Today we presented preclinical data associated with our TLR7 ISACs technology. The poster presentation titled “Optimization of purine-based TLR7 agonists as payloads for immune-stimulating antibody conjugates (ISACs)” shows the potential of using novel purine-based TLR7 agonists as payloads for ISACs.
ISACs consist of antibodies conjugated to immune stimulants and are designed to induce antitumor immune response. Despite promising preclinical results, ISAC clinical development has been hampered by systemic toxicities or lack of efficacy. Substituted purines have previously been identified as a privileged scaffold to elicit TLR7 activation. The preclinical data presented today, demonstrates newly designed purine-based TLR7 agonists conjugated to trastuzumab which show significant tumor volume reduction in a HER2-high gastric cancer xenograft model without associated body weight loss (BWL) in animal models.
Key data highlights:
- 220 purine small molecules were generated and evaluated for TLR7-agonism. The most promising 40 compounds were conjugated to trastuzumab as a model antibody system and the corresponding ISACs demonstrated favorable biophysical properties
- Purine-based ISACs showed potent immune response in both murine and human immune cells in vitro. This cross-species conservation of activity negates the use of surrogate molecules for in vivo studies, providing greater translational relevance than other platforms
- In vivo efficacy studies in an N87 derived xenograft model indicate activity comparable or superior to the clinically evaluated NJH395 drug-linker
- Tolerability studies in Balb/c mice suggest trastuzumab conjugated with our lead drug-linker has a significant tolerability advantage compared to trastuzumab conjugated to the benchmark NJH395 drug-linker
Additional information on the TLR7 ISACs technology is available in our October 20, 2022 early R&D day presentation (listen to the webcast). For further information, or to learn more about potential partnership opportunities, please reach out to bd@zymeworks.com.
