89Zr-Immuno-Positron Emission Tomography in Oncology

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89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry.

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89Zr Radiochemistry Review

89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry.

Heskamp S, Raavé R, Boerman O, Rijpkema M, Goncalves V, Denat F.


Bioconjug Chem. 2017 Aug 24. doi: 10.1021/acs.bioconjchem.7b00325.

Abstract

Immuno-positron emission tomography (immunoPET) with 89Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for 89Zr is desferrioxamine (DFO). Preclinical studies have shown that DFO is not an ideal chelator because the 89Zr–DFO complex is partly unstable in vivo, which results in the release of 89Zr from the chelator and the subsequent accumulation of 89Zr in bone. This bone accumulation interferes with accurate interpretation and quantification of bone uptake on PET images. Therefore, there is a need for novel chelators that allow more stable complexation of 89Zr. In this Review, we will describe the most recent developments in 89Zr radiochemistry, including novel chelators and site-specific conjugation methods.

89ZR RADIOCHEMISTRY REVIEW
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In vitro and in vivo comparison of the novel

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In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

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Conference Abstract: DFO-cyclo versus DFO

In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Victor Goncalves, Franck Denat


ESRR 18, 19th European Symposium on Radiopharmacy and Radiopharmaceuticals, 05-08 April 2018, Groningen, Netherlands

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO). Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation of 89Zr in mineral bone tissue. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for a more stable 89Zr chelator. Here we report DFO-cyclo*, a preorganized extended DFO derivative introducing an octacoordination, and investigate the stability of its 89Zr complex over the unsaturated hexacoordinated 89Zr-DFO complex in vitro and in vivo.

CONFERENCE ABSTRACT: DFO-CYCLO VERSUS DFO
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In vitro and in vivo evaluation of novel 89Zr-chelators

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In vitro and in vivo evaluation of novel 89Zr-chelators (Conference Abstract)

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Conference Abstract: 89Zr chelate evaluation

In vitro and in vivo evaluation of novel 89Zr-chelators (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Adrien Dubois, Laurene Da Costa, Victor Goncalves, Franck Denat


Third international edition of the symposium on Technetium and Other Radiometals in Chemistry and Medicine (TERACHEM 2018), September 26-29, 2018, Bressanone (BZ), Italy

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO).1 Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation in mineral bone. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for more stable 89Zr chelators.

CONFERENCE ABSTRACT: 89ZR CHELATE EVALUATION
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Development and evaluation of a new Interleukin

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Development and evaluation of a new Interleukin-2 PET radioligand Al[18F]RESCA-IL2: comparison with [18F]FB-IL2 (Conference Abstract)

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Conference Abstract: IL-2 PET

Development and evaluation of a new Interleukin-2 PET radioligand Al[18F]RESCA-IL2: comparison with [18F]FB-IL2 (Conference Abstract)

I.F. Antunes, E.L. van der Veen, E.E.M. Deneer, F. Cleeren, G. Bormans, P.H Elsinga, R.A.J.O. Dierckx, E.G.E de Vries, E.F.J. de Vries


31st Annual Congress of the European Association of Nuclear Medicine, 13-17 October 2018, Düsseldorf

 

Aim

Interleukin-2 is a 15.5 kDa glycoprotein that binds with high affinity to IL2 receptors (IL2R) that are overexpressed on activated T-cells, which are involved in various pathological diseases, such as autoimmune diseases, but also play a major role in the tumor immune response. We have developed 18F-FB-IL2 which has been successfully used for detecting activated T-cells in rodents [1]. Recently, a GMP-compliant production of 18F-FB-IL2 for clinical use was implemented, but the production method proved to be complex and time-consuming. Therefore, we now developed a simplified method to label IL2 with 18F. Here we present the synthesis of Al 18F-RESCA-IL2 and its comparison to 18F-FB-IL2.

