The two clinically-approved antibody-drug conjugates, AdcetrisTM and KadcylaTM, demonstrate that targeting cytotoxic payloads directly to tumors is an effective clinical approach. However, at the molecular level, these therapeutics are composed of heterogeneous mixtures resulting from the nonselective ligation of cytotoxic payload to cysteine and lysine residues, respectively. The nonselective ligation approaches used to generate these two ADCs render it difficult to optimize their biological, physical, and pharmacological properties. Redwood Bioscience creates site-selective, stable linkages that allow us to design ADCs with enhanced efficacy, safety, and pharmacokinetics. Additionally, we are able to control payload stoichiometry and placement. Redwood Bioscience creates homogeneous ADCs using the SMARTagTM technology, in which a genetically encoded 5 amino acid “aldehyde-tag” sequence contains a cysteine that is cotranslationally converted to formylglycine via an enzymatic transformation. This method affords control over the placement of the reactive formylglycine aldehyde side chain, which can then be ligated using carbonyl bioconjugation methods. Here, we will present our novel protein modification platform—including our new conjugation chemistries and linker libraries—and its application to ADC generation. We will address SMARTagTM ADC safety, pharmacokinetics, and efficacy in preclinical tumor models, and discuss how these parameters are impacted by linker selection and payload placement on the antibody.
Citation Format: Romas Kudirka. Next-generation site-specific antibody-drug conjugates using the SMARTagTM technology platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 636. doi:10.1158/1538-7445.AM2015-636