Abstract
Abstract The previously described β-glucuronide linker system (Jeffrey S.C. et al, Bioconj. Chem. 17, 831-840, 2006) was designed to release the toxic payload from an antibody-drug conjugate via the activity of β-glucuronidase, a known lysosomal enzyme. This linker system was shown to be suitable for the generation of potent ADCs utilizing the microtubule disrupting agent monomethylauristatin E (MMAE) as the delivered payload, and is thus an alternative to the protease-cleavable linker valine-citrulline-p-amino benzyl alcohol (vc-PAB). We have recently observed that ADCs utilizing the β-glucuronide linker system to deliver an MMAE payload exhibit potent cytotoxic activity in some cell lines that are resistant to conjugates utilizing the vc-PAB linker to deliver the same drug. To better understand this phenomenon, we have used mass spectrometry to compare the concentration and distribution of MMAE released from both glucuronide and vc-PAB linked ADCs in cell culture. Our data demonstrate that cellular accumulation of released MMAE is considerably greater when delivered by a glucuronide ADC relative to a vc-PAB ADC. We have also employed live-cell fluorescence microscopy to monitor the process of enzymatic cleavage of glucuronide and vc-PAB conjugates. The results of these studies suggest that the two linker systems deliver drug via distinct cellular mechanisms, possibly due to unique intracellular locations of drug release. We propose a model for how these unique linker systems can lead to differences in cellular accumulation of free drug and ultimately increased cytotoxicity. Citation Format: Nicole M. Okeley, Heather A. VanEpps, Xinqun Zhang, Jocelyn R. Setter, Patrick J. Burke, Joseph Z. Hamilton, Robert P. Lyon. Differential MMAE delivery from ADCs utilizing the valine-citrulline-PAB and β-glucuronide cleavable linker systems. [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 4465. doi:10.1158/1538-7445.AM2014-4465
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