Development And Pharmacological Properties Of Pegylated Glucuronide-Auristatin Linkers

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Antibody-drug conjugates (ADCs) are an emerging therapeutic modality for the treatment of cancer, exemplified by the recent clinical success of brentuximab vedotin and ado-trastuzumab emtansine. The majority of ADCs currently in development include functionalities that are hydrophobic, resulting in increased plasma clearance. Consequently, there has been significant interest in generating new linkers that compensate for this potential liability. In an attempt to mitigate the pharmacokinetic impact of monomethylauristatin E (MMAE) when conjugated to an antibody, we prepared drug-linkers incorporating a polyethylene glycol (PEG) polymer. Initial work demonstrated that incorporation of a discrete PEG24 polymer into the cleavable β-glucuronide-MMAE linker system could either increase or decrease the plasma clearance of the resulting ADCs, depending upon the configuration of the PEG. When inserted into the drug-linker as a stretcher unit between the maleimide and the cleavage site, PEG24 elicited increased ADC plasma clearance. Conversely, incorporation of the PEG24 as a side chain from a modified lysine residue adjacent to the maleimide resulted in ADCs with slower clearance. These differences in ADC pharmacokinetics translated into corresponding differences in antitumor activity in two xenograft models. Thus, incorporation of PEG24 into ADC linkers impacts both pharmacokinetics and activity in a structure-dependent manner. Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Joshua H. Hunter, Scott C. Jeffrey, Svetlana O. Doronina, Nicole M. Okeley, David W. Meyer, Peter D. Senter, Robert P. Lyon. Development and pharmacological properties of PEGylated glucuronide-auristatin linkers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1786. doi:10.1158/1538-7445.AM2014-1786