Abstract
Abstract Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics for targeted drug delivery. However, the synthesis of novel linkers for generating stable ADCs remains a key goal in the development of effective ADCs. Here we describe a unique linker (CORDLink) platform technology based on coordination chemistry that maintains the integrity of the antibody without impacting binding to the target. Using an anti-HER2 monoclonal antibody and camptothecin, as examples of the targeting antibody and a highly cytotoxic payload respectively, we demonstrate that the linker enables the formation of a stable ADC via supramolecular coordinate bond. The robustness of our process and consistency was characterized through a variety of analytical tools, such as SE-HPLC, CEX-HPLC and HI-HPLC, while peptide mapping was done to elucidate the exact site of attachment. The ADCs were found to remain intact in media and serum using a fluorescence-based RP-HPLC method. The anti-HER2 antibody recognizes HER2 receptors on cancer cells inducing internalization of the conjugate. The ADC showed significant cytotoxicity in cells expressing HER2 receptor but not in HER2 negative cell lines with IC50s in the nM range. We have established robust characterization methods to validate and confirm the integrity of the prototype ADCs in vitro. Studies are underway to further evaluate these molecules in vivo. The CORDLink technology offers a highly versatile platform that can be leveraged to deliver a broad range of payloads to selected cells using different targeting molecules. Citation Format: Nimish Gupta, Johny Kancharla, Shelly Kaushik, Samad Hossain, Arindam Sarkar, Aniruddha Sengupta, Monideepa Roy, Shiladitya Sengupta. Supramolecular assembly of antibody-drug conjugates using CORDLink platform for targeted drug delivery. [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 649. doi:10.1158/1538-7445.AM2015-649
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