2. Academic Validation
  3. Enhancing the bystander effect of antibody-drug conjugate by using a novel caspase-3 cleavable peptide linker to overcome tumor heterogeneity

Enhancing the bystander effect of antibody-drug conjugate by using a novel caspase-3 cleavable peptide linker to overcome tumor heterogeneity

  • J Control Release. 2025 Jun 10:382:113738. doi: 10.1016/j.jconrel.2025.113738.
Ha Kyeong Lee 1,  Byoungmo Kim 2,  Yoon Gun Ko 3,  Seung Woo Chung 4,  Wan Seob Shim 2,  So-Young Choi 5,  Se-Ra Lee 5,  Sang Yoon Kim 6,  Youngro Byun 7
Affiliations

Affiliations

  • 1 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 3 Pharosgen Co. Ltd, 2-404 Jangji-dong 892, Seoul 05852, Republic of Korea.
  • 4 Center for Nanomedicine, Wilmer Eye Institute and Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 5 New Drug Development Center Osong Medical Innovation Foundation 123 Osongsaengmyeong-ro, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea.
  • 6 Pharosgen Co. Ltd, 2-404 Jangji-dong 892, Seoul 05852, Republic of Korea. Electronic address: sykim3715@pharosgen.co.kr.
  • 7 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: yrbyun@snu.ac.kr.
PMID: 40246243 DOI: 10.1016/j.jconrel.2025.113738
Abstract

Tumor heterogeneity is a major obstacle to effective targeted therapies, including those utilizing antibody-drug conjugates (ADCs). Although some ADCs employ the bystander effect to eliminate neighboring antigen-negative cells, their efficacy often diminishes as antigen-positive cell populations decrease within heterogeneous tumors. To address this limitation in ADC therapies, we developed a novel ADC using a Caspase substrate, Asp-Glu-Val-Asp (DEVD), as a linker to generate a more potent and sustained bystander effect. The DEVD ADC effectively targeted antigen-positive cells and released its payload via Cathepsin B cleavage. Notably, it exhibited a significant bystander effect mediated by the caspase-3-triggered extracellular cleavage of the linker, enhancing payload release into the tumor microenvironment. In breast Cancer xenograft models, the DEVD ADC maintained its efficacy and continued to exert a bystander effect even after the depletion of antigen-positive cells, thereby overcoming challenges posed by tumor heterogeneity. These findings emphasize the potential of DEVD linkers in enhancing ADC efficacy against heterogeneous solid tumors, offering a promising strategy to improve therapeutic outcomes.

Keywords

Antibody-drug conjugate; Bystander effect; Caspase-3; DEVD linker; Dual activation; Tumor heterogeneity.

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