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

  • Oncoimmunology. 2022 Nov 4;11(1):2141007. doi: 10.1080/2162402X.2022.2141007.
Jessica D Weaver  1 ,  Edward C Stack  1 ,  Joshua A Buggé  1 ,  Changyun Hu  1 ,  Lara McGrath  1 ,  Amy Mueller  1 ,  Masie Wong  1 ,  Boris Klebanov  1 ,  Tanzila Rahman  1 ,  Rosemary Kaufman  1 ,  Christine Fregeau  1 ,  Vikki Spaulding  1 ,  Michelle Priess  1 ,  Kristen Legendre  1 ,  Sarah Jaffe  1 ,  Dhruvkumar Upadhyay  1 ,  Anirudh Singh  1 ,  Chang-Ai Xu  1 ,  Kristin Krukenberg  1 ,  Yan Zhang  1 ,  Yassine Ezzyat  1 ,  Dorothée Saddier Axe  2 ,  Michelle R Kuhne  2 ,  Michael A Meehl  1 ,  Donald R Shaffer  1 ,  Brian M Weist  2 ,  Dmitri Wiederschain  1 ,  Fabien Depis  1 ,  Monica Gostissa  1
Affiliations
  • 1. Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA.
  • 2. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
PMID: 36352891 DOI: 10.1080/2162402X.2022.2141007
Abstract

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.

Keywords
CCR8; PD-1 resistance; T regulatory cells; cancer immunotherapy; treg depletion.
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