89Zr-immuno-PET using the anti-LAG-3 tracer [89Zr]Zr-BI 754111: demonstrating target specific binding in NSCLC and HNSCC

Abstract

Purpose Although lymphocyte activation gene-3 (LAG-3) directed therapies demonstrate promising clinical anti-cancer activity, only a subset of patients seems to benefit and predictive biomarkers are lacking. Here, we explored the potential use of the anti-LAG-3 antibody tracer [89Zr]Zr-BI 754111 as a predictive imaging biomarker and investigated its target specific uptake as well as the correlation of its tumor uptake and the tumor immune infiltration. Methods Patients with head and neck (N = 2) or lung cancer (N = 4) were included in an imaging substudy of a phase 1 trial with BI 754091 (anti-PD-1) and BI 754111 (anti-LAG-3). After baseline tumor biopsy and [18F]FDG-PET, patients were given 240 mg of BI 754091, followed 8 days later by administration of [89Zr]Zr-BI 754111 (37 MBq, 4 mg). PET scans were performed 2 h, 96 h, and 144 h post-injection. To investigate target specificity, a second tracer administration was given two weeks later, this time with pre-administration of 40 (N = 3) or 600 mg (N = 3) unlabeled BI 754111, followed by PET scans at 96 h and 144 h post-injection. Tumor immune cell infiltration was assessed by immunohistochemistry and RNA sequencing. Results Tracer uptake in tumors was clearly visible at the 4-mg mass dose (tumor-to-plasma ratio 1.63 [IQR 0.37-2.89]) and could be saturated by increasing mass doses (44 mg: 0.67 [IQR 0.50–0.85]; 604 mg: 0.56 [IQR 0.42–0.75]), demonstrating target specificity. Tumor uptake correlated to immune cell-derived RNA signatures. Conclusions [89Zr]Zr-BI-754111 PET imaging shows favorable technical and biological characteristics for developing a potential predictive imaging biomarker for LAG-3-directed therapies. Trial registration ClinicalTrials.gov, NCT03780725. Registered 19 December 2018

A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer

“…Interestingly, they found that [ 89 Zr]-pembrolizumab uptake not only correlated with response to anti-PD-1 therapy ( p = 0.014), but also with progression-free survival (PFS) ( p = 0.0025) and overall survival (OS) ( p = 0.026) ( 23 ). More recently, a study performed in patients with head and neck squamous cell carcinoma and NSCLC showed [ 89 Zr]-BI 754111, a LAG-3 targeting mAb, to be a predictive imaging biomarker for anti-LAG-3 therapy ( 21 ).…”

“…The use of radiotracers other than [ 18 F]-FDG is emerging as a non-invasive method to monitor in real time the immune landscape of patients receiving ICIs. This approach is currently under evaluation and may potentially enter routine clinical practice if proven effective ( 21 ). Monoclonal antibody-based PET (immuno-PET) is another potential biomarker to 1) verify optimal delivery of targeted agents to tumors and, 2) measure target expression ( 22 , 23 ).…”

Synthesis and Characterization of a Novel PET Tracer for Noninvasive Evaluation of FGL1 Status in Tumors

“…Iris H C Miedema conducted PET imaging on lung cancer patients treated with LAG3 antibodies using 4 mg of 89 Zr-labeled antibody ( 89 Zr−BI 754111). The results showed that the tumor-to-plasma uptake ratio was only 1.63 at 90 h p.i.. 19 Meanwhile, there was a significant correlation between the high expression of FGL1 and LAG3 in solid tumors and the low infiltration of active CD8+ T cells. Interestingly, the amount of FGL1 can be more than eight times higher than that of LAG3.…”

Construction and Preclinical Evaluation of 124I/125I-Labeled Antibody Targeting T Cell Immunoglobulin and Mucin Domain-3

“…Therefore, there is a clear clinical need to develop predictive biomarkers, which can be detected by positron emission tomography (PET) using radiolabeled monoclonal antibodies. 10 Positron emission tomography (PET)/computed tomography (CT) can be used for noninvasive and dynamic whole-body scanning with different tracers to predict the response to ICIs therapy and guide drug delivery strategies by reflecting the expression of biomarkers in vivo. 11 The physical half-life of 124 I (t 1/2 = 100.2 h) is similar to the time needed for monoclonal antibody metabolism in vivo and has been extensively studied in both experimental and clinical immuno-PET.…”

“…Monitoring TIM3 expression is important to accurately guide the use of TIM3-targeted ICIs, as well as the underlying mechanisms in immunotherapy. Therefore, there is a clear clinical need to develop predictive biomarkers, which can be detected by positron emission tomography (PET) using radiolabeled monoclonal antibodies . Positron emission tomography (PET)/computed tomography (CT) can be used for noninvasive and dynamic whole-body scanning with different tracers to predict the response to ICIs therapy and guide drug delivery strategies by reflecting the expression of biomarkers in vivo.…”