Introduction
Monoclonal antibodies (mAbs) are increasingly used as therapeutic agents in neuro-oncology and neurodegenerative disease. Despite their growing clinical relevance, their ability to penetrate the brain remains poorly understood due to the restrictive nature o
...
Introduction
Monoclonal antibodies (mAbs) are increasingly used as therapeutic agents in neuro-oncology and neurodegenerative disease. Despite their growing clinical relevance, their ability to penetrate the brain remains poorly understood due to the restrictive nature of the blood–brain barrier (BBB). Positron Emission Tomography (PET) imaging with Zirconium-89 (89Zr)-labeled mAbs allows for quantification of antibody uptake in organs and tumors. This study aims to quantify the baseline, non-specific uptake of 89Zr-labeled mAbs in brain tissue. Additionally, the influence of target expression, BBB disruption, lesion viability, and dosing on antibody uptake was investigated.
Methods
Retrospective Positron Emission Tomography/Computed Tomography (PET/CT) data from
three clinical trials with 89Zr-labeled mAbs were analyzed. Ki values, representing irreversible
tracer uptake, were derived using Patlak analysis from scans ≥1-day post-injection. Brain tissue
and metastases were delineated manually, and Ki values were compared across cohorts with no target expression, target expression, and brain metastases. Interobserver reliability was assessed, and statistical comparisons were performed using Kruskal–Wallis and Wilcoxon tests.
Results
Uptake in normal brain tissue was assessed in 18 patients, two of whom had post-treatment brain metastases that were included in the analysis. Ki in target-negative brain tissue was low but measurable (median: 2.0 × 10-5 µL · g-1· h-1, IQR: 1.5 − 3.2), indicating baseline non-specific
uptake. Ki was significantly higher in target-positive brain tissue (median: 3.9 × 10-5 µL · g-1
· h-1, IQR: 2.5 − 4.6), and substantially elevated in post-treatment brain metastases (median:
120 × 10-5 µL · g-1· h-1 , IQR: 115 − 180). Notably, uptake was particularly high in posttreatment lesions with viable tumor tissue (median: 180 × 10-5 µL · g-1· h-1, n = 2), compared to post-treatment lesions with therapy-related imaging changes (52.1 × 10-5 µL · g-1· h-1). In a
subset of five patients with two injections with different doses of non-labeled mAb, three showed decreased Ki at higher mass doses.
Conclusion
Irreversible brain uptake of mAbs can be quantified using Patlak-derived Ki values, even at low
levels. The data establish a baseline for non-specific brain uptake. The uptake is significantly
higher in the presence of target expression and even higher in brain metastases, likely due to
BBB disruption. These findings support the use of PET imaging with Patlak analysis as a non-invasive method to evaluate CNS target engagement and drug delivery in early-phase clinical
trials.
