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Experimental Medicine Study to Measure Immune Checkpoint Receptors PD-1 and GITR Turnover Rates In Vivo in Humans
Michael E Lassman1, Derek L Chappell1, Thomas McAvoy1
1Translational Molecular Biomarkers, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Abstract:
Development of monoclonal antibodies (mAbs) targeting immune-checkpoint receptors (IMRs) for the treatment of cancer is one of the most active areas of investment in the biopharmaceutical industry. A key decision in the clinical development of anti-IMR mAbs is dose selection. Dose selection can be challenging because the traditional oncology paradigm of administering the maximum tolerated dose is not applicable to anti-IMR mAbs. Instead, dose selection should be informed by the pharmacology of immune signaling. Engaging an IMR is a key initial step to triggering pharmacologic effects, and turnover (i.e., the rate of protein synthesis) of the IMR is a key property to determining the dose level needed to engage the IMR. Here, we applied the stable isotope labeling mass spectrometry technique using 13 C6 -leucine to measure the in vivo turnover rates of IMRs in humans. The 13 C6 -leucine was administered to 10 study participants over 15 hours to measure 13 C6 -leucine enrichment kinetics in 2 IMR targets that have been clinically pursued in oncology: GITR and PD-1. We report the first measurements of GITR and PD-1 median half-lives associated with turnover to be 55.6 and ≥ 49.5 hours, respectively. The approach outlined here can be applied to other IMRs and, more generally, to protein targets.
Insights
Determining the right dose for cancer treatments targeting immune-checkpoint receptors (ICRs) is crucial. This study measured the in vivo turnover rates of GITR and PD-1, providing key data for optimizing anti-ICR monoclonal antibody therapy.
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.
