Forkhead-box P3 Transcription Factor ASO
Regulatory T cells (Tregs) contribute to cancer progression by suppressing anti‑tumour immunity. Tregs specifically require expression of the lineage defining Forkhead-box P3 transcription factor (FOXP3) for their development and function, but this protein cannot be targeted with conventional small molecule or biologic drugs.
AZD8701 is a clinical candidate antisense oligonucleotide (ASO) targeting FOXP3 mRNA for degradation in Treg cells to relieve immunosuppression in cancer.
AZD8701 is a potent human specific ASO with a 62 nM cellular IC50 measured by protein abundance in human Treg cells in vitro. In in vitro assays AZD8701 reduced Treg suppressive capacity of human Tregs measured by conventional T cell proliferation in culture.
Mouse surrogate ASOs were used to further assess in vitro and in vivo pharmacology. Mouse specific FoxP3_ASO exhibited 80 nM IC50 potency in mouse Tregs. FoxP3_ASO reduced suppressive capacity of Tregs in vitro, reduced FOXP3 levels in tumour and peripheral tissues and promoted anti-tumour responses in immunocompetent murine tumour models.
Suitable for and exclusions
Restricted to preclinical oncology studies (proposals) only