화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.436, No.3, 519-524, 2013
Cleavage of the interchain disulfide bonds in rituximab increases its affinity for Fc gamma RIIIA
The Fc region of human IgG1 mediates effector function via binding to Fc gamma receptors and complement activation. The H and L chains of IgG1 antibodies are joined by four interchain disulfide bonds. In this study, these bonds within the therapeutic IgG1 rituximab (RTX) were cleaved either by mild reduction followed by alkylation or by mild S-sulfonation; consequently, two modified RTXs - A-RTX (alkylated) and S-RTX (S-sulfonated) - were formed, and both were almost as potent as unmodified RTX when binding CD20 antigen. Unexpectedly, each modified RTX had a higher binding affinity for Fc gamma RIIIA (CD16A) than did unmodified RTC. However, S-RTX and A-RTX were each less potent than RTX in an assay of antibody-dependent cellular cytotoxicity (ADCC). In this ADCC assay, each modified RTX showed decreased secretion of granzyme B, but no change in perforin secretion, from effector cells. These results provide significant information on the structures within IgG1 that are involved in binding Fc gamma RIIIA, and they may be useful in the development of therapeutic antagonists for Fc gamma RIIIA. (C) 2013 Elsevier Inc. All rights reserved.