Advantages Of Polyacetal Polymer-Based Adcs: Application To Low Expression Targets

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The application of biodegradable polymers to antibody-drug conjugate (ADC) design can provide numerous advantages, including significantly higher drug-antibody ratios, the use of alternative payloads with potencies considered insufficient for direct conjugation, the improvement of ADC physico-chemical properties, especially for highly hydrophobic payloads, and the potential expansion of protein recognition scaffolds beyond the commonly used IgGs. The basis of the novel polymer-based conjugation system described herein is a hydrophilic, fully biodegradable polyacetal carrier, (poly(1-hydroxymethylethylene hydroxymethylformal) or PHF) modified with chemically orthogonal linkers. A bioconjugation linker is used for efficient covalent attachment of a targeting moiety to the PHF scaffold, while a second, chemically distinct linker is used to attach multiple copies of a drug payload to the polymer to control the mechanism and rate of drug release. Utilizing multiple copies of a proprietary dolastatin derivative chemically conjugated to PHF, we have developed a potent and effective drug conjugation platform for ADC application, which has been named Dolaflexin™. Here, we report the preparation and characterization of a novel trastuzumab DolaflexinTM ADC, employing a maleimide-based bioconjugation approach. The resulting ADC, with a drug-antibody ratio of 20, exhibits enhanced stability and improved pharmacokinetics, with a prolonged plasma half-life and tumor-specific accumulation. Active drug release and accumulation in tumor tissue was also confirmed by LC/MS/MS methods. The activity of this novel trastuzumab-dolaflexin ADC was evaluated in multiple tumor xenograft models with significant variations in target antigen expression levels. Models including BT474 breast cancer, NCI-N87 gastric cancer, and JIMT1 breast cancer models were utilized, and comparisons to a variety of controls and ADC reference standards were made. Significant advantages of the polyacetal polymer-based ADCs in comparison to conventional ADCs, particularly in models with low target antigen expression, were observed. Details of these studies and potential applications for the development of new ADC therapeutics based on this approach will be presented. Citation Format: Alex Yurkovetskiy, Natalya Bodyak, Mao Yin, Joshua D. Thomas, Patrick Conlon, Cheri A. Stevenson, Alex Uttard, LiuLiang Qin, Dmitry R. Gumerov, Elena Ter-Ovaneysan, Venu R. Gurijala, Dennis McGillicuddy, Roberta E. Glynn, Michael DeVit, Laura L. Poling, Peter U. Park, Timothy B. Lowinger. Advantages of polyacetal polymer-based ADCs: Application to low expression targets. [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 2645. doi:10.1158/1538-7445.AM2014-2645