ORKA-002, a novel extended half-life monoclonal antibody targeting IL-17A/F for the treatment of psoriatic disease

Summary: Abstract Body: 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 and deliver enhanced clinical profile. 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. 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. 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 psoriatic disease and other inflammatory conditions amenable to IL-17 inhibition. Clinical studies are planned to explore this potential. Byron Kwan¹, Joseph Merola⁴, Andrew Blauvelt³, Daniel Rios¹, Joana Ministro¹, Jacob Milligan¹, Ghassan Fayad¹, Christopher Finch², Eugenia Levi², Jason Oh¹, Hussam Shaheen¹ 1. Paragon Therapeutics Inc, Waltham, MA, United States. 2. Oruka Therapeutics Inc, Menlo Park, CA, United States. 3. Blauvelt Consulting, LLC, Portland, OR, United States. 4. The University of Texas Southwestern Medical Center, Dallas, TX, United States. Translational Studies: Preclinical