Abstract 2866: BAY 3375968: An afucosylated anti-CCR8 antibody depleting activated intratumoral regulatory T cells as a cancer immunotherapy

Abstract Regulatory T cells (Tregs) play an indispensable role in mediating peripheral tolerance to self-antigens. They can also promote tumor growth by suppressing the function of effector CD8+ and CD4+ T cells in the tumor microenvironment (TME). Furthermore, Tregs are identified as one of the key resistance mechanisms hampering the efficacy of immune checkpoint inhibitors (ICIs) across many tumor types. Therefore, there is a high need for safe and effective agents that would specifically deplete tumor-infiltrating Tregs while sparing both peripheral Tregs and effector T cells. Chemokine receptor 8 (CCR8) is predominantly expressed on activated tumor-infiltrating Tregs and marks the most suppressive and proliferative Treg population. CCR8+ Tregs are associated with high tumor grade and poor overall survival across many tumor types such as lung, breast, or head-neck cancer. Thus, unlike other approaches directed against Tregs, targeting CCR8 offers the opportunity to specifically deplete intra-tumoral Tregs without impacting peripheral Tregs or other immune cells. BAY 3375968 is a non-internalizing fully human glycoengineered (afucosylated) monoclonal IgG1 antibody, which in vitro selectively depleted human CCR8+ Tregs via antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). In vivo efficacy studies using mouse surrogate antibodies showed strong monotherapeutic efficacy across a variety of murine tumor models with clear correlation of intratumoral CCR8+ Treg depletion and CD8+ T cell increase. The monotherapeutic efficacy of CCR8 depleting antibodies was further enhanced by combinations with ICIs. BAY 3375968 also showed a good safety profile in cynomolgus monkeys. In conclusion, CCR8 is a novel Treg depleting immunotherapy target, and due to its highly tumor-restricted expression profile, BAY 3375968 may provide superior clinical safety and efficacy profile comparing to other less specific Treg targeting approaches. Based on the promising pre-clinical data, preparations for a phase I clinical trial investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of BAY 3375968 are underway. Citation Format: Helge Roider, Su-Yi Tseng, Sabine Hoff, Sandra Berndt, Katharina Filarski, Uwe Gritzan, Beatrix Stelte-Ludwig, Wiebke M. Nadler, Joanna Grudzinska-Goebel, Philipp Ellinger, Mark Trautwein, Matyas Gorjanacz. BAY 3375968: An afucosylated anti-CCR8 antibody depleting activated intratumoral regulatory T cells as a cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2866.