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

Intratumoral T regulatory cells (Tregs) 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. CCR8 is a G protein-coupled receptor (GPCR) 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 the 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 (ADCC) and antibody dependent cellular phagocytosis (ADCP). Ex vivo studies evaluating human dissociated tumor cells (DTCs) 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, NCT06657144).