Abstract 4700: Induced phenotype targeted ADC by using caspase enzymatic cleavable peptide linker to overcome tumor heterogeneity
Authors: Ha Kyeong Lee, Byoungmo Kim, Hyo Won Chang, Sang Yoon Kim, Youngro Byun
Journal: Cancer Research (2024)

Abstract Antibody-drug conjugates (ADCs) have ushered in a new era of precision cancer therapy, and the caspase-3-cleavable linker has demonstrated its potential as a game-changing addition to the ADC toolkit. The DEVD peptide, specifically cleaved by caspase and lysosomal enzymes, in combination with the KG peptide, provides the necessary flexibility to achieve targeted cancer cell apoptosis. This research explores the key attributes and actions of the linker, aiming to highlight its potential for revolutionizing ADC therapy. The caspase-3-cleavable linker operates through caspase-3 activation during apoptosis. After targeting cancer cells with specific antigens, the ADC is internalized into the cells, and the linker is cleaved by caspase-3, releasing the drug and initiating apoptosis. The specificity of caspase-3 extends the drug’s effect to neighboring cells, even those lacking the target antigen. This cascade effect ensures the continuous activation of ADCs until all cancer cells are eradicated. Firstly, it overcomes tumor heterogeneity by activating the drug outside of the cell. Traditional bystander killing effects rely on internalization followed by drug release and penetration of neighbor cancer cells. However, this linker's unique mechanism ensures that the drug is activated by caspase-3 outside the cell without the need for internalization, effectively targeting all cancer cells within the tumor tissue. This is achieved through the induced phenotype targeting effect (IPTE), which involves caspase-3 cleavage of the linker, inducing a phenotype in the tumor tissue that targets all cancer cells, regardless of their specific markers. Secondly, it maintains therapeutic efficacy even as the target antigen decreases. Current targeted therapies face a challenge as target antigens may diminish during treatment, leading to reduced drug effectiveness. However, the unique mechanism of the linker ensures that the drug continues to be activated as long as there is caspase-3 secretion, resulting in continuous activation of ADCs in the tumor, with a feedback amplification loop that ensures therapeutic efficacy until all cancer cells are eliminated. Lastly, the linker's superior physicochemical properties allow for a maximum drug-to-antibody ratio (DAR). Its hydrophilic nature enables independent drug conjugation, increasing therapeutic potential and mitigating aggregation issues. This innovation addresses the current limitations in ADC conjugation technologies. In summary, the caspase-3-cleavable linker represents a significant leap forward in the field of ADCs. Its unique attributes offer promising prospects for more effective and targeted cancer treatments. This linker is poised to revolutionize the landscape of targeted cancer therapy, bringing us one step closer to the dream of eradicating cancer cells with precision and efficiency. Citation Format: Ha Kyeong Lee, Byoungmo Kim, Hyo Won Chang, Sang Yoon Kim, Youngro Byun. Induced phenotype targeted ADC by using caspase enzymatic cleavable peptide linker to overcome tumor heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4700.