Receptor Occupancy Measurement of Anti-PD-1 Antibody Drugs in Support of Clinical Trials

Abstract

Aim: The reliable measurement of receptor occupancy (RO) provides informative data for efficacy and safety evaluation. This study aimed to assess factors affecting RO measurement of anti-PD-1 antibodies in clinical studies. Materials & methods: RO performance was assessed using different T-cell activation markers measured by flow cytometry. The validated methodology was then used in support of a clinical study. Results: The optimized active cell population was comprised of CD45RO+ or CD45RA− T cells. The bioanalytical method was validated for inter- and intra-assay precision (coefficient of variation ≤30%) and sample storage stability for 3 days. Consistent RO saturation was observed in Phase Ia clinical trial, although receptor regulation appeared to be different. The formation of anti-drug antibodies had markedly influenced pharmacokinetics and RO. Conclusion: RO measurement in combination with pharmacokinetics and anti-drug antibodies data could allow the integrated evaluation and better understanding of efficacy and safety.

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

“…Downmodulation of PD-1 expression by ~25% in cancer patients during the treatment with anti-PD-1 mAbs has been reported. 16 , 18 The PD-1 pathway has a sophisticated system of recycling that rescue internalized receptor from degradation and maintain surface receptors at a certain level. 19 Hence, the use of equation 3 allows dynamic changes in the number of bound receptors normalized to the baseline to be monitored: if PD-1 receptors are completely occupied by an antibody that induces receptor internalization, decreasing expression below the baseline level (Figure S5).…”

“… 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. 32 The full list of parameters related to the PD-1 receptor is presented in Table 1 .…”

Regional Delivery of Anti-PD-1 Agent for Colorectal Liver Metastases Improves Therapeutic Index and Anti-Tumor Activity

“…With regards to achieving sufficient therapeutic concentrations, multiple dose-range finding studies have investigated optimal CPI dosing [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]. Both preclinical models and clinical trials have demonstrated that there is no meaningful increase in efficacy between doses with over 100-fold differences and that lower doses already saturate the majority of the relevant receptors up to 100% [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. The data indicate that lower doses may be equally as effective, especially when targeted appropriately using techniques such as RD.…”

A human receptor occupancy assay to measure anti‐PD‐1 binding in patients with prior anti‐PD‐1

“…These antibodies target programmed cell death protein 1 (PD‐1) on the surface of antigen‐specific dysfunctional (“exhausted”) T cells [ 11 ] by binding to defined PD‐1 extracellular epitopes [ 12 ]. In addition, several other anti‐PD‐1 therapeutic mAbs are in clinical development or already approved [ 10 , 13 , 14 , 15 ], highlighting the importance of this molecule for CIT. In the case of the clinical development of CPIs, some trials included RO by flow cytometry to confirm the degree of PD‐1 occupancy in patients and establish pharmacokinetics–pharmacodynamics (PK–PD) relationships.…”