Identification of a Novel Linker Enabling the Bioconjugation of a Cyclic Dinucleotide for the STING Antibody-Drug Conjugate TAK-500
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.
Authors
- Nina Molchanova (ORCID: https://orcid.org/0009-0007-8133-6962)
- Michelle L. Ganno (ORCID: https://orcid.org/0009-0001-3322-0670)
- Jian Huang
- Jenna Malley (ORCID: https://orcid.org/0000-0001-9862-5452)
- Kenneth M. Gigstad
- Elizabeth E. H. Rice
- Nanda K. Gulavita
- Štěpán Vyskočil (ORCID: https://orcid.org/0000-0001-8178-7113)
- David Lok
- Adnan O. Abu‐Yousif (ORCID: https://orcid.org/0000-0002-7670-0041)
- Kojo Abdul-Hadi
- Vicky A. Appleman (ORCID: https://orcid.org/0000-0002-9132-1322)
- Zhigen Hu
- Shih‐Chung Huang
- Tianlin Xu
- Jianing Wang (ORCID: https://orcid.org/0009-0003-4168-7873)
- Linlin Dong (ORCID: https://orcid.org/0000-0002-7944-8582)
- Zhan Shi (ORCID: https://orcid.org/0000-0003-4464-3086)
- Li‐Ting Ma (ORCID: https://orcid.org/0000-0001-6028-0831)
- Dylan B. England (ORCID: https://orcid.org/0000-0002-2550-0963)
- Rachel E. Gershman
- Hong Myung Lee
- Ji Zhang (ORCID: https://orcid.org/0000-0002-1135-7713)
- He Xu (ORCID: https://orcid.org/0000-0002-5882-4147)
- David Cardin
- Konstantin I. Piatkov (ORCID: https://orcid.org/0009-0004-9337-6329)
- Dong Mei Zhang
- Miho Mizutani
Institutions
- Takeda (United States) (US)
- Takeda (Japan) (JP)
Publication Details
- Journal
- Bioconjugate Chemistry
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1021/acs.bioconjchem.5c00424
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80