TAK-188, an antibody-drug conjugate with a novel amanitin payload, disrupts immune suppression and leads to potent anti-tumor immunity through selective depletion of CCR8 + intratumoral regulatory T-cells

Regulatory T cells (Tregs) play a critical role in mediating tolerance to self-antigens and are a major contributor to an immunosuppressive tumor microenvironment (TME). The presence of Tregs in solid tumors is associated with poor prognosis and decreased overall survival in patients, as well as resistance to immunotherapy in several tumor types. CCR8 is a chemokine receptor identified to be highly expressed on tumor-infiltrating Tregs, with lower expression on peripheral Tregs and other cells, making it an attractive target for immunotherapy. Current CCR8-targeting therapeutics in development aim to achieve Treg depletion via Fc-enabled antibody-dependent cellular cytotoxicity, which relies on the presence of effector cells that can vary in frequency and may be functionally inhibited in the TME. In contrast, TAK-188 is a first-in-class anti-CCR8 antibody-drug conjugate designed to facilitate antitumor efficacy by direct cytotoxic depletion of intra-tumoral CCR8 + Tregs using a novel amanitin payload that can kill both dividing and quiescent cells. The specificity and potency of TAK-188 was evaluated preclinically using CCR8-expressing cells, dissociated human tumor samples, and syngeneic tumor models in human CCR8 knock-in mice. The preclinical data showed that TAK-188 specifically bound to and killed CCR8 + cells in vitro. TAK-188 also demonstrated dose-dependent anti-tumor activity in syngeneic tumor models and anti-tumor memory following tumor rechallenge in human CCR8 knock-in mice. TAK-188 selectively killed CCR8 + Tregs in vivo, demonstrating a robust decrease in tumor Tregs and an increase in CD8 + T cells that together resulted in an increased CD8/Treg ratio in the TME. In a mouse syngeneic tumor model, TAK-188 as a single agent was more efficacious than Fc-enabled anti-CCR8 antibodies and shifted the phenotype of immune cells in the TME to be more favorable for anti-tumor activity. Finally, TAK-188 potently and specifically depleted Tregs in dissociated human tumor samples while sparing conventional CD4 + and CD8 + T cells, supporting the mechanism of action of direct tumor Treg killing without the need for exogenous effector cells. In conclusion, TAK-188 robustly depletes CCR8 + cells both in vitro and in vivo and demonstrates anti-tumor activity as a single agent in nonclinical models. Based on this promising preclinical data, a Phase 1 study of TAK-188 has been opened (NCT07205718).