2. Academic Validation
  3. Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8

Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8

  • Nat Commun. 2023 Dec 1;14(1):7940. doi: 10.1038/s41467-023-43601-8.
Dawei Sun 1,  Yonglian Sun 2,  Eric Janezic 3,  Tricia Zhou 3,  Matthew Johnson 1,  Caleigh Azumaya 1,  Sigrid Noreng 1 4,  Cecilia Chiu 2,  Akiko Seki 5 6,  Teresita L Arenzana 5 7,  John M Nicoludis 1,  Yongchang Shi 3,  Baomei Wang 5,  Hoangdung Ho 1,  Prajakta Joshi 8,  Christine Tam 8,  Jian Payandeh 1 9,  Laëtitia Comps-Agrar 3,  Jianyong Wang 3,  Sascha Rutz 10,  James T Koerber 11,  Matthieu Masureel 12
Affiliations

Affiliations

  • 1 Department of Structural Biology, Genentech Inc., South San Francisco, CA, 94080, USA.
  • 2 Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, 94080, USA.
  • 3 Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USA.
  • 4 Septerna Inc., South San Francisco, CA, 94080, USA.
  • 5 Department of Cancer Immunology, Genentech Inc., South San Francisco, CA, 94080, USA.
  • 6 Tune Therapeutics, Durham, NC, 27701, USA.
  • 7 HIBio, South San Francisco, CA, 94080, USA.
  • 8 Department of Biomolecular Resources, Genentech Inc., South San Francisco, CA, 94080, USA.
  • 9 Exelixis Inc., Alameda, CA, 94502, USA.
  • 10 Department of Cancer Immunology, Genentech Inc., South San Francisco, CA, 94080, USA. rutz.sascha@gene.com.
  • 11 Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, 94080, USA. koerber.james@gene.com.
  • 12 Department of Structural Biology, Genentech Inc., South San Francisco, CA, 94080, USA. masureel.matthieu@gene.com.
PMID: 38040762 DOI: 10.1038/s41467-023-43601-8
Abstract

The C-C motif Chemokine Receptor 8 (CCR8) is a class A G-protein coupled receptor that has emerged as a promising therapeutic target in Cancer. Targeting CCR8 with an antibody has appeared to be an attractive therapeutic approach, but the molecular basis for chemokine-mediated activation and antibody-mediated inhibition of CCR8 are not fully elucidated. Here, we obtain an antagonist antibody against human CCR8 and determine structures of CCR8 in complex with either the antibody or the endogenous agonist ligand CCL1. Our studies reveal characteristic antibody features allowing recognition of the CCR8 extracellular loops and CCL1-CCR8 interaction modes that are distinct from other Chemokine Receptor - ligand pairs. Informed by these structural insights, we demonstrate that CCL1 follows a two-step, two-site binding sequence to CCR8 and that antibody-mediated inhibition of CCL1 signaling can occur by preventing the second binding event. Together, our results provide a detailed structural and mechanistic framework of CCR8 activation and inhibition that expands our molecular understanding of chemokine - receptor interactions and offers insight into the development of therapeutic Antibodies targeting chemokine GPCRs.

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