Background Intratumoral Tregs (itTregs) promote an immunosuppressive tumor microenvironment (TME) and are frequently associated with a lack of response to immunotherapy. Since broad Treg depletion leads to autoimmunity, preferential targeting of itTregs is an attractive strategy to enhance antitumor immune responses while preserving immune homeostasis. CCR8 is a seven transmembrane G-protein coupled receptor upregulated on tumor resident Tregs. Here, we report the molecular and pharmacological characteristics of CHS-114, a clinical stage human anti-CCR8 afucosylated monoclonal antibody (mAb), that has shown an acceptable safety profile and proof of mechanism by selectively depleting CCR8+ Tregs in Phase 1 clinical studies (NCT05635643).

Methods Expression and occurrence of CCR8⁺ itTregs were characterized by flow cytometry and by immunofluorescence on tumor samples across various tumor types. Dissociated tumor cells from primary tumors were cultured with CHS-114 and allogeneic NK cells to examine itTregs depletion. The antitumor activity of an anti-CCR8 mAb and CHS-114 was assessed in the mouse B16F10 melanoma model and in the MC38 tumor bearing human CCR8 knock-in (huCCR8KI) mice respectively. A first-in-human, Phase 1 dose escalation study of CHS-114 was initiated in patients with advanced solid tumors (SRF114-101; NCT05635643) and peripheral CCR8+ Tregs depletion was monitored.

Results CHS-114 is a highly selective, human anti-CCR8 afucosylated mAb, that lacks off-target binding and only binds human CCR8. We demonstrated that CHS-114 can selectively deplete CCR8+ itTregs in dissociated tumor samples, while mediating the activation of NK cells, monocytes, and T cells and elevating levels of proinflammatory cytokines. Treatment of tumor bearing huCCR8KI mice with CHS-114 resulted in significant antitumor activity, that was accompanied by decreased itTregs and increased immune cell infiltration. Furthermore, in vitro studies using human PBMCs treated with the combination of CHS-114 and toripalimab (anti-PD-1 mAb) elicited a stronger immune activation than either single agent treatment. In a Phase 1 clinical study (NCT05635643), CHS-114 treatment of cancer patients resulted in robust depletion of peripheral CCR8+ Tregs and an acceptable safety profile.

Conclusions Selective depletion of intratumoral CCR8+ Tregs with CHS-114 resulted in robust antitumor activity by reshaping the TME towards a proinflammatory milieu in preclinical studies, providing rationale for an orthogonal approach to checkpoint inhibition for eliciting antitumor immunity and evaluating CHS-114 in combination with other IO agents, such as toripalimab for the treatment of cancer.