Experimental Medicine Study to Measure Immune Checkpoint Receptors PD-1 and GITR Turnover Rates In Vivo in Humans.

Area of Science:

• Biopharmaceutical industry
• Oncology
• Immunology

Background:

• Monoclonal antibodies (mAbs) targeting immune-checkpoint receptors (ICRs) are a significant focus in cancer treatment development.
• Selecting the appropriate dose for anti-ICR mAbs is challenging, as the traditional maximum tolerated dose paradigm is unsuitable.
• Dose selection requires understanding the pharmacology of immune signaling, particularly the turnover rate of ICRs.

Purpose of the Study:

• To measure the in vivo turnover rates of immune-checkpoint receptors (ICRs) in humans.
• To establish a method for determining dose levels for anti-ICR mAb therapies based on receptor pharmacology.
• To report the half-lives of GITR and PD-1 turnover.

Main Methods:

• Utilized stable isotope labeling mass spectrometry with ¹³C₆-leucine administration over 15 hours in 10 participants.
• Measured ¹³C₆-leucine enrichment kinetics in vivo for two key ICR targets: GITR and PD-1.
• Calculated median half-lives associated with the turnover of GITR and PD-1.

Main Results:

• The median half-life for GITR turnover was determined to be 55.6 hours.
• The median half-life for PD-1 turnover was found to be ≥49.5 hours.
• This study presents the first in vivo measurements of GITR and PD-1 turnover rates in humans.

Conclusions:

• The developed stable isotope labeling mass spectrometry approach provides a method to measure in vivo ICR turnover rates.
• This methodology can inform optimal dose selection for anti-ICR mAb cancer therapies.
• The approach is applicable to other immune-checkpoint receptors and protein targets in general.