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785 STING-agonist ADCs targeting tumor-associated antigens coordinate immune-mediated killing of antigen-negative cancer cells
  1. Phonphimon Wongthida,
  2. Kalli Catcott,
  3. Kelly Lancaster,
  4. Keith Bentley,
  5. Anouk Dirksen,
  6. Bingfan Du,
  7. Timothy Eitas,
  8. Eugene Kelleher,
  9. Naniye Malli,
  10. Rebecca Mosher,
  11. Marina Protopopova,
  12. Pamela Shaw,
  13. Cheri Stevenson,
  14. Joshua Thomas,
  15. Alex Uttard,
  16. Jeremy Duvall,
  17. Dorin Toader,
  18. Marc Damelin,
  19. Raghida Bukhalid and
  20. Timothy Lowinger
  1. Mersana Therapeutics, Cambridge, MA, United States


Background The tumor microenvironment is a complex, multicellular system, composed not only of malignant cancer cells but also of a diversity of stromal cells including vascular cells, immune cells, and fibroblasts that support tumorigenesis. Antigens expressed on these cells tend to be widely expressed across a range of malignancies, presenting unique opportunities for development of anti-cancer therapies.

Methods We have previously demonstrated that STING-agonist antibody-drug conjugates (Immunosynthen ADCs) targeting tumor cell antigens induce target-dependent anti-tumor immune responses in vitro and in vivo. To that effect, we hypothesized that Immunosynthen ADCs targeting tumor-associated antigens would coordinate immune-mediated killing of cancer cells not expressing the tumor-associated antigens (antigen-negative cancer cells) and induce anti-tumor activity.

Results Herein, we demonstrate that targeting tumor-associated antigens with STING-agonist ADCs activate the STING pathway in immune cells via Fcγ receptor-mediated uptake. In addition, due to the intrinsic ability of certain tumor-associated cells to activate the STING pathway, STING-agonist ADCs targeting those cells can induce STING signaling in both the targeted cells and the immune cells, which constitutes a therapeutic advantage of ADCs that activate the STING pathway. In triple co-cultures of antigen-positive tumor-associated cells, antigen-negative cancer cells, and immune cells, the STING-agonist ADC specifically induced potent cell killing of the antigen-negative cancer cells with minimal impact on the immune and tumor-associated cells, thus representing a non-traditional, yet highly effective mechanism of ADC targeting. In vivo efficacy studies showed that STING-agonist ADCs developed for two tumor-associated antigens induced complete, sustained tumor regressions in syngeneic tumor models and exhibited immunological memory after rechallenge. CD8+ T cells contributed to the anti-tumor activity of the STING-agonist ADCs.

Conclusions In summary, Immunosynthen STING-agonist ADCs targeting tumor-associated antigens represent a novel approach for ADC-mediated cancer immunotherapy and enable the multifaceted activation of the STING pathway in a tumor-targeted manner beyond tumor antigens.

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