Differential expression of CCR8 in tumors versus normal tissue allows specific depletion of tumor-infiltrating T regulatory cells by GS-1811, a novel Fc-optimized anti-CCR8 antibody

• Published in: Oncoimmunology Vol. 11; no. 1; p. 2141007
• Main Authors: Weaver, Jessica D., Stack, Edward C., Buggé, Joshua A., Hu, Changyun, McGrath, Lara, Mueller, Amy, Wong, Masie, Klebanov, Boris, Rahman, Tanzila, Kaufman, Rosemary, Fregeau, Christine, Spaulding, Vikki, Priess, Michelle, Legendre, Kristen, Jaffe, Sarah, Upadhyay, Dhruvkumar, Singh, Anirudh, Xu, Chang-Ai, Krukenberg, Kristin, Zhang, Yan, Ezzyat, Yassine, Saddier Axe, Dorothée, Kuhne, Michelle R., Meehl, Michael A., Shaffer, Donald R., Weist, Brian M., Wiederschain, Dmitri, Depis, Fabien, Gostissa, Monica
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 31.12.2022; Taylor & Francis Group
• Subjects: cancer immunotherapy; CCR8; Original Research; PD-1 resistance; T regulatory cells; treg depletion
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2022.2141007

The presence of T regulatory (Treg) cells in the tumor microenvironment is associated with poor prognosis and resistance to therapies aimed at reactivating anti-tumor immune responses. Therefore, depletion of tumor-infiltrating Tregs is a potential approach to overcome resistance to immunotherapy. However, identifying Treg-specific targets to drive such selective depletion is challenging. CCR8 has recently emerged as one of these potential targets. Here, we describe GS-1811, a novel therapeutic monoclonal antibody that specifically binds to human CCR8 and is designed to selectively deplete tumor-infiltrating Tregs. We validate previous findings showing restricted expression of CCR8 on tumor Tregs, and precisely quantify CCR8 receptor densities on tumor and normal tissue T cell subsets, demonstrating a window for selective depletion of Tregs in the tumor. Importantly, we show that GS-1811 depleting activity is limited to cells expressing CCR8 at levels comparable to tumor-infiltrating Tregs. Targeting CCR8 in mouse tumor models results in robust anti-tumor efficacy, which is dependent on Treg depleting activity, and synergizes with PD-1 inhibition to promote anti-tumor responses in PD-1 resistant models. Our data support clinical development of GS-1811 to target CCR8 in cancer and drive tumor Treg depletion in order to promote anti-tumor immunity.