Author Manuscript Published OnlineFirst on November 9, 2016; DOI: 10.1158/1535-7163.MCT-16-0343 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Optimization of a PEGylated glucuronide-monomethylauristatin E linker for antibody-drug conjugates Patrick J. Burke, Joseph Z. Hamilton, Scott C. Jeffrey, Joshua H. Hunter, Svetlana O. Doronina, Nicole M. Okeley, Jamie B. Miyamoto, Martha E. Anderson, Ivan J. Stone, Michelle L. Ulrich, Jessica K. Simmons, Erica E. McKinney, Peter D. Senter, and Robert P. Lyon Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, WA 98021 Running title: Optimized glucuronide-monomethylauristatin E linker for ADCs Keywords: antibody-drug conjugates, auristatin, drug-linker, PEGylation, pharmacokinetics Corresponding author: Patrick J. Burke, Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, WA 98021. Phone: 425-527-4766; Fax: 425-527-4109; Email:
[email protected] Conflict of interest statement: The authors disclose no potential conflicts of interest. Word count: 5309 words # figures/tables: 7 1 Downloaded from mct.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 9, 2016; DOI: 10.1158/1535-7163.MCT-16-0343 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract The emergence of antibody-drug conjugates (ADCs) such as brentuximab vedotin and ado- trastuzumab emtansine has led to increased efforts to identify new payloads and develop improved drug-linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR).