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

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 13C6‐leucine to measure the in vivo turnover rates of IMRs in humans. The 13C6‐leucine was administered to 10 study participants over 15 hours to measure 13C6‐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.