In the tumor microenvironment (TME), regulatory T cells (Treg) induce immune tolerance by suppression of CD8 effector T cell activity. High levels of Treg infiltration in the TME lead to a poor prognosis in patients with various types of cancers. The chemokine receptor CCR4 is highly expressed on Treg where it functions to attract them into the TME through selective interactions with the chemokines CCL17 and CCL22. To reduce the prevalence of Treg in the TME we have discovered and developed FLX475 a potent and selective CCR4 receptor inhibitor.<br/><br/>Earlier CCR4 programs have been challenged by their inability to achieve sufficient CCR4 receptor occupancy even at high oral doses. Therefore a key goal of this discovery program was to identify an agent that would offer around the clock CCR4 receptor blockade with daily oral dosing. A screening strategy was designed to discover compounds that could potently block CCR4-induced chemotaxis under a full serum load in vitro, have good preclinical pharmacokinetics and demonstrate the ability to block Treg entry into tumors in an in vivo mouse model. Preclinical development activities suggested FLX475 would achieve high receptor occupancy at reasonable oral doses that would be well tolerated in the clinic.<br/><br/>In Phase I healthy volunteer studies, FLX475 demonstrated good PK and tolerability along with sustained high levels of CCR4 receptor occupancy. In Phase I/II oncology studies, both the effect of FLX475 on the CD8:Treg ratio in the TME and its efficacy in selected cancer indications are being investigated.

Discovery and early clinical development of FLX475, a potent and selective CCR4 inhibitor

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.