title: Optimization of a PEGylated Glucuronide-Monomethylauristatin E Linker for Antibody-Drug Conjugates.
abstract: The emergence of antibody-drug conjugates (ADC), 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). We recently reported on the incorporation of a discrete PEG24polymer as a side chain in a β-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control. In this work, we optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo Multiple PEG-glucuronide-MMAE linkers were prepared with PEG size up to 24 ethylene oxide units, and homogeneous DAR 8 ADCs were evaluated. A clear relationship was observed between PEG length and conjugate pharmacology when tested in vivo Longer PEG chains resulted in slower clearance, with a threshold length of PEG8beyond which clearance was not impacted. Conjugates bearing PEG of sufficient length to minimize plasma clearance provided a wider therapeutic window relative to faster clearing conjugates bearing shorter PEGs. A lead PEGylated glucuronide-MMAE linker was identified incorporating a self-stabilizing maleimide and a PEG12side chain emerged from these efforts, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs. Mol Cancer Ther; 16(1); 116-23. ©2016 AACR.
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington. pburke@seagen.com.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Burke
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Joseph Z
authors.initials: JZ
authors.lastname: Hamilton
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Hunter
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Svetlana O
authors.initials: SO
authors.lastname: Doronina
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Okeley
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Miyamoto
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Martha E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Stone
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Ulrich
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Simmons
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Erica E
authors.initials: EE
authors.lastname: McKinney
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lyon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008301:Maleimides / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008301:Maleimides; D009842:Oligopeptides; C043592:maleimide; D011092:Polyethylene Glycols; C495575:monomethyl auristatin E