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873 S-531011, a novel anti-human CCR8 antibody: anti-tumor responses through depletion of tumor-infiltrating CCR8-positive Tregs
  1. Ryohei Nagai1,
  2. Morio Nagira1,
  3. Wataru Nogami1,
  4. Michinari Hirata1,
  5. Azumi Ueyama1,
  6. Mai Yoshikawa1,
  7. Naganari Ohkura2,
  8. Hisashi Wada2 and
  9. Yoji Nagira1
  1. 1Shionogi and Co., Ltd., Osaka, ID, Japan
  2. 2Osaka University, Osaka, Japan


Background Regulatory T cells (Tregs) are suppressive immune cells required for the maintenance of immune homeostasis, but tumor-infiltrating Tregs are known to suppress the antitumor immune system and promote tumor progression. Therefore, selective reduction of tumor-infiltrating Tregs is anticipated to reinvigorate antitumor immunity without inducing autoimmunity. S-531011 is a novel anti-human IgG1 antibody targeting human CCR8 (C-C motif chemokine receptor 8) which is selectively expressed in tumor-infiltrating Tregs, with both in vitro antibody dependent cellular cytotoxicity (ADCC) against CCR8-expressing cells and neutralizing activity against CCL1-CCR8 signaling. Here, to evaluate antitumor activities and safety aspects of S-531011, we conducted non-clinical pharmacology studies of S-531011 using human CCR8 knock-in (KI) mice and human tissues.

Methods S-531011 was administrated to CT26WT tumor-bearing hCCR8-KI mice, and the effect on the presence of tumor-infiltrating CCR8+ Treg and tumor growth were evaluated. We also investigated the antitumor efficacy of S-531011 in combination with anti-mouse PD-1 antibody. Next, human lung cancer tissues and human NK-cells were co-cultured, and the ex vivo ADCC against tumor-infiltrating Tregs by S-531011 was verified. We also incubated human peripheral blood-derived mononuclear cells (PBMC) from healthy individuals with S-531011 to investigate the effects on the proportion of Tregs in human PBMC.

Results Intravenous administration of S-531011 to CT26WT tumor-bearing hCCR8-KI mice significantly reduced tumor-infiltrating CCR8+ Tregs and markedly suppressed tumor growth. Furthermore, the combined therapy of S-531011 with anti-mouse PD-1 antibody showed greater anti-tumor effect than monotherapy without any apparent side effects. Ex vivo ADCC studies using human lung cancer tissues and FCM analysis of CCR8 expression in tumor-infiltrating Tregs suggested that most of the tumor-infiltrating CCR8+ Tregs were depleted by S-531011. On the other hand, S-531011 didn’t reduce Tregs in human PBMC.

Conclusions S-531011 is a promising drug which has a strong antitumor effect by depleting tumor-infiltrating CCR8+ Tregs, as a not only monotherapy but also combination therapy with other immune checkpoint inhibitors.

Ethics Approval The present study was approved by the Institutional Ethics Committee of Osaka University Hospital (approved number: 13266-15) and Shionogi Co., Ltd. (approved number: 021-003). Animal studies were approved by the Institutional Animal Care and Use Committee (approved number: S20093D, S20197D and S20198D).

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