Identification of a Novel Linker Enabling the Bioconjugation of a Cyclic Dinucleotide for the STING Antibody-Drug Conjugate TAK-500

  • Bioconjug Chem. 2025 Nov 19;36(11):2423-2435. doi: 10.1021/acs.bioconjchem.5c00424.
Hong Myung Lee  1 ,  Kojo Abdul-Hadi  1 ,  Vicky A Appleman  1 ,  David Cardin  1 ,  Linlin Dong  1 ,  Dylan England  1 ,  Michelle L Ganno  1 ,  Rachel Gershman  1 ,  Kenneth Gigstad  1 ,  Nanda Gulavita  1 ,  Zhigen Hu  1 ,  Jian Huang  1 ,  Shih-Chung Huang  1 ,  David Lok  1 ,  Liting Ma  1 ,  Jenna Malley  1 ,  Miho Mizutani  1 ,  Nina Molchanova  1 ,  Konstantin I Piatkov  1 ,  Elise Rice  1 ,  Zhan Shi  1 ,  Stepan Vyskocil  1 ,  Jianing Wang  1 ,  He Xu  1 ,  Tianlin Xu  1 ,  Dong Mei Zhang  1 ,  Ji Zhang  1 ,  Adnan O Abu-Yousif  1
Affiliations
  • 1. Takeda Pharmaceuticals International Company, Cambridge, Massachusetts 02139, United States.
PMID: 41143331 DOI: 10.1021/acs.bioconjchem.5c00424
Abstract

STING activates the innate immune system by inducing type-1 interferon (IFN) production and has been pursued as a therapeutic option in immuno-oncology. The targeted delivery of STING agonists to CCR2+ immune cells could enhance the therapeutic window of the agonists by selectively activating the STING pathway within targeted immune cells. The chemistry strategy was established to enable the targeted delivery of the cyclic dinucleotide STING agonist dazostinag to CCR2+ cells through an antibody-drug conjugate (ADC) approach. A self-immolative spacer between the adenine of dazostinag and the Cathepsin-B cleavable Val-Ala dipeptide linker rendered a linker payload that exhibits strong plasma stability while allowing the rapid payload release upon internalization into lysosomes. The stochastic cysteine conjugation of the dazostinag containing these linkers provided ADC TAK-500 and its mouse surrogate mTAK-500 with DAR = 4. In syngeneic tumor-bearing mouse models, mTAK-500 showed target specific antitumor activity as well as the induction of immune-stimulating cytokines.

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