysine 446 (K446). Mutation of K446 to arginine (K446R) to prevent ubiquitination greatly enhanced recruitment of steroid receptor co-activator 1 (SRC1), a co-activator critical for RORγt activity. Correspondingly, the K446R mutation potentiated Th17 differentiation. We also showed that the ubiquitin specific protease 15 (USP15) interacted with RORγt, removed ubiquitin from K446, and stimulated RORγt activity by enhancing co-activator SRC1 recruitment. Knockdown of USP15 or expression of inactive USP15 impaired Th17 differentiation, suggesting a positive role for USP15-mediated deubiquitination of RORγt in Th17 differentiation. Therefore, ubiquitination of K446 limits RORγt-mediated Th17 differentiation by inhibiting the recruitment of co-activator SRC1. Our study will inform the development of treatments that target RORγt ubiqutination pathways to limit Th17-mediated autoimmunity.

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Discovery and mechanism of ustekinumab

Cited by 272 publications

References 74 publications

Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt

Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt

Anti-cytokine therapies in T1D: Concepts and strategies

Ubiquitination of RORγt at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment

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