Dataset Information

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.

SUBMITTER: Miedema IHC

PROVIDER: S-EPMC10199858 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Miedema Iris H C IHC Huisman Marc C MC Zwezerijnen Gerben J C GJC Grempler Rolf R Pitarch Alejandro Perez AP Thiele Andrea A Hesse Raphael R Elgadi Mabrouk M Peltzer Alexander A Vugts Danielle J DJ van Dongen Guus A M S GAMS de Gruijl Tanja D TD Menke-van der Houven van Oordt C Willemien CW Bahce Idris I

European journal of nuclear medicine and molecular imaging 20230302 7

<h4>Purpose</h4>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 [<sup>89</sup>Zr]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.<h4>Methods</h4>Patients ...[more]

PMID: 36859619

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Project description:Immuno-PET using desferrioxamine (DFO)-conjugated zirconium-89 ([89Zr]Zr4+)-labeled antibodies is a powerful tool used for preclinical and clinical molecular imaging. However, a comprehensive study evaluating the variables involved in DFO-conjugation and 89Zr-radiolabeling of antibodies and their impact on the in vitro and in vivo behavior of the resulting radioimmunoconjugates has not been adequately performed. Here, we synthesized different DFO-conjugates of the HER2-targeting antibody (Ab)-trastuzumab, dubbed T5, T10, T20, T60, and T200-to indicate the molar equivalents of DFO used for bioconjugation. Next we radiolabeled the immunoconjugates with ([89Zr]Zr4+) under a comprehensive set of reaction conditions including different buffers (PBS, chelexed-PBS, TRIS/HCl, HEPES; ± radioprotectants), different reaction volumes (0.1-1 mL), variable amounts of DFO-conjugated Ab (5, 25, 50 μg), and radioactivity (0.2-1.0 mCi; 7.4-37 MBq). We evaluated the effects of these variables on radiochemical yield (RCY), molar activity (Am)/specific activity (As), immunoreactive fraction, and ultimately the in vivo biodistribution profile and tumor targeting ability of the trastuzumab radioimmunoconjugates. We show that increasing the degree of DFO conjugation to trastuzumab increased the RCY (∼90%) and Am/As (∼194 MBq/nmol; 35 mCi/mg) but decreased the HER2-binding affinity (3.5×-4.6×) and the immunoreactive fraction of trastuzumab down to 50-64%, which translated to dramatically inferior in vivo performance of the radioimmunoconjugate. Cell-based immunoreactivity assays and standard binding affinity analyses using surface plasmon resonance (SPR) did not predict the poor in vivo performance of the most extreme T200 conjugate. However, SPR-based concentration free calibration analysis yielded active antibody concentration and was predictive of the in vivo trends. Positron emission tomography (PET) imaging and biodistribution studies in a HER2-positive xenograft model revealed activity concentrations of 38.7 ± 3.8 %ID/g in the tumor and 6.3 ± 4.1 %ID/g in the liver for ([89Zr]Zr4+)-T5 (∼1.4 ± 0.5 DFOs/Ab) at 120 h after injection of the radioimmunoconjugates. On the other hand, ([89Zr]Zr4+)-T200 (10.9 ± 0.7 DFOs/Ab) yielded 16.2 ± 3.2 %ID/g in the tumor versus 27.5 ± 4.1 %ID/g in the liver. Collectively, our findings suggest that synthesizing trastuzumab immunoconjugates bearing 1-3 DFOs per Ab (T5 and T10) combined with radiolabeling performed in low reaction volumes using Chelex treated PBS or HEPEs without a radioprotectant provided radioimmunoconjugates having high Am/As (97 MBq/nmol; 17.5 ± 2.2 mCi/mg), highly preserved immunoreactive fractions (86-93%), and favorable in vivo biodistribution profile with excellent tumor uptake.

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Dataset Information

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

Purpose

Methods

Results

Conclusions

Trial registration

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Purpose

Methods

Results

Conclusions

Trial registration

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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