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The classic pathway ( CP ) of complement is believed to significantly contribute to alloantibody‐mediated transplant injury, and targeted complement inhibition is currently considered to be a promising approach for preventing rejection. Here, we investigated the mode of action and efficacy of the humanized anti‐C1s monoclonal antibody  TNT 009 and its parental mouse variant,  TNT 003, in preclinical  in vitro  models of  HLA  antibody–triggered  CP  activation. In flow cytometric assays, we measured the attachment of C1 subcomponents and C4/C3 split products (C4b/d, C3b/d) to  HLA  antigen–coated flow beads or  HLA ‐mismatched aortic endothelial cells and splenic lymphocytes. Anti‐C1s antibodies profoundly inhibited C3 activation at concentrations >20 μg/ mL , in both solid phase and cellular assays. While C4 activation was also prevented, this was not the case for C1 subcomponent attachment. Analysis of serum samples obtained from 68 sensitized transplant candidates revealed that the potency of inhibition was related to the extent of baseline  CP  activation. This study demonstrates that anti‐C1s antibodies  TNT 009 and  TNT 003 are highly effective in blocking  HLA  antibody–triggered complement activation downstream of C1. Our results provide the foundation for clinical studies designed to investigate the potential of  TNT 009 in the treatment or prevention of complement‐mediated tissue injury in sensitized transplant recipients.

american journal of transplantation

Effect of the Anti‐C1s Humanized Antibody  TNT 009 and Its Parental Mouse Variant  TNT 003 on  HLA  Antibody–Induced Complement Activation—A Preclinical  In Vitro  Study