Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody

Jauw, Yvonne W. S.; Huisman, Marc C.; Nayak, Tapan K.; Vugts, Daniëlle J.; Christen, Randolph D.; Naegelen, Valérie Méresse; Ruettinger, Dominik; Heil, Florian; Lammertsma, Adriaan A.; Verheul, Henk M.W.; Hoekstra, Otto S.; Dongen, Guus A.M.S. van; Oordt, C. Willemien Menke-van der Houven van

doi:10.1186/s13550-018-0358-8

Cited by 12 publications

(7 citation statements)

References 18 publications

(21 reference statements)

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“…89 Zr-labeled RG7356 was therefore further injected into monkeys as a cross-reactive species and revealed remarkably high uptake in the spleen 7 . A first-in-human trial of 89 Zr-labeled RG7356 in patients with solid malignancies also demonstrated high splenic uptake that required co-injection of excess cold Ab to achieve tumor targeting 8 , 9 . These previous studies indicate that radiolabeled Abs raised against the constant domain of CD44 protein of the host species accumulate to high levels in the spleen.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, CD44 is a major marker of cancer stemness as characterized by self-renewal capacity, epithelial-mesenchymal transition, and treatment resistance 1 . CD44 thus provides an attractive target for cancer treatment 2 – 4 , and radiolabeled anti-CD44 antibodies (Abs) are being investigated for targeted imaging 5 – 9 , as well as radio-immunotherapy of solid tumors 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

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89Zr anti-CD44 immuno-PET monitors CD44 expression on splenic myeloid cells and HT29 colon cancer cells

Park

Jung

Lee

et al. 2021

Sci Rep

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CD44 is a cell-surface glycoprotein involved in cell–cell interaction, adhesion, and migration. CD44 is found on colon cancer cells and on immune cells. Previous studies of 89Zr PET imaging of CD44 have relied on an anti-human antibody (Ab), which can influence biodistribution in murine models. In this study, we used an Ab that cross-reacts with both human and mouse origin CD44 of all isoforms to unveil the type of leukocyte responsible for high splenic anti-CD44 uptake and investigate how its regulation can influence tumor immuno-PET. The Ab was site-specifically labeled with 89Zr-deferoxamine on cysteine residues. 89Zr-anti-CD44 demonstrated high-specific binding to HT29 human colon cancer cells and monocytic cells that showed CD44 expression. When 89Zr-anti-CD44 was administered to Balb/C nude mice, there was remarkably high splenic uptake but low SNU-C5 tumor uptake (1.2 ± 0.7%ID/g). Among cells isolated from Balb/C mouse spleen, there was greater CD44 expression on CD11b positive myeloid cells than lymphocytes. In cultured monocytic and macrophage cells, LPS stimulation upregulated CD44 expression and increased 89Zr-anti-CD44 binding. Similarly, normal Balb/C mice that underwent lipopolysaccharide (LPS) stimulation showed a significant upregulation of CD44 expression on splenic myeloid cells. Furthermore, LPS treatment stimulated a 2.44-fold increase of 89Zr-anti-CD44 accumulation in the spleen, which was attributable to splenic myeloid cells. Finally, in Balb/C nude mice bearing HT29 tumors, we injected 89Zr-anti-CD44 with greater Ab doses to reduce binding to splenic cells. The results showed lower spleen uptake and improved tumor uptake (2.9 ± 1.3%ID/g) with a total of 300 μg of Ab dose, and further reduction of spleen uptake and greater tumor uptake (5.7 ± 0.0%ID/g) with 700 μg Ab dose. Thus, using an 89Zr labeled Ab that cross-reacts with both human and mouse CD44, we demonstrate that CD44 immuno-PET has the capacity to monitor CD44 regulation on splenic myeloid cells and may also be useful for imaging colon tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

89Zr anti-CD44 immuno-PET monitors CD44 expression on splenic myeloid cells and HT29 colon cancer cells

Park

Jung

Lee

et al. 2021

Sci Rep

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“…In this review, we will describe in-depth some selected markers (i.e., CD20, CD38, CD146, and CD105). However, there are many other CD antigens that have shown potential as molecular imaging targets, including CD54 (known as intercellular adhesion molecule, ICAM-1), CD44, ,− CD47, − and CD138. , …”

