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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
Author(s) -
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.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14256
Subject(s) - complement system , antibody , medicine , immunology , monoclonal antibody , in vitro , human leukocyte antigen , complement dependent cytotoxicity , transplantation , alternative complement pathway , classical complement pathway , antigen , biology , antibody dependent cell mediated cytotoxicity , biochemistry , surgery
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.