S-531011, a Novel Anti-Human CCR8 Antibody, Induces Potent Antitumor Responses through Depletion of Tumor-Infiltrating CCR8-Expressing Regulatory T Cells

• Published in: Molecular cancer therapeutics Vol. 22; no. 9; pp. 1063 - 1072
• Main Authors: Nagira, Yoji, Nagira, Morio, Nagai, Ryohei, Nogami, Wataru, Hirata, Michinari, Ueyama, Azumi, Yoshida, Tetsuya, Yoshikawa, Mai, Shinonome, Satomi, Yoshida, Hiroshi, Haruna, Miya, Miwa, Hiroto, Chatani, Natsumi, Ohkura, Naganari, Wada, Hisashi, Tanaka, Hidekazu
• Format: Journal Article
• Language: English
• Published: American Association for Cancer Research 05.09.2023
• Subjects: Large Molecule Therapeutics
• DOI: 10.1158/1535-7163.MCT-22-0570
• ISSN: 1535-7163; 1538-8514

Although regulatory T cells (Treg) are inhibitory immune cells that are essential for maintaining immune homeostasis, Tregs that infiltrate tumor tissue promote tumor growth by suppressing antitumor immunity. Selective reduction of tumor-infiltrating Tregs is, therefore, expected to activate antitumor immunity without affecting immune homeostasis. We previously reported that selective Treg depletion targeted by a C-C motif chemokine receptor 8 (CCR8) resulted in induction of strong antitumor immunity without any obvious autoimmunity in mouse models. Thus, herein, we developed a novel humanized anti-CCR8 monoclonal antibody, S-531011, aimed as a cancer immunotherapy strategy for patients with cancer. S-531011 exclusively recognized human CCR8 among all chemokine receptors and showed potent antibody-dependent cell-mediated cytotoxicity activity toward CCR8+ cells and neutralization activity against CCR8-mediated signaling. We observed that S-531011 reduced tumor-infiltrating CCR8+ Tregs and induced potent antitumor activity in a tumor-bearing human-CCR8 knock-in mouse model. Moreover, combination therapy with S-531011 and anti-mouse programmed cell death 1 (PD-1) antibody strongly suppressed tumor growth compared with anti–PD-1 antibody alone with no observable adverse effects. S-531011 also depleted human tumor-infiltrating Tregs, but not Tregs derived from human peripheral blood mononuclear cells. These results suggest that S-531011 is a promising drug for inducing antitumor immunity without severe side effects in the clinical setting.