CONFERENCE ABSTRACT: IL-2 PET
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Evaluation of the in vitro and in vivo characteristics

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Evaluation of the in vitro and in vivo characteristics of the novel89Zr-octacoordinated chelator DFO-cyclo* compared to the hexacoordinated DFO (Conference Abstract)

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Conference Abstract: Novel 89Zr chelator

Evaluation of the in vitro and in vivo characteristics of the novel89Zr-octacoordinated chelator DFO-cyclo* compared to the hexacoordinated DFO (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Victor Goncalves, Franck Denat


31st Annual Congress of the European Association of Nuclear Medicine, 13-17 October 2018, Duesseldorf

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO). Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation in mineral bone tissue. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for a more stable 89Zr chelator. Here we report DFO-cyclo*, a preorganized extended DFO derivative introducing an octacoordination, and investigate the stability of its 89Zrr complex over the unsaturated hexacoordinated 89Zr-DFO complex in vitro and in vivo.

CONFERENCE ABSTRACT: NOVEL 89ZR CHELATOR
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Feasibility of PET/CT system performance harmonisation

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Feasibility of PET/CT system performance harmonisation for quantitative multicentre 89Zr studies

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PET/CT Harmonization for Multicenter Studies

Feasibility of PET/CT system performance harmonisation for quantitative multicentre 89Zr studies

Andres Kaalep, Marc Huisman, Terez Sera, Danielle Vugts, Ronald Boellaard, on behalf of EARL, EATRIS and the TRISTAN Consortium


EJNMMI Physics 2018 (5):26 doi: 10.1186/s40658-018-0226-7.

 

Purpose

The aim of this study was to investigate the variability in quantitative performance and feasibility of quantitative harmonisation in 89Zr PET/CT imaging.

Methods

Eight EANM EARL-accredited (Kaalep A et al., Eur J Nucl Med Mol Imaging 45:412-22, 2018) PET/CT systems were investigated using phantom acquisitions of uniform and NEMA NU2-2007 body phantoms. The phantoms were filled according to EANM EARL guidelines for 18F-FDG, but 18F-FDG solution was replaced by a 89Zr calibration mixture. For each system, standard uptake value (SUV) accuracy and recovery coefficients (RC) using SUVmean, SUVmax and SUVpeak metrics were determined.

Results

All eight investigated systems demonstrated similarly shaped RC curves, and five of them exhibited closely aligning recoveries when SUV bias correction was applied. From the evaluated metrics, SUVpeak was found to be least sensitive to noise and reconstruction differences among different systems.

Conclusions

Harmonisation of PET/CT scanners for quantitative 89Zr studies is feasible when proper scanner-dose calibrator cross-calibration and harmonised image reconstruction procedures are followed. An accreditation programme for PET/CT scanners would facilitate multicentre 89Zr quantitative studies.

PET/CT HARMONIZATION FOR MULTICENTER STUDIES
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Integrating molecular nuclear imaging in clinical research

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Integrating molecular nuclear imaging in clinical research to improve anticancer therapy

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Review: PET to improve anti-cancer therapy

Integrating molecular nuclear imaging in clinical research to improve anticancer therapy

Elisabeth G. E. de Vries, Laura Kist de Ruijter, Marjolijn N. Lub-de Hooge, Rudi A. Dierckx, Sjoerd G. Elias & Sjoukje F. Oosting


Nature Reviews Clinical Oncology (2018); doi: 10.1038/s41571-018-0123-y.

Abstract

Effective patient selection before or early during treatment is important to increasing the therapeutic benefits of anticancer treatments. This selection process is often predicated on biomarkers, predominantly biospecimen biomarkers derived from blood or tumour tissue; however, such biomarkers provide limited information about the true extent of disease or about the characteristics of different, potentially heterogeneous tumours present in an individual patient. Molecular imaging can also produce quantitative outputs; such imaging biomarkers can help to fill these knowledge gaps by providing complementary information on tumour characteristics, including heterogeneity and the microenvironment, as well as on pharmacokinetic parameters, drug–target engagement and responses to treatment. This integrative approach could therefore streamline biomarker and drug development, although a range of issues need to be overcome in order to enable a broader use of molecular imaging in clinical trials. In this Perspective article, we outline the multistage process of developing novel molecular imaging biomarkers. We discuss the challenges that have restricted the use of molecular imaging in clinical oncology research to date and outline future opportunities in this area.

REVIEW: PET TO IMPROVE ANTI-CANCER THERAPY
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Development of a CD8 tracer for in vivo evaluation of CD8

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Development of a CD8 tracer for in vivo evaluation of CD8 T cell tumor infiltration during immunotherapy (Conference Abstract)

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Conference Abstract: Tracer for CD8 T-cell tumor infiltration

Development of a CD8 tracer for in vivo evaluation of CD8 T cell tumor infiltration during immunotherapy (Conference Abstract)

René Raavé, Milou Boswinkel, Gerwin Sandker, Peter Wierstra, Erik H. J. G. Aarntzen, Sandra Heskamp


EMIM 2019, Glasgow: #858. EMIM 2019 Abstracts.

Abstract

Introduction

Immunotherapy is considered a hallmark in cancer treatment by its profound and durable clinical responses in patients with various types of cancer. However, only a subgroup of patients responds to immunotherapy and methods for accurate early response monitoring are lacking. Noninvasive quantitative imaging of CD8+ cytotoxic T cells can provide dynamic and spatial information of anti-tumor response. In the present study we characterized an 111In-labeled anti-mouse CD8 antibody for imaging of tumor infiltrating CD8+ cytotoxic T cells in vitro and in vivo in mice bearing murine CT26 colon tumors.

Methods

An anti-mouse CD8 antibody (clone: YTS 169.4) was randomly conjugated with a 30 times molar excess of NCS-DTPA and radiolabeled with 111In. Using CD8+ TK1 mice lymphoma cells, the immunoreactivity, IC50, internalization and affinity characteristics were determined. CT26 tumor bearing BALB/c mice (10-12 weeks old) were intravenously injected with 8.5 µg (8.5 MBq) [111In]In-DTPA-anti-CD8. One group received an excess of non-radiolabeled CD8 antibody (250 µg). SPECT/CT imaging was performed and organs were collected to quantify tracer uptake at 4h, 24h, 48h and 72h after injection. Autoradiography and immunohistochemistry were performed on paraffin embedded tissue sections of tumor, spleen, lymph nodes and duodenum.

Results/Discussion

In vitro assays demonstrated that the immunoreactive fraction was 44%, IC50 was 1.77 nM, Kd was 3.83 nM, and 6.5% internalization of the total membrane bound activity after 4.5 h of incubation. CD8+ T cell containing organs (lymph nodes, spleen and duodenum) were clearly visible on SPECT scans of mice injected with [111In]In-DTPA-CD8-antibody at all time points. Mice that received an excess of non-radiolabeled CD8-antibody showed most uptake in the spleen. Low to moderate tumor uptake was visible in all groups. Ex vivo biodistribution data confirmed results from SPECT imaging. In the lymph nodes, spleen, duodenum and tumor, an uptake of 38.6 ± 12.3% ID/g (±SD), 87.1 ± 18.0% ID/g, 31.7 ± 16.9% ID/g, and 12.9 ±2.9% ID/g at 24h after injection, respectively. The tumor-to-blood ratio increased from 0.48 at 4h after injection to 2.23 at 72h after injection. Autoradiography and immunohistochemistry confirmed these findings.

Conclusions

The CD8 antibody showed specific uptake in CD8+ T cell containing tissues in vivo, but uptake in the tumor was limited because of presence low number of CD8+ T cells. In the future, this tracer has potential for in vivo evaluation of CD8+ T cell infiltration in tumors and lymphoid tissues before and during immunotherapy.

CONFERENCE ABSTRACT: TRACER FOR CD8 T-CELL TUMOR INFILTRATION
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Evaluation of novel 89Zr chelators and corresponding

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Evaluation of novel 89Zr chelators and corresponding 89Zr-labeled immunoconjugates (Conference Abstract)

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Conference Abstract: Novel 89Zr chelators and immunoconjugates

Evaluation of novel 89Zr chelators and corresponding 89Zr-labeled immunoconjugates (Conference Abstract)

Pierre Adumeau, René Raavé, Christian B. Jacobsen, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Adrien Dubois, Laurène Da Costa, Victor Goncalves, Franck Denat


EMIM 2019, Glasgow, #654. EMIM 2019 Abstracts.

Abstract

Introduction

For immunoPET with 89Zr, the current gold standard to label antibodies is desferrioxamine (DFO).1 However, preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, leading to 89Zr release and subsequent accumulation in mineral bone. This bone uptake may impede the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for more stable 89Zr chelators.

Methods

We have synthesized new octacoordinating 89Zr-bifunctional chelating agents derivated from the DFO* chelator.2 These new chelators were synthesized by coupling different hydroxamic acid-bearing arms to DFO, followed by the introduction of an isothiocyanate moiety. The model antibody trastuzumab was conjugated to the NCS-derivated chelators and DFO-pPhe-NCS as a reference, and radiolabeled with 89Zr. The stability of the radiolabeled chelators and radiolabeled conjugates were evaluated in human plasma, and in PBS in presence of EDTA or DFO. The in vitro behavior of the most promising compounds was investigated more thoroughly using HER2-experessing SK-OV3 cells, and in vivo distribution was studied in mice with subcutaneous SK-OV3 xenografts by PET/CCT imaging and ex vivo tissue analysis.

Results/Discussion

The bifunctional chelators were conjugated efficiently to trastuzumab. Radiolabeling of the conjugates with 89Zr yielded the radioconjugates with high yield, purity and specific activity (RCY >95%, RCP >99%, SA >100 MBq/mg). When challenged with EDTA or DFO, the 89Zr-chelates and the corresponding radioconjugates displayed an improved stability compared to 89Zr-DFO and 89Zr-DFO-trastuzumab, with the best results obtained for the chelator dubbed cycloDFO*. The immunoreactive fraction and IC50 were similar for 89Zr-DFO-trastuzumab and 89Zr-cycloDFO*-trastuzumab. Internalisation after 2h was significantly higher for 89Zr-cycloDFO*-trastuzumab compared to 89Zr-DFO-trastuzumab. Accumulation of 89Zr in bone was significantly lower for 89Zr-DFO-cyclo*-trastuzumab compared to 89Zr-DFO-trastuzumab in knee (3.6 ± 0.4% vs 5.9 ±0.6%), femur (2.2 ± 0.2% vs 3.4 ± 0.3%), and sternum (3.5± 0.4% vs 4.5 ±0.4%) at 72 h after injection. Uptake in the SK-OV3 tumor was similar for both antibody conjugates.

Conclusions

The new 89Zr-chelators and the associated radioconjugates show improved in vitro stability compared to DFO and 89Zr-DFO-trastuzumab. The radioconjugate derivated from the more promising chelator, 89Zr-cycloDFO*-trastuzumab, demonstrated a better in vivo stability compared to 89Zr-DFO-trastuzumab. Therefore, less radiation exposure to bone marrow and improved bone metastasis detection could be achieved using cycloDFO*.

References

1 S. Heskamp, R. Raavé, O. Boerman, M. Rijpkema, V. Goncalves, F. Denat, Bioconjugate Chem., 2017, 28, 2211-2223.

2 D. Vugts, C. Klaver, C. Sewing, A. Poot, K. Adamzek; S. Huegli, C. Mari, G. Visser, I. Valverde, G. Gasser, T. Mindt, G. van Dongen, Eur. J. Nucl. Med. Mol. Imaging, 2017, 44, 286-295

CONFERENCE ABSTRACT: NOVEL 89ZR CHELATORS AND IMMUNOCONJUGATES
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Direct comparison of the in vitro and in vivo stability

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Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89Zr-immunoPET.

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89Zr-DFO Derivative Stability

Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89Zr-immunoPET.

René Raavé, Gerwin Sandker, Pierre Adumeau, Christian Borch Jacobsen, Floriane Mangin, Michel Meyer, Mathieu Moreau, Claire Bernhard, Laurène Da Costa, Adrien Dubois, Victor Goncalves, Magnus Gustafsson, Mark Rijpkema, Otto Boerman, Jean-Claude Chambron, Sandra Heskamp, Franck Denat


European Journal of Nuclear Medicine and Molecular Imaging August 2019, Volume 46, Issue 9, pp 1966–1977 doi:10.1007/s00259-019-04343-2.

 

Abstract

 

Currently, the most commonly used chelator for labelling antibodies with 89Zr for immunoPET is desferrioxamine B (DFO). However, preclinical studies have shown that the limited in vivo stability of the 89Zr-DFO complex results in release of 89Zr, which accumulates in mineral bone. Here we report a novel chelator DFOcyclo*, a preorganized extended DFO derivative that enables octacoordination of the 89Zr radiometal. The aim was to compare the in vitro and in vivo stability of [89Zr]Zr-DFOcyclo*, [89Zr]Zr-DFO* and [89Zr]Zr-DFO.

Methods

The stability of 89Zr-labelled chelators alone and after conjugation to trastuzumab was evaluated in human plasma and PBS, and in the presence of excess EDTA or DFO. The immunoreactive fraction, IC50, and internalization rate of the conjugates were evaluated using HER2-expressing SKOV-3 cells. The in vivo distribution was investigated in mice with subcutaneous HER2+ SKOV-3 or HER2− MDA-MB-231 xenografts by PET/CT imaging and quantitative ex vivo tissue analyses 7 days after injection.

Results

89Zr-labelled DFO, DFO* and DFOcyclo* were stable in human plasma for up to 7 days. In competition with EDTA, DFO* and DFOcyclo* showed higher stability than DFO. In competition with excess DFO, DFOcyclo*-trastuzumab was significantly more stable than the corresponding DFO and DFO* conjugates (p < 0.001). Cell binding and internalization were similar for the three conjugates. In in vivo studies, HER2+ SKOV-3 tumour-bearing mice showed significantly lower bone uptake (p < 0.001) 168 h after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5 ± 0.3%ID/g, knee 2.1 ± 0.4%ID/g) or [89Zr]Zr-DFO*-trastuzumab (femur 2.0 ± 0.3%ID/g, knee 2.68 ± 0.4%ID/g) than after injection with [89Zr]Zr-DFO-trastuzumab (femur 4.5 ± 0.6%ID/g, knee 7.8 ± 0.6%ID/g). Blood levels, tumour uptake and uptake in other organs were not significantly different at 168 h after injection. HER2− MDA-MB-231 tumour-bearing mice showed significantly lower tumour uptake (p < 0.001) after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (16.2 ± 10.1%ID/g) and [89Zr]Zr-DFO-trastuzumab (19.6 ± 3.2%ID/g) than HER2+ SKOV-3 tumour-bearing mice (72.1 ± 14.6%ID/g and 93.1 ± 20.9%ID/g, respectively), while bone uptake was similar.

Conclusion

89Zr-labelled DFOcyclo* and DFOcyclo*-trastuzumab showed higher in vitro and in vivo stability than the current commonly used 89Zr-DFO-trastuzumab. DFOcyclo* is a promising candidate to become the new clinically used standard chelator for 89Zr immunoPET.

89ZR-DFO DERIVATIVE STABILITY
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