Background: Interleukin 17 (IL-17) is a pro-inflammatory cytokine that has been implicated in the pathogenesis of multiple autoimmune conditions, including psoriasis and psoriatic arthritis (PsA). The IL-17 family of cytokines includes 6 members (IL-17A to IL-17F). Both IL-17A and IL-17F are key drivers in the pathogenesis of psoriatic disease, being highly overexpressed in psoriatic plaques and inflamed synovium of patients with PsA. Recently, a biologic molecule targeting both IL-17A and IL-17F, bimekizumab (BIME), has demonstrated high efficacy that exceeds therapies targeting IL-17A only.

Objectives: ORKA-002 is a novel, extended half-life, humanized, monoclonal antibody that binds to IL-17A/F with high affinity. ORKA-002 has been engineered to have optimized properties with the aim of delivering an enhanced clinical profile compared to currently available treatments for psoriatic arthritis and other inflammatory diseases.

Methods: ORKA-002 was evaluated in multiple in vitro and ex vivo assays in comparison to BIME. Binding affinity to IL-17A and IL-17F was determined by surface plasmon resonance (SPR). Antagonism of IL-17A and IL-17F signaling was evaluated via assays measuring NFκB activation in reporter cell lines. Inhibition of IL-17A-induced or IL-17F-induced IL-6 secretion was assessed using in vitro cellular assays using normal human dermal fibroblasts. Half-life extension was measured via pharmacokinetic (PK) analysis in cynomolgus monkeys dosed with a single bolus of ORKA-002.

Results: ORKA-002 bound specifically to human IL-17A and IL-17F with high affinity. IL-17A/F binding affinity and functional potencies for IL-17A/F antagonism were comparable to BIME. The half-life of ORKA-002 was significantly extended in cynomolgus monkeys compared to BIME. Based on allometric scaling of the clearance of ORKA-002 observed in this study, predictive simulations of ORKA-002 PK in humans suggest that subcutaneous maintenance dosing every four to six months could be achieved while maintaining high antibody exposures.

Conclusion: ORKA-002 exhibits high selectivity and affinity for IL-17A and IL-17F in vitro , potent inhibition of downstream cellular signaling ex vivo , and an extended half-life in non-human primates compared to BIME, providing the potential for comparable or increased efficacy compared with BIME combined with dosing every four to six months. Pre-clinical evidence for ORKA-002 reported here may lead to therapeutic improvements for psoriasis, psoriatic arthritis, and other inflammatory conditions amenable to IL-17 inhibition. Clinical studies are planned to explore this potential.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Byron Kwan Paragon, Joseph F. Merola Oruka, Andy Blauvelt Oruka, Daniel Rios Paragon, Joana Ministro Paragon, Jacob Milligan Paragon, Ghassan Fayad Paragon, Christopher Finch Oruka, Eugenia Levi Oruka, Oruka, Jason Oh Paragon, Hussam Shaheen Paragon: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.