| Autor: |
Wahrmann, M., Mühlbacher, J., Marinova, L., Regele, H., Huttary, N., Eskandary, F., Cohen, G., Fischer, G. F., Parry, G. C., Gilbert, J. C., Panicker, S., Böhmig, G. A. |
| Zdroj: |
American Journal of Transplantation; September 2017, Vol. 17 Issue: 9 p2300-2311, 12p |
| Abstrakt: |
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 TNT009 and its parental mouse variant, TNT003, in preclinical in vitromodels of HLAantibody–triggered CPactivation. In flow cytometric assays, we measured the attachment of C1 subcomponents and C4/C3 split products (C4b/d, C3b/d) to HLAantigen–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 CPactivation. This study demonstrates that anti‐C1s antibodies TNT009 and TNT003 are highly effective in blocking HLAantibody–triggered complement activation downstream of C1. Our results provide the foundation for clinical studies designed to investigate the potential of TNT009 in the treatment or prevention of complement‐mediated tissue injury in sensitized transplant recipients. This study demonstrates the mode of action and inhibition efficacy of the novel humanized anti‐C1s antibody TNT009 and its parental mouse variant TNT003 on anti‐HLA antibody‐triggered complement deposition in cellular and solid‐phase flow cytometric assays. |
| Databáze: |
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