Abstract |
Stability of recombinant monoclonal antibodies (mAbs) is essential for their clinical application. The presence of the two degradation hotspots, namely, LC-Asn30 and HC-Asp102, in its complementary determinant regions prevents trastuzumab (Herceptin®) from being supplied in a drug product format of liquid formulation. To improve the stability, a new antibody was created by replacing the two residues with chemically similar amino acids of LC-Gln30 and HC-Glu102. This new mAb, named as T-mAb2, exhibited a simple and more uniform charge heterogeneity profile than T-mAb1, which is trastuzumab made in our laboratory, as displayed by the difference between their main peak area percentages (82.9% for T-mAb2 vs. 60.5% for T-mAb1). Computer modeling results, physicochemical and biological characterization, and stability profiling studies on T-mAb2 and T-mAb1 demonstrated that stability of T-mAb2 was significantly improved. In comparison with T-mAb1, although its in vitro human epidermal growth factor receptor 2 (HER2)-target binding activities were reduced slightly, in vivo tumor growth inhibiting activity was not affected, as demonstrated by the study results using the SKOV3 xenograft mouse model. Hence, a new anti-HER2 antibody was generated with improved stability that could be used to produce the drug product in liquid formulation for cost saving and more convenient usage.
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Authors | Yuemei Yang, Jian Zhao, Shusheng Geng, Chunmei Hou, Xingyin Li, Xiaoling Lang, Chunxia Qiao, Yan Li, Jiannan Feng, Ming Lv, Beifen Shen, Boyan Zhang |
Journal | Journal of pharmaceutical sciences
(J Pharm Sci)
Vol. 104
Issue 6
Pg. 1960-1970
(Jun 2015)
ISSN: 1520-6017 [Electronic] United States |
PMID | 25820189
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association. |
Chemical References |
- Antineoplastic Agents
- ERBB2 protein, human
- Receptor, ErbB-2
- Trastuzumab
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Topics |
- Animals
- Antineoplastic Agents
(chemistry, immunology, therapeutic use)
- Breast
(drug effects, immunology, pathology)
- Breast Neoplasms
(drug therapy, immunology, pathology)
- Cell Line, Tumor
- Female
- Humans
- Mice
- Mice, Inbred BALB C
- Models, Molecular
- Protein Stability
- Proteolysis
- Receptor, ErbB-2
(immunology)
- Trastuzumab
(chemistry, immunology, therapeutic use)
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