Background/Purpose: 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 the inflamed synovium of patients with PsA. Recently, a biologic targeting both IL-17A and IL-17F, bimekizumab (BIME), has demonstrated high efficacy that exceeds therapies targeting IL-17A only. 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 psoriasis and other inflammatory diseases.

Methods: ORKA-002 was evaluated across multiple in vitro and ex vivo assays alongside 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 assessed through NFκB activation assays in reporter cell lines. Inhibition of IL-17A-induced or IL-17F-induced IL-6 secretion was measured in vitro using normal human dermal fibroblasts. Half-life extension was evaluated via pharmacokinetic (PK) analysis in cynomolgus monkeys following a single bolus dose 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. In cynomolgus monkeys, ORKA-002 demonstrated a significantly extended half-life relative to BIME. Predictive simulations, based on allometric scaling of ORKA-002 PK parameters, suggest that in humans, subcutaneous maintenance dosing every four to six months could sustain 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. These characteristics could result in comparable or increased efficacy compared to BIME with just two to three doses of ORKA-002 a year. Pre-clinical evidence for ORKA-002 reported here may lead to therapeutic improvements for psoriatic disease and other inflammatory conditions amenable to IL-17 inhibition. Clinical studies are planned to explore this potential.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-orka-002-a-novel-extended-half-life-monoclonal-antibody-targeting-il-17a-f-for-the-treatment-of-psoriasis-and-other-indications/