Selective targeting of the IL23 pathway: Generation and characterization of a novel high-affinity humanized anti-IL23A antibody

Singh, Sanjaya; Kroe‐Barrett, Rachel; Canada, Keith A.; Zhu, Xiang; Sepulveda, Eliud; Wu, Helen; He, Yan; Raymond, E.; Ahlberg, Jennifer; Frego, Lee; Amodeo, Laura M; Catron, Katrina M; Presky, David H.; Hanke, J H

doi:10.1080/19420862.2015.1032491

Cited by 97 publications

(75 citation statements)

References 66 publications

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“…In particular, R381Q within the interleukin 23 receptor ( IL23R ) is a loss-of-function allele that confers protection against developing IBD (3). Importantly, monoclonal antibodies blocking the IL-23 pathway have demonstrated efficacy in IBD, as well as a favorable safety profile (4). CD-predominant loci include nucleotide-binding oligomerization domain-containing protein 2 NOD2 and a number of autophagy genes (e.g.…”

Section: Introductionmentioning

confidence: 99%

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

et al. 2018

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Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of non-synonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2,066 CD cases and 3,633 healthy controls. We detected association signals in the LRRK2 gene that conferred CD risk (N2081D variant, P=9.5×10−10) or protection (N551K variant, tagging R1398H-associated haplotype, P=3.3×10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with similar genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant is associated with increased kinase activity, whereas neither N551K nor R1398H on the protective haplotype altered kinase activity. R1398H, but not N551K, increased GTPase activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.

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Section: Introductionmentioning

confidence: 99%

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

et al. 2018

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“…Risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany) is a humanised monoclonal antibody that targets the pl9 subunit, which is specific to interleukin-23. 15 Thus, treatment with risankizumab might downregulate interleukin-23-mediated inflammation without affecting interleukin-12-dependent T-cell pathways which, in animal models, are important for infection and cancer immunity. 16,17 This selective approach might have advantages over agents that target both cytokines.…”

Section: Introductionmentioning

confidence: 99%

Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study

et al. 2017

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“…Risankizumab is a humanized IgG1 mAb with kappa light chains, targeting specifically the p19 subunit of IL-23 [15]. By blocking IL-23 from binding to its receptor, risankizumab inhibits IL-23-dependent cell signaling and the release of proinflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

et al. 2018

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Background and Objectives Risankizumab is a humanized anti-interleukin-23 monoclonal antibody in development for the treatment of several inflammatory diseases. This work characterized the pharmacokinetics of risankizumab and evaluated covariates that may affect its exposures using phase I and II trial data in subjects with psoriasis and Crohn's disease. Methods Plasma concentration measurements from a phase I study and a phase II study in subjects with psoriasis (n = 157; single doses of 0.01-5 mg/kg intravenously, 0.25-1 mg/kg subcutaneously, and 18 mg subcutaneously, and multiple doses of 90 and 180 mg subcutaneously), and a phase II study in subjects with Crohn's disease (n = 115; doses of 200 or 600 mg intravenously every 4 weeks followed by 180 mg subcutaneously every 8 weeks) were analyzed using non-linear mixedeffects modeling. The model was qualified using bootstrap and simulation-based diagnostics. Results A two-compartment model with first-order absorption and elimination described the pharmacokinetics of risankizumab. Considering the body weight and baseline albumin central tendency differences between disease populations, risankizumab clearance, steady-state volume of distribution, and terminal-phase elimination half-life were estimated to be approximately 0.35 L/day, 11.7 L, and 27 days, respectively, for a typical 90-kg subject with psoriasis with an albumin level of 42 g/L, and 0.31 L/day, 8.45 L, and 22 days, respectively, for a typical 65-kg subject with Crohn's disease with an albumin level of 37 g/L. Risankizumab absolute subcutaneous bioavailability and absorption rate constant were 72% and 0.18 day −1 , respectively. Inter-individual variability for clearance was 37%. Conclusions Risankizumab displayed pharmacokinetic characteristics typical for an IgG1 monoclonal antibody with no apparent target-mediated disposition. Accounting for the effects of body weight and baseline albumin explained the small differences in the pharmacokinetics of risankizumab between psoriasis and Crohn's disease, with no further differences between the patient populations. Electronic supplementary materialThe online version of this article (https ://doi.org/10.1007/s4026 2-018-0704-z) contains supplementary material, which is available to authorized users. Key PointsA robust two-compartment model with dose-and timeindependent pharmacokinetic parameters was developed to characterize the disposition of risankizumab, an antiinterleukin-23 monoclonal antibody, in subjects with plaque psoriasis and Crohn's disease.Of the factors evaluated (demographics, disease population, laboratory values, and anti-drug antibody development), only body weight and baseline albumin level were statistically correlated with risankizumab clearance. Body weight had a modest effect on risankizumab exposure while albumin had no meaningful impact.After accounting for differences in body weight and baseline albumin levels between psoriasis and Crohn's disease patient populations, no significant differences in the pharmacokinetics of ri...

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Selective targeting of the IL23 pathway: Generation and characterization of a novel high-affinity humanized anti-IL23A antibody

Cited by 97 publications

References 66 publications

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

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