Discovery and Characterization of a First-in-Class LIV1-TLR7/8 Immunomodulatory Conjugate with Robust Myeloid Activation and Antitumor Activity

J Med Chem. 2025 Jun 12;68(11):11322-11339. doi: 10.1021/acs.jmedchem.5c00264. Epub 2025 May 24.

Abstract

Herein, we describe the discovery of a novel immunostimulatory drug conjugate (IMC) that employs TLR7/8 agonists conjugated to a tumor-targeting LIV1 antibody. Targeting TLR7/8 agonists to LIV1-expressing tumors enables localized delivery, thereby minimizing systemic toxicity while promoting inflammation and T cell recruitment within the tumor microenvironment (TME) for enhanced antitumor efficacy. Dual activation of TLR7 and TLR8 within the TME facilitates the recruitment of diverse immune cells and induces a broad spectrum of pro-inflammatory cytokines, effectively reshaping the immunosuppressive TME by upregulating costimulatory molecules. The mechanism of action of the IMC involves tumor recognition via surface antigens and Fcγ-mediated phagocytosis, followed by activation of myeloid cells to efficiently present tumor antigens to T-cells, thereby eliciting antitumor immunity. The designed IMCs demonstrate the ability to activate myeloid cells in the presence of tumor cells, display robust antitumor activity, and are well tolerated in toxicology studies.

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Drug Discovery
  • Female
  • Humans
  • Immunoconjugates* / chemistry
  • Immunoconjugates* / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells* / drug effects
  • Myeloid Cells* / immunology
  • Neoplasm Proteins* / immunology
  • Structure-Activity Relationship
  • Toll-Like Receptor 7* / agonists
  • Toll-Like Receptor 7* / immunology
  • Toll-Like Receptor 8* / agonists
  • Toll-Like Receptor 8* / immunology
  • Tumor Microenvironment / drug effects

Substances

  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Antineoplastic Agents
  • Immunoconjugates
  • TLR7 protein, human
  • TLR8 protein, human
  • Neoplasm Proteins