Publication Date:
2016-01-09
Description:
The Fc domain of human IgG1 binds to Fc receptors (FcRs) to induce effector functions such as phagocytosis. There are four interchain disulfide bonds between the H and L chains. In this study, the disulfide bonds within the IgG1 trastuzumab (TRA), which is specific for HER2, were cleaved by mild S-sulfonation or by mild reduction followed by S-alkylation with three different reagents. The cleavage did not change the binding activities of TRA to HER2-bearing SK-BR-3 cells. The binding activities of TRA to FcRIIA and FcRIIB were greatly enhanced by modification with mild reduction and S-alkylation with ICH 2 CONH 2 or N-(4-aminophenyl) maleimide, while the binding activities of TRA to FcRI and FcRIIIA were decreased by any of the four modifications. However, the interchain disulfide bond cleavage by the different modifications did not change the antibody-dependent cell-mediated phagocytosis (ADCP) of SK-BR-3 cells by activated THP-1 cells. The order of FcR expression levels on the THP-1 cells was FcRII 〉 FcRI 〉 FcRIII and ADCP was inhibited by blocking antibodies against FcRI and FcRII. These results imply that the effect of the interchain disulfide bond cleavage on FcRs binding and ADCP is dependent on modifications of the cysteine residues and the FcR isotypes.
Print ISSN:
0021-924X
Electronic ISSN:
1756-2651
Topics:
Biology
,
Chemistry and Pharmacology
Permalink
