Synthesis and evaluation of hydrophilic linkers for antibody-maytansinoid conjugates.
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| Abstract |
The synthesis and biological evaluation of hydrophilic heterobifunctional cross-linkers for conjugation of antibodies with highly cytotoxic agents are described. These linkers contain either a negatively charged sulfonate group or a hydrophilic, noncharged PEG group in addition to an amine-reactive N-hydroxysuccinimide (NHS) ester and sulfhydryl reactive termini. These hydrophilic linkers enable conjugation of hydrophobic organic molecule drugs, such as a maytansinoid, at a higher drug/antibody ratio (DAR) than hydrophobic SPDB and SMCC linkers used earlier without triggering aggregation or loss of affinity of the resulting conjugate. Antibody-maytansinoid conjugates (AMCs) bearing these sulfonate- or PEG-containing hydrophilic linkers were, depending on the nature of the targeted cells, equally to more cytotoxic to antigen-positive cells and equally to less cytotoxic to antigen-negative cells than conjugates made with SPDB or SMCC linkers and thus typically displayed a wider selectivity window, particularly against multidrug resistant (MDR) cancer cell lines in vitro and tumor xenograft models in vivo.
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| Authors | Robert Y Zhao, Sharon D Wilhelm, Charlene Audette, Gregory Jones, Barbara A Leece, Alexandru C Lazar, Victor S Goldmacher, Rajeeva Singh, Yelena Kovtun, Wayne C Widdison, John M Lambert, Ravi V J Chari |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 10 Pg. 3606-23 (May 26 2011) ISSN: 1520-4804 [Electronic] United States |
| PMID | 21517041 (Publication Type: Journal Article) |
| Chemical References |
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