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

Abstract

Dose selection for IMR monoclonal antibodies (mAbs) must be informed by the characterization of pharmacology of immune activation. Intuitively, engaging a target with higher turnover will require more drug relative to engaging a target with lower turnover. Therefore, characterization of target turnover is important to inform dose selection.

Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study

“…The PD-1 turnover rate was estimated on the basis of in vivo data on 13 C6-leucine administration and subsequent quantification of isotope-labeled receptors in peripheral blood mononuclear cells, the reported PD-1 median half-live is 49.5 hours. 31 The internalization rate of bound PD-1 should be substantially higher than the degradation rate that results in the apparent receptor downmodulation (median fold change ~0.75) during the course of treatment with anti-PD-1 mAbs. 16 , 18 All these processes occur at the cellular membrane, the surface area of which was estimated based on the spherical volume of cell.…”

Toward Project Optimus for Oncology Precision Medicine: Multi‐Dimensional Dose Optimization Enabled by Quantitative Clinical Pharmacology

“…1 The critical role of clinical pharmacology principles and prospective dose optimization ahead of designing pivotal registration-enabling trials have been reinforced in recent seminal publications, 2 White Papers, 3 and cross-sector public workshops 4 that have galvanized the oncology drug development community and offered a call to action for reforming current approaches. Clinical Pharmacology and Therapeutics (CPT) has been a home for research articles and reviews illustrating contemporary integrative approaches to inform dose selection of oncology therapeutics, including molecularly targeted small molecules, [5][6][7] immunotherapies, [8][9][10][11] antibody-drug conjugates, [12][13][14] and cell therapies. [15][16][17] Several examples have catalyzed active scientific discussion contributing to growing appreciation of the biological complexity, population variability, and analytical methodology that demand careful consideration for robust dose optimization in oncology drug development.…”