Abstract
Pertuzumab is an antihuman HER2 antibody developed for HER2 positive breast cancer. Glycosylation profiles are always the important issue for antibody based therapy. Previous findings have suggested the impact of glycosylation profiles on the function of antibodies, like pharmacodynamics, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, the roles of fucose and sialic acid in the function of therapeutic antibodies still need further investigation, especially the role of sialic acid in nonfucosylated antibodies. This study focused on the pharmacokinetic and pharmacodynamic properties of pertuzumab after glycoengineering. Herein, nonfucosylated pertuzumab was produced in CHOFUT8−/− cells, and desialylated pertuzumab was generated by enzymatic hydrolysis. Present data indicated that fucose was critical for ADCC activity by influencing the interaction between pertuzumab and FcγRIIIa, nevertheless removal of sialic acid increased the ADCC and CDC activity of pertuzumab. Meanwhile, regarding to sialic acid, sialidase hydrolysis directly resulted in asialoglycoprotein receptors (ASGPRs) dependent clearance in hepatic cells in vitro. The pharmacokinetic assay revealed that co-injection of asialofetuin can protect desialylated pertuzumab against ASGPRs-mediated clearance. Taken together, the present study elucidated the importance of fucose and sialic acid for pertuzumab, and also provided further understanding of the relationship of glycosylation/pharmacokinetics/pharmacodynamics of therapeutic antibody.
Highlights
Breast cancer is the most commonly diagnosed malignancy in women worldwide
This study indicated that fucose and sialic acid descended the antibodydependent cellular cytotoxicity (ADCC) activity of pertuzumab, while the removal of sialic acid could result in an increased complement-dependent cytotoxicity (CDC) activity, but induced a relatively poorer PK behavior
The results showed the average sialic acid level for pertuzumab was 2.3~2.6% (Table S1) and no significant difference were observed compared to nonfucosylated pertuzumab
Summary
Breast cancer is the most commonly diagnosed malignancy in women worldwide. About 0.226 million new cases were diagnosed in 2012 and an estimated 0.23 million would be diagnosed among women in 20151,2. HER2 is implicated in the pathogenic mechanisms of certain types of breast cancer by promoting cell growth and survival[8,9]. Whether the correlations between mAbs and glycosylation profiles are positive or negative is not determined and is likely dependent on the properties of different antibodies[21]. Antibody glycoengineering, such as the deletion of FUT8 gene, could enhance the FcγRIIIa binding affinity and lead to an increased ADCC activity[33,34]. We found that sialic acid affected the PK/PD relationship of pertuzumab, and would be critical quality attributes (CQA) for mAbs production
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