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Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
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Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have

Catherine A Sabatos-Peyton1, James Nevin2, Ansgar Brock3

  • 1Exploratory Immuno-oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, USA.

Oncoimmunology
|January 9, 2018
PubMed

Insights

Blocking Tim-3 (T-cell immunoglobulin and mucin-domain containing-3) is crucial for effective anti-tumor immunity. This study shows that successful cancer immunotherapies targeting Tim-3 interfere with its binding to phosphatidylserine and CEACAM1.

Area of Science:

  • Immunology
  • Cancer Biology
  • Drug Development

Background:

  • Tim-3 (T-cell immunoglobulin and mucin-domain containing-3) blockade shows promise in preclinical cancer models and patient T cells for enhancing anti-tumor immunity.
  • Clinical development of anti-Tim-3 antibody therapeutics is of significant interest for cancer immunotherapy.
  • Multiple Tim-3 ligands (galectin-9, phosphatidylserine, HMGB1, CEACAM1) complicate therapeutic strategies, raising questions about which interactions are critical for efficacy.

Purpose of the Study:

  • To investigate the binding properties of functional anti-murine and anti-human Tim-3 antibodies.
  • To determine which Tim-3 ligand interactions are affected by efficacious anti-Tim-3 antibodies.
  • To inform the development and screening of anti-Tim-3 antibody candidates for cancer immunotherapy.

Main Methods:

  • Characterization of anti-murine and anti-human Tim-3 antibodies.
  • Assessment of antibody binding to Tim-3.
  • Evaluation of the impact of antibody binding on Tim-3 interactions with its ligands, including phosphatidylserine and CEACAM1.

Main Results:

  • All tested functional anti-Tim-3 antibodies bind to Tim-3.
  • This binding interferes with Tim-3's interaction with both phosphatidylserine and CEACAM1.
  • The findings provide insights into the mechanism of action for effective Tim-3 blockade.

Conclusions:

  • Effective anti-Tim-3 antibodies function by disrupting Tim-3 binding to specific ligands, notably phosphatidylserine and CEACAM1.
  • Understanding these critical receptor-ligand interactions is essential for the rational design and selection of anti-Tim-3 antibody therapeutics.
  • This research aids in the development of more effective cancer immunotherapies targeting the Tim-3 pathway.
Keywords:
HDxMSTim-3antibodycheckpoint receptorligand

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