Dual complement and P-selectin inhibitor, IHP-102, prevents lung vaso-occlusion in P-selectin-deficient townes SS mice

Abstract Background Sickle cell disease (SCD) is the most common monogenic blood disorder that is widely recognized for its hallmark vaso-occlusive episodes (VOEs). VOEs are not only debilitatingly painful but also cause lasting damage to tissues and organs due to the repeated ischemic injury, emphasizing the need for an acute disease-modifying therapeutic to alleviate VOE burden. Treatment options for SCD are very limited and there remains a major gap for resolving acute VOE. We are therefore developing IHP-102 as an acute rescue therapeutic that targets the multifaceted pathomechanisms underlying VOE. IHP-102 is a novel glycan therapeutic that was designed to have polypharmacologic activity against complement and the vascular adhesion processes, both of which are recognized in the pathogenesis of VOE. The complex mechanisms involved in VOE demand robust intervention and a single therapeutic agent that targets multiple pathways offers great promise. Aims IHP-102 was previously shown to reduce vaso-occlusion by more than 80% in Townes SS mice, while historically P-selectin blockade reduced vaso-occlusions by only 50%. Here we aimed to extend these findings and further elucidate the contribution of complement activity of IHP-102 on vaso-occlusion. Methods We investigated IHP-102 in Townes SS (SCD) mice intravenously (IV) challenged with oxy-hemoglobin (IV oxyHb) to induce vaso-occlusion, which was quantified in the lung vasculature using quantitative fluorescence intravital lung microscopy (qFILM). Mice were treated with subcutaneous (SC) IHP-102 prior to IV oxy-Hb challenge. To determine the contribution of complement inhibition, we assessed the effect of IHP-102 on lung vaso-occlusion in SCD mice with P-selectin inhibited by either an anti-P-selectin function blocking Ab (RB40.34) or using SCD mice genetically deficient in P-selectin (SCD-Selp-/-). Results In Townes SCD-Selp-/- mice, IHP-102 reduced lung vaso-occlusion by more than 60% as measured by the number of pulmonary vaso-occlusions occlusions per field of view (#PVO/FOV) (n = 5 mice/group; p < 0.01). IHP-102 also reduced lung vaso-occlusion in SCD mice pretreated with P-selectin blocking Ab. These results indicate the anti-complement activity of IHP-102 provides significant additional therapeutic benefit beyond P-selectin inhibition. Summary/Conclusion While adhesion mechanisms through P-selectin are partially responsible for VOE, recent clinical data suggest targeting P-selectin alone may be insufficient. In contrast, the polypharmacologic activity of IHP-102 demonstrates strong therapeutic potential with profound benefit beyond P-selectin inhibition. Additionally, IHP-102 is dosed by SC route and can therefore be self-administered in the ambulatory setting, thus circumventing a largely ill-equipped healthcare system that has plagued SCD care. IHP-102 has the potential to transform management of VOE, offering significant relief from disease and the associated debilitating pain and organ damage.