دورية أكاديمية
Site-specific antibody-drug conjugation through glycoengineering.
| العنوان: | Site-specific antibody-drug conjugation through glycoengineering. |
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| المؤلفون: | Zhou Q; Sanofi-Genzyme R&D Center, Genzyme Corporation, A Sanofi Company , Framingham, Massachusetts 01701, United States., Stefano JE, Manning C, Kyazike J, Chen B, Gianolio DA, Park A, Busch M, Bird J, Zheng X, Simonds-Mannes H, Kim J, Gregory RC, Miller RJ, Brondyk WH, Dhal PK, Pan CQ |
| المصدر: | Bioconjugate chemistry [Bioconjug Chem] 2014 Mar 19; Vol. 25 (3), pp. 510-20. Date of Electronic Publication: 2014 Feb 28. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9010319 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4812 (Electronic) Linking ISSN: 10431802 NLM ISO Abbreviation: Bioconjug Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Chemical Society, c1990- |
| مواضيع طبية MeSH: | Antibodies/*chemistry , Antibodies, Monoclonal, Humanized/*pharmacology , Antineoplastic Agents/*pharmacology , Neoplasms, Experimental/*drug therapy, Animals ; Antibodies, Monoclonal, Humanized/chemistry ; Antineoplastic Agents/chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Glycosylation ; Humans ; Mice ; Mice, SCID ; Molecular Structure ; Neoplasms, Experimental/pathology ; Polysaccharides/chemistry ; Sialic Acids/chemistry ; Sialic Acids/metabolism ; Sialyltransferases/chemistry ; Sialyltransferases/metabolism ; Structure-Activity Relationship ; Trastuzumab |
| مستخلص: | Antibody-drug conjugates (ADCs) have been proven clinically to be more effective anti-cancer agents than native antibodies. However, the classical conjugation chemistries to prepare ADCs by targeting primary amines or hinge disulfides have a number of shortcomings including heterogeneous product profiles and linkage instability. We have developed a novel site-specific conjugation method by targeting the native glycosylation site on antibodies as an approach to address these limitations. The native glycans on Asn-297 of antibodies were enzymatically remodeled in vitro using galactosyl and sialyltransferases to introduce terminal sialic acids. Periodate oxidation of these sialic acids yielded aldehyde groups which were subsequently used to conjugate aminooxy functionalized cytotoxic agents via oxime ligation. The process has been successfully demonstrated with three antibodies including trastuzumab and two cytotoxic agents. Hydrophobic interaction chromatography and LC-MS analyses revealed the incorporation of ~1.6 cytotoxic agents per antibody molecule, approximating the number of sialic acid residues. These glyco-conjugated ADCs exhibited target-dependent antiproliferative activity toward antigen-positive tumor cells and significantly greater antitumor efficacy than naked antibody in a Her2-positive tumor xenograft model. These findings suggest that enzymatic remodeling combined with oxime ligation of the native glycans of antibodies offers an attractive approach to generate ADCs with well-defined product profiles. The site-specific conjugation approach presented here provides a viable alternative to other methods, which involve a need to either re-engineer the antibody sequence or develop a highly controlled chemical process to ensure reproducible drug loading. |
| المشرفين على المادة: | 0 (Antibodies) 0 (Antibodies, Monoclonal, Humanized) 0 (Antineoplastic Agents) 0 (Polysaccharides) 0 (Sialic Acids) EC 2.4.99.- (Sialyltransferases) P188ANX8CK (Trastuzumab) |
| تواريخ الأحداث: | Date Created: 20140219 Date Completed: 20141216 Latest Revision: 20151119 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/bc400505q |
| PMID: | 24533768 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4812 |
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| DOI: | 10.1021/bc400505q |