Section: Immunopet Imaging Of Cancersmentioning

confidence: 99%

ImmunoPET: Concept, Design, and Applications

et al. 2020

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Immuno-positron emission tomography (immunoPET) is a paradigmshifting molecular imaging modality combining the superior targeting specificity of monoclonal antibody (mAb) and the inherent sensitivity of PET technique. A variety of radionuclides and mAbs have been exploited to develop immunoPET probes, which has been driven by the development and optimization of radiochemistry and conjugation strategies. In addition, tumor-targeting vectors with a short circulation time (e.g., Nanobody) or with an enhanced binding affinity (e.g., bispecific antibody) are being used to design novel immunoPET probes. Accordingly, several immunoPET probes, such as 89 Zr-Df-pertuzumab and 89 Zr-atezolizumab, have been successfully translated for clinical use. By noninvasively and dynamically revealing the expression of heterogeneous tumor antigens, immunoPET imaging is gradually changing the theranostic landscape of several types of malignancies. ImmunoPET is the method of choice for imaging specific tumor markers, immune cells, immune checkpoints, and inflammatory processes. Furthermore, the integration of immunoPET imaging in antibody drug development is of substantial significance because it provides pivotal information regarding antibody targeting abilities and distribution profiles. Herein, we present the latest immunoPET imaging strategies and their preclinical and clinical applications. We also emphasize current conjugation strategies that can be leveraged to develop next-generation immunoPET probes. Lastly, we discuss practical considerations to tune the development and translation of immunoPET imaging strategies.

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“…High expression of CD40 in healthy organs might induce a sink effect that alters the antibody kinetics and atherosclerotic plaque targeting. In certain cases, a saturation of the sink organs can improve targeting to the organs of interest [22]. To investigate this, we evaluated the effect of a higher mass dose ("high dose" of 1000 µg) on the pharmacokinetics and aorta uptake of [ 89 Zr]Zr-anti-CD40 mAb in ApoE −/− mice.…”

Section: Ex Vivo Biodistribution and Blood Kinetics Of [ 89 Zr]zr-ant...mentioning

confidence: 99%

Immuno-PET Imaging of Atherosclerotic Plaques with [89Zr]Zr-Anti-CD40 mAb—Proof of Concept

Poels

Schreurs

Jansen

et al. 2022

Biology

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Non-invasive imaging of atherosclerosis can help in the identification of vulnerable plaque lesions. CD40 is a co-stimulatory molecule present on various immune and non-immune cells in the plaques and is linked to inflammation and plaque instability. We hypothesize that a 89Zr-labeled anti-CD40 monoclonal antibody (mAb) tracer has the potential to bind to cells present in atherosclerotic lesions and that CD40 Positron Emission Tomography (PET) can contribute to the detection of vulnerable atherosclerotic plaque lesions. To study this, wild-type (WT) and ApoE−/− mice were fed a high cholesterol diet for 14 weeks to develop atherosclerosis. Mice were injected with [89Zr]Zr-anti-CD40 mAb and the aortic uptake was evaluated and quantified using PET/Computed Tomography (CT) imaging. Ex vivo biodistribution was performed post-PET imaging and the uptake in the aorta was assessed with autoradiography and compared with Oil red O staining to determine the tracer potential to detect atherosclerotic plaques. On day 3 and 7 post injection, analysis of [89Zr]Zr-anti-CD40 mAb PET/CT scans showed a more pronounced aortic signal in ApoE−/− compared to WT mice with an increased aorta-to-blood uptake ratio. Autoradiography revealed [89Zr]Zr-anti-CD40 mAb uptake in atherosclerotic plaque areas in ApoE−/− mice, while no signal was found in WT mice. Clear overlap was observed between plaque areas as identified by Oil red O staining and autoradiography signal of [89Zr]Zr-anti-CD40 mAb in ApoE−/− mice. In this proof of concept study, we showed that PET/CT with [89Zr]Zr-anti-CD40 mAb can detect atherosclerotic plaques. As CD40 is associated with plaque vulnerability, [89Zr]Zr-anti-CD40 mAb has the potential to become a tracer to detect vulnerable atherosclerotic plaques.

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Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody

Cited by 12 publications

References 18 publications

89Zr anti-CD44 immuno-PET monitors CD44 expression on splenic myeloid cells and HT29 colon cancer cells

89Zr anti-CD44 immuno-PET monitors CD44 expression on splenic myeloid cells and HT29 colon cancer cells

ImmunoPET: Concept, Design, and Applications

Immuno-PET Imaging of Atherosclerotic Plaques with [89Zr]Zr-Anti-CD40 mAb—Proof of Concept

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