A new study has characterized the complement-inhibiting properties of SAR445088, a next-generation classical pathway complement inhibitor specific for the active form of C1s that shows promise for treating cold agglutinin disease (CAD).
The study, published in Clinical Immunology, also found that selective binding to active C1s may improve its dosing profile over sutimlimab.
“While sutimlimab binds both the active and inactive forms of C1s, SAR445088 is specific for the active form resulting in an enhanced pharmacokinetic profile,” the authors wrote. “In turn, this may lower the dose and/or reduce the dosing frequency required for SAR445088 and minimize target-mediated drug disposition.”
The research team measured SAR445088’s ability to block the classical pathway of complement using two approaches: an ELISA-based Wieslab assay and a hemolysis assay that used antibody-sensitized sheep red blood cells.
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The specificity of SAR445088 was assessed using a ligand binding assay. A precursor to SAR445088 known as TNT010, which has the same antigen-binding region of SAR445088, was also assessed regarding its ability to inhibit complement activity mediated by autoantibodies from patients with CAD.
The in vitro results demonstrated SAR445088’s ability to inhibit C3b/iC3B deposition in CAD as well as to inhibit extravascular hemolysis. Furthermore, the addition of TNT010 reduced C3b/iC3b deposition on blood cells, reflecting lower rates of phagocytosis. The authors suspect the reduction of extravascular and intravascular hemolysis is due to a reduction in deposition of C4b and C3b/iC3b and membrane attack complex formation caused by activation of the complement pathway.
Although the in vitro results show SAR445088’s potent inhibition of the classical complement pathway, further clinical studies will be required to determine its in vivo activity in patients with CAD and other immune-mediated diseases. Several clinical trials are already underway to assess SAR445088’s utility in antibody-mediated rejection and chronic inflammatory demyelinating polyneuropathy.
Simmons K, Chan J, Hussain S, et al. Anti-C1s humanized monoclonal antibody SAR445088: a classical pathway complement inhibitor specific for the active form of C1s. Clin Immunol. Published online May 4, 2023. doi:10.1016/j.clim.2023.109629