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Updated: Jun 14, 2025
Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
Discovery and Evaluation of TLR-Targeted Immune Agonists
Natalia Chernyak1, Bhagyashree Bhagwat2, Saraswathi Naravula2
1Discovery Chemistry, Merck & Co., Inc., South San Francisco, California 94080, United States.
Abstract:
Toll-like receptor (TLR) activation converts immunologically inactive tumors into immunologically active tumors by activating tumor residing antigen-presenting cells and recruitment of cytotoxic T lymphocytes. Targeted immune agonists (TIAs) are antibody drug conjugates with small-molecule TLR agonist payloads. The mechanism of action of TIAs involves tumor antigen recognition, Fcγ-receptor-dependent phagocytosis, and TLR-mediated activation to drive tumor killing by myeloid cells. Several new low DAR anti-HER2 TIAs conjugated with novel TLR7 or dual-TLR7/8 agonists with cleavable and noncleavable linkers were synthesized and profiled. In vitro studies demonstrated that these TIAs activate myeloid cells only in the presence of antigen-expressing cancer cells. Evaluation in ELISpot-based assays confirmed the low immunogenicity of these constructs. Systemic administration of the novel TIAs in tumor-bearing mice resulted in tumor reduction at low doses. These results provide a strong rationale for further development of the TIAs as a novel class of immunotherapeutics.
Insights
Targeted immune agonists (TIAs) convert inactive tumors into active ones by activating immune cells. New anti-HER2 TIAs showed potent tumor reduction in mice, supporting their development as novel immunotherapeutics.
Area of Science:
- Immunology
- Oncology
- Drug Development
Background:
- Toll-like receptor (TLR) activation transforms immunologically inert tumors into active ones, enhancing anti-tumor immunity.
- Targeted immune agonists (TIAs) are antibody-drug conjugates designed to activate TLRs within the tumor microenvironment.
Purpose of the Study:
- To synthesize and characterize novel, low drug-antibody ratio (DAR) anti-HER2 TIAs.
- To evaluate the in vitro and in vivo efficacy of these novel TIAs as a potential cancer immunotherapy.
Main Methods:
- Synthesis of anti-HER2 TIAs with varying linkers and TLR7 or TLR7/8 agonists.
- In vitro assessment of myeloid cell activation in the presence of antigen-expressing cancer cells.
- ELISpot assays to evaluate immunogenicity.
- In vivo studies in tumor-bearing mice to assess anti-tumor activity.
Main Results:
- Novel TIAs demonstrated antigen-specific myeloid cell activation in vitro.
- Constructs exhibited low immunogenicity in ELISpot assays.
- Systemic administration of TIAs led to significant tumor reduction in mice at low doses.
Conclusions:
- The novel TIAs effectively activate the immune system against tumors.
- These findings support the further development of TIAs as a promising new class of immunotherapeutics for cancer treatment.
