Background CCR8 is a chemokine G-protein coupled receptor (GPCR) preferentially expressed on immunosuppressive tumor-infiltrating regulatory T cells (Tregs). As a consequence, anti-CCR8 depleting antibodies represent a novel highly promising immuno-therapy approach due to their potential to modulate the tumor micro-environment (TME) and to enhance anti-tumor immune responses.

Methods At Domain Therapeutics, we have discovered a novel anti-CCR8 mAb candidate named DT-7012 that was fully characterized. We particularly focused on deciphering how DT-7012 interfere with receptor-ligand binding in conditions expected to have a strong impact on the mechanism of action such as presence of CCL1 ligand or pH conditions. DT-7012 was demonstrated as having an ideal and differentiated pharmacological profile which translates into effective functional activity in multiple cell lines, and in human samples.

Results Our results showed that DT-7012 was able to bind the human CCR8 with high affinity independently of its post-translational modification pattern or the presence of its ligand CCL1, to block CCL1-induced CCR8 internalization, to induce killing activities against the CCR8-expressing cell lines, Tregs derived from the blood of healthy donor, and Tregs from lung cancer patients. The binding and killing activity of DT-7012 was specific to CCR8 and CCR8+ cells, without affecting the other immune cell populations, suggesting a good safety profile of the Domain’s candidate.

Conclusions These data demonstrate major competitive advantages over the competitive anti-CCR8 mAbs currently in clinical development making DT-7012 a potential novel best-in-class anti-CCR8 mAb candidate.