CHS-114: An Afucosylated Anti-CCR8 Monoclonal Antibody that Selectively Depletes Intratumoral Treg Cells and Induces Antitumor Immune Responses.

Intratumoral T regulatory cells (Treg) promote an immunosuppressive tumor microenvironment and are frequently associated with a lack of response to immunotherapy. Selective targeting of intratumoral Tregs while sparing broader Tregs and effector T-cell populations is an attractive strategy to enhance antitumor immune responses. C-C motif chemokine receptor 8 (CCR8) is a G protein-coupled receptor that is predominantly upregulated on tumor-resident Tregs in a range of human solid tumors, making it a promising target for their selective depletion. In preclinical studies using mouse tumor models, anti-mouse CCR8 antibody treatment resulted in depletion of CCR8+ intratumoral Tregs, significant antitumor activity, and enhanced survival in combination with anti-PD-1. CHS-114 is a highly selective, afucosylated human anti-CCR8 monoclonal antibody that is being developed as a cancer immunotherapy. CHS-114 selectively binds human CCR8 and potently kills CCR8 expressing cells by inducing antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Ex vivo studies evaluating human dissociated tumor cells demonstrated the selectivity of CHS-114 in depleting intratumoral Tregs while sparing CCR8-negative Tregs and effector T cells. Treatment of tumor-bearing human CCR8 knock-in (huCCR8KI) mice with CHS-114 resulted in significant tumor growth inhibition (62.6%) accompanied by remodeling of the tumor-immune microenvironment and enhanced differentiation of a subset of cytotoxic CD8+ T cells. Based on the promising preclinical data, we are evaluating CHS-114 in clinical trials as an investigational agent for the treatment of solid tumors with and without the anti-PD-1 antibody toripalimab (NCT05635643 and NCT06657144).