Dataset Information

A novel human anti-interleukin-1? neutralizing monoclonal antibody showing in vivo efficacy.

ABSTRACT: The pro-inflammatory cytokine interleukin (IL)-1? is a clinical target in many conditions involving dysregulation of the immune system; therapeutics that block IL-1? have been approved to treat diseases such as rheumatoid arthritis (RA), neonatal onset multisystem inflammatory diseases, cryopyrin-associated periodic syndromes, active systemic juvenile idiopathic arthritis. Here, we report the generation and engineering of a new fully human antibody that binds tightly to IL-1? with a neutralization potency more than 10 times higher than that of the marketed antibody canakinumab. After affinity maturation, the derived antibody shows a>30-fold increased affinity to human IL-1? compared with its parent antibody. This anti-human IL-1? IgG also cross-reacts with mouse and monkey IL-1?, hence facilitating preclinical development. In a number of mouse models, this antibody efficiently reduced or abolished signs of disease associated with IL-1? pathology. Due to its high affinity for the cytokine and its potency both in vitro and in vivo, we propose that this novel fully human anti-IL-1? monoclonal antibody is a promising therapeutic candidate and a potential alternative to the current therapeutic arsenal.

SUBMITTER: Goh AX

PROVIDER: S-EPMC4011920 | biostudies-literature | 2014 May-Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel human anti-interleukin-1β neutralizing monoclonal antibody showing in vivo efficacy.

Goh Angeline X H AX Bertin-Maghit Sebastien S Ping Yeo Siok S Ho Adrian W S AW Derks Heidi H Mortellaro Alessandra A Wang Cheng-I CI

mAbs 20140326 3

The pro-inflammatory cytokine interleukin (IL)-1β is a clinical target in many conditions involving dysregulation of the immune system; therapeutics that block IL-1β have been approved to treat diseases such as rheumatoid arthritis (RA), neonatal onset multisystem inflammatory diseases, cryopyrin-associated periodic syndromes, active systemic juvenile idiopathic arthritis. Here, we report the generation and engineering of a new fully human antibody that binds tightly to IL-1β with a neutralizati ...[more]

PMID: 24671001

Similar Datasets

Project description:Canakinumab is a high-affinity human monoclonal anti-interleukin-1? (IL-1?) antibody of the IgG1/? isotype designed to bind and neutralize the activity of human IL-1?, a pro-inflammatory cytokine. Canakinumab is currently being investigated on the premise that it would exert anti-inflammatory effects on a broad spectrum of diseases, driven by IL-1?. This paper focuses on the analysis of the pharmacokinetic and pharmacodynamic data from the canakinumab clinical development programme, describing results from the recently approved indication for the treatment of cryopyrin-associated periodic syndromes (CAPS) under the trade name ILARIS®, as well as diseases such as rheumatoid arthritis, asthma and psoriasis. Canakinumab displays pharmacokinetic properties typical of an IgG1 antibody. In a CAPS patient weighing 70?kg, slow serum clearance (0.174?L/day) was observed with a low total volume of distribution at steady state (6.0?L), resulting in a long elimination half-life of 26 days. The subcutaneous absolute bioavailability was high (70%). Canakinumab displays linear pharmacokinetics, with a dose-proportional increase in exposure and no evidence of accelerated clearance or time-dependent changes in pharmacokinetics following repeated administration was observed. The pharmacokinetics of canakinumab in various diseases (e.g. CAPS, rheumatoid arthritis, psoriasis or asthma) are comparable to those in healthy individuals. No sex- or age-related pharmacokinetic differences were observed after correction for body weight. An increase in total IL-1? was observed in both healthy subjects and all patient populations following canakinumab dosing, reflecting the ability of canakinumab to bind circulating IL-1?. The kinetics of total IL-1? along with the pharmacokinetics of canakinumab were characterized by a population-based pharmacokinetic-binding model, where the apparent in vivo dissociation constant, signifying binding affinity of canakinumab to circulating IL-1?, was estimated at 1.07?±?0.173?nmol/L in CAPS patients. During development of canakinumab a cell line change was introduced. Pharmacokinetic characterization was performed in both animals and humans to assure that this manufacturing change did not affect the pharmacokinetic/pharmacodynamic properties of canakinumab.

Project description:ImportancePalmoplantar pustulosis (PPP) is a recalcitrant skin disease with no biologics currently approved for treatment. The involvement of interleukin 23 (IL-23) and cytokines of the type 17 helper T cell lineage in the pathogenesis of PPP has been recently postulated.ObjectiveTo evaluate the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP.Design, setting, and participantsThis double-blind, randomized, placebo-controlled, parallel-group, 24-week trial was conducted between May 14, 2013, and September 27, 2014, at 11 centers in Japan. Participants were patients with moderate to severe PPP that did not respond adequately to conventional treatments.InterventionsPatients were randomized 1:1 to receive guselkumab, 200 mg, by subcutaneous injection or matching placebo at weeks 0 and 4.Main outcomes and measuresChanges in total scores of skin-related outcomes from baseline at the end of week 16 (primary clinical cutoff) and through week 24 were measured. Serum biomarker analyses were performed at baseline, week 4, and week 16, and safety was monitored through week 24.ResultsOf 49 randomized patients (35 [71%] women; median [range] age, 52 [28-77] years), 41 completed the study at week 24. Mean (SD) PPP severity index total scores (primary end point) improved significantly from baseline in guselkumab-treated patients (-3.3 [2.43]) vs placebo (-1.8 [2.09]) (least squares mean difference, -1.5; 95% CI, -2.9 to -0.2; P = .03). At week 16, PPP area and severity index scores (least squares mean difference, -5.65; 95% CI, -9.80 to -1.50; P = .009) and proportion of patients achieving 50% reduction in these scores (difference in proportion, 39.2; 95% CI, 14.0-64.3; P = .009) improved significantly. A numerically higher proportion of patients had a physician's global assessment score of 1 or less in the guselkumab group vs placebo. Improvement in efficacy scores was maintained through week 24 in the guselkumab group. Significant reductions from baseline in serum IL-17A and IL-17F cytokine levels were observed at weeks 4 and 16. Frequency of treatment-emergent adverse events was comparable between the guselkumab group (19 of 25 patients [76%]) and the placebo group (18 of 24 patients [75%]). Frequent adverse effects included nasopharyngitis (14 patients [29%]), headache (3 patients [6%]), contact dermatitis (3 patients [6%]), and injection site erythema (3 patients [6%]). No major safety concerns emerged during the study.Conclusions and relevanceTargeting IL-23 and its associated immune cascade with guselkumab may be a safe and useful therapeutic option for treatment of PPP.Trial registrationclinicaltrials.gov Identifier: NCT01845987.

Dataset Information

A novel human anti-interleukin-1? neutralizing monoclonal antibody showing in vivo efficacy.

Publications

A novel human anti-interleukin-1β neutralizing monoclonal antibody showing in vivo efficacy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets