using-16-18f-fluoro-17-estradiol-pet-to-visualize-estrogen-receptor

Using 16&#945;-[18F]-Fluoro-17&#946;-Estradiol PET to Visualize Estrogen Receptor &#945; Expression in Human Breast Cancer Xenografts in Female Ovariectomized Mice

To demonstrate how estrogen receptor alpha (ER&#945;) positive breast cancer xenografts may be visualized in BALB/c nude mice using ...

Olivia Newton-John Cancer Research Institute

La Trobe University

B7-H3 is a transmembrane protein widely expressed in a variety of cancers and has been shown to play a role in anti-tumor immunity. This study aims to develop a molecular imaging probe to identify B7-H3 expression in tumors and to develop Zr-DS-5573a as a theranostic that could aid patient selection in clinical Phase I studies.  The anti-B7-H3 humanised monoclonal antibody DS-5573a was labeled with zirconium-89 (Zr-), and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen binding affinity (Scatchard analysis), and serum stability .  biodistribution and imaging studies were performed with positron emission tomography and magnetic resonance imaging (PET/MRI) studies to identify and quantitate Zr-DS-5573a tumor uptake in a B7-H3-positive breast cancer model (MDA-MB-231) and a B7-H3-negative murine colon cancer model (CT26). Imaging and biodistribution studies were also performed in MDA-MB-231 tumor-bearing SCID mice in the absence and presence of therapeutic DS-5573a antibody dose (3 mg/kg DS-5573a). Zr-DS-5573a showed high and specific binding to B7-H3-expressing MDA-MB-231 cells (immunoreactivity on day 0, 75.0 ± 2.9%), and low binding to B7-H3-negative CT26 cells (immunoreactivity on day 0, 10.85 ± 0.11%) . Zr-DS-5573a demonstrated good serum stability  with 57.2 ± 2.0% of immunoreactivity remaining on day 7.  biodistribution studies showed high uptake of Zr-DS-5573a in B7-H3-expressing MDA-MB-231 tumor-bearing mice, achieving 32.32 ± 6.55 %ID/g on day 7 post injection in BALB/c / mice and 25.76 ± 1.79 %ID/g in SCID mice, with minimal evidence of non-specific uptake in normal tissues, and excellent tumor localization on PET/MRI. In a combined imaging/therapy study, receptor saturation was demonstrated in tumors responding to therapy. Zr-DS-5573a demonstrates specific and prolonged targeting of B7-H3-expressing tumors . Saturation of binding sites was demonstrated in tumors responding to DS-5573a therapy. These results indicate that Zr-DS-5573a has potential to target B7-H3-expressing tumors in cancer patients. Furthermore Zr-DS-5573a has the potential to provide important insights into T cell biology through its specific binding to B7-H3.

Molecular imaging of T cell co-regulator factor B7-H3 with Zr-DS-5573a.

Altered lipid metabolism and subsequent changes in cellular lipid composition have been observed in prostate cancer cells, are associated with poor clinical outcome, and are promising targets for metabolic therapies. This study reports for the first time on the synthesis of a phospholipid radiotracer based on the phospholipid 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (PC44:12) to allow tracking of polyunsaturated lipid tumor uptake via PET imaging. This tracer may aid in the development of strategies to modulate response to therapies targeting lipid metabolism in prostate cancer.

Synthesis and fluorine-18 radiolabeling of a phospholipid as a PET imaging agent for prostate cancer.

Τhis study aimed to optimize the Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of Zr-Df-bintrafusp alfa and Zr-Df-control radioconjugates.

Radiolabelling and preclinical characterization of Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-βRII fusion protein bintrafusp alfa.

Tissue transglutaminase 2 (TG2) is a calcium-dependent enzyme which cross-links proteins. It is overexpressed in many diseases and plays a key role in tissue remodeling, including cell adhesion and migration. Overexpression of TG2 in breast cancer is a marker for patients at risk of recurrence. Non-invasive imaging of TG2 can therefore play an important role in patient management. TG2 probes labeled with the positron emitters C and F have thus far not found widespread application due to purity and metabolism issues. Our approach was to radiolabel a TG2 selective, 13-mer amino acid peptide, which was modified with a 5-azidopentanoic acid group at the N-terminus via a copper free click chemistry approach.

F-labeling and initial in vivo evaluation of a Hitomi peptide for imaging tissue transglutaminase 2.

Anti-ASCT2 antibody drug conjugate (ADC) MEDI7247 has been under development as a potential anti-cancer therapy for patients with selected relapsed/refractory hematological malignancies and advanced solid tumors by MedImmune. Although promising efficacy was observed in the clinic, pharmacokinetic (PK) analyses observed low exposure of MEDI7247 in phase I hematological patients. To investigate the biodistribution properties of MEDI7247, MEDI7247 and control antibodies were radiolabeled with zirconium-89 and in vitro and in vivo properties characterized.

Preclinical radiolabeling, in vivo biodistribution and positron emission tomography of a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2.

ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo.

Radiolabelling and preclinical characterisation of [Zr]Zr-Df-ATG-101 bispecific to PD-L1/4-1BB.

CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial.

Targeting of immune checkpoint regulator V-domain Ig suppressor of T-cell activation (VISTA) with Zr-labelled CI-8993.

Cachexia is a complex syndrome characterized by unintentional weight loss, progressive muscle wasting and loss of appetite. Anti-Fn14 antibody (mAb 002) targets the TWEAK receptor (Fn14) in murine models of cancer cachexia and can extend the lifespan of mice by restoring the body weight of mice. Here, we investigated glucose metabolic changes in murine models of cachexia via [F]FDG PET imaging, to explore whether Fn14 plays a role in the metabolic changes that occur during cancer cachexia.

Article	Year
Molecular imaging of T cell co-regulator factor B7-H3 with Zr-DS-5573a. Theranostics\| PubMed ID: 30128047	2018
Synthesis and fluorine-18 radiolabeling of a phospholipid as a PET imaging agent for prostate cancer. Nuclear medicine and biology\| PubMed ID: 33310350	2021
Radiolabelling and preclinical characterization of Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-βRII fusion protein bintrafusp alfa. European journal of nuclear medicine and molecular imaging\| PubMed ID: 33608805	2021
F-labeling and initial in vivo evaluation of a Hitomi peptide for imaging tissue transglutaminase 2. Nuclear medicine and biology\| PubMed ID: 36502585	2023
Preclinical radiolabeling, in vivo biodistribution and positron emission tomography of a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2. Nuclear medicine and biology\| PubMed ID: 37473513	2023
Radiolabelling and preclinical characterisation of [Zr]Zr-Df-ATG-101 bispecific to PD-L1/4-1BB. European journal of nuclear medicine and molecular imaging\| PubMed ID: 38730087	2024
Targeting of immune checkpoint regulator V-domain Ig suppressor of T-cell activation (VISTA) with Zr-labelled CI-8993. European journal of nuclear medicine and molecular imaging\| PubMed ID: 39060374	2024
Targeting Fn14 as a therapeutic target for cachexia reprograms the glycolytic pathway in tumour and brain in mice. European journal of nuclear medicine and molecular imaging\| PubMed ID: 39060375	2024
Correction to: Targeting of immune checkpoint regulator V-domain Ig suppressor of T-cell activation (VISTA) with Zr-labelled CI-8993. European journal of nuclear medicine and molecular imaging\| PubMed ID: 39186103	2024

Ingrid Julienne Georgette Burvenich

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