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Improving Trastuzumab's Stability Profile by Removing the Two Degradation Hotspots.

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.
AuthorsYuemei Yang, Jian Zhao, Shusheng Geng, Chunmei Hou, Xingyin Li, Xiaoling Lang, Chunxia Qiao, Yan Li, Jiannan Feng, Ming Lv, Beifen Shen, Boyan Zhang
JournalJournal of pharmaceutical sciences (J Pharm Sci) Vol. 104 Issue 6 Pg. 1960-1970 (Jun 2015) ISSN: 1520-6017 [Electronic] United States
PMID25820189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
Chemical References
  • Antineoplastic Agents
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab
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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