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Identification and preclinical development of an anti-proteolytic uPA antibody for rheumatoid arthritis
Kasper Almholt1, Jishu Wang2, Jesper Pass3
1Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark. KAHL@novonordisk.com.
Abstract:
Blocking the proteolytic capacity of urokinase-type plasminogen activator (uPA) with a monoclonal antibody (mAb) reduces arthritis progression in the collagen-induced mouse arthritis model to an extent that is on par with the effect of blocking tumor necrosis factor-alpha by etanercept. Seeking to develop a novel therapy for rheumatoid arthritis, a humanized mAb, NNC0266-0043, was selected for its dual inhibition of both the zymogen activation and the proteolytic capacity of human uPA. The antibody revealed nonlinear elimination kinetics in cynomolgus monkeys consistent with binding to and turnover of endogenous uPA. At a dose level of 20.6 mg kg-1, the antibody had a plasma half-life of 210 h. Plasma uPA activity, a pharmacodynamic marker of anti-uPA therapy, was reduced to below the detection limit during treatment, indicating that an efficacious plasma concentration was reached. Pharmacokinetic modeling predicted that sufficient antibody levels can be sustained in arthritis patients dosed subcutaneously once weekly. The anti-uPA mAb was also well tolerated in cynomolgus monkeys at weekly doses up to 200 mg kg-1 over 4 weeks. The data from cynomolgus monkeys and from human material presented here indicates that anti-uPA mAb NNC0266-0043 is suitable for clinical testing as a novel therapeutic for rheumatic diseases. KEY MESSAGES: Background: Anti-uPA therapy is on par with etanercept in a mouse arthritis model. A new humanized antibody blocks activation and proteolytic activity of human uPA. The antibody represents a radically novel mode-of-action in anti-rheumatic therapy. The antibody has PK/PD properties in primates consistent with QW clinical dosing.
Insights
A new antibody targeting urokinase-type plasminogen activator (uPA) shows promise for rheumatoid arthritis treatment. This anti-uPA therapy matches etanercept
Area of Science:
- Rheumatology
- Immunology
- Pharmacology
Background:
- Blocking urokinase-type plasminogen activator (uPA) effectively reduces arthritis progression in mouse models.
- Current therapies like etanercept target tumor necrosis factor-alpha.
- uPA plays a significant role in inflammatory processes relevant to rheumatic diseases.
Purpose of the Study:
- To develop and evaluate a novel humanized monoclonal antibody (mAb), NNC0266-0043, for rheumatoid arthritis.
- To assess the dual inhibition of human uPA zymogen activation and proteolytic activity by NNC0266-0043.
- To determine the pharmacokinetic and pharmacodynamic properties of NNC0266-0043 in non-human primates for potential clinical application.
Main Methods:
- Characterization of NNC0266-0043's inhibition of human uPA activation and proteolysis.
- Assessment of NNC0266-0043 pharmacokinetics, including elimination kinetics and half-life, in cynomolgus monkeys.
- Evaluation of plasma uPA activity as a pharmacodynamic marker for anti-uPA therapy efficacy.
- Pharmacokinetic modeling to predict dosing regimens for human subjects.
Main Results:
- NNC0266-0043 demonstrated nonlinear elimination kinetics in cynomolgus monkeys, consistent with target engagement.
- A plasma half-life of 210 hours was observed at a dose of 20.6 mg/kg.
- Plasma uPA activity was suppressed below detection limits, indicating therapeutic concentrations were achieved.
- Pharmacokinetic modeling suggests weekly subcutaneous dosing is feasible for arthritis patients.
- The antibody was well-tolerated in cynomolgus monkeys at doses up to 200 mg/kg weekly for 4 weeks.
Conclusions:
- Anti-uPA mAb NNC0266-0043 exhibits favorable pharmacokinetic and pharmacodynamic properties in primates.
- The antibody's dual inhibition mechanism offers a novel therapeutic approach for rheumatic diseases.
- NNC0266-0043 is suitable for clinical investigation as a potential treatment for rheumatoid arthritis and other rheumatic conditions.
