Antibody Positron Emission Tomography Imaging in Anticancer Drug Development

Lamberts, Laetitia E.; Williams, Simon P.; Scheltinga, Anton G.T. Terwisscha van; Hooge, Marjolijn N. Lub-de; Schröder, Carolien P.; Gietema, Jourik A.; Brouwers, Adrienne H.; Vries, Elisabeth G.E. de

doi:10.1200/jco.2014.57.8278

Cited by 96 publications

(100 citation statements)

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“…ImmunoPET can be used to determine target antigen expression at whole-body level and to provide information about antibody biodistribution and organ pharmacokinetics, information that is usually lacking from phase I study designs (21). Zr) is the preferred radioisotope for PET imaging of internalizing targets such as MSLN, as it residualizes in the target tissue after cellular internalization, causing increasing tumor-to-normal tissue ratios over time (22).…”

Section: Introductionmentioning

confidence: 99%

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

Lamberts

Oordt

Weele

et al. 2016

Clinical Cancer Research

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Section: Introductionmentioning

confidence: 99%

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

Lamberts

Oordt

Weele

et al. 2016

Clinical Cancer Research

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“…PET imaging is increasingly used in the development of targeting agents (13). It could provide useful information about the pharmacologic behavior and tumor-targeting properties of these agents, facilitating patient selection and the management of clinical dose-finding studies (13,28).…”

Section: Discussionmentioning

confidence: 99%

“…Molecular imaging can provide additional insight in biodistribution and tumor accumulation. Molecular imaging is currently used in drug development of monoclonal antibodies (13) and might facilitate decision making in future early clinical trials with MSB0010853. We radiolabeled MSB0010853 with 89 Zr, because the long half-life of 89 Zr (78.4 h) allows us to follow MSB0010853 in vivo and determine tumor uptake up to several days after injection.…”

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confidence: 99%

Human Epidermal Growth Factor Receptor 3–Specific Tumor Uptake and Biodistribution of⁸⁹Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging

et al. 2017

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The human epidermal growth factor receptor 3 (HER3) is an interesting target for antitumor therapy. For optimal HER3 signaling inhibition, a biparatopic Nanobody construct (MSB0010853) was developed that binds 2 different HER3 epitopes. In addition, MSB0010853 contains a third HER3 epitope that binds albumin to extend its circulation time. MSB0010853 is cross-reactive with HER3 and albumin of mouse origin. We aimed to gain insight into MSB0010853 biodistribution and tumor uptake by radiolabeling the Nanobody construct with 89 Zr. Methods: MSB0010853 was radiolabeled with 89 Zr. Dose-and time-dependent tumor uptake was studied in nude BALB/c mice bearing a subcutaneous HER3 overexpressing H441 non-small cell lung cancer xenograft. Dose-dependent biodistribution of 89 Zr-MSB0010853 was assessed ex vivo at 24 h after intravenous injection. Protein doses of 5, 10, 25, 100, and 1,000 mg were used. Time-dependent biodistribution of MSB0010853 was analyzed ex vivo at 3, 6, 24, and 96 h after intravenous administration of 25 mg of 89 Zr-MSB0010853. PET imaging and biodistribution were performed 24 h after administration of 25 mg of 89 Zr-MSB0010853 to mice bearing human H441, FaDu (high HER3 expression), or Calu-1 (no HER3 expression) tumor xenografts. Results: Radiolabeling of MSB0010853 with 89 Zr was performed with a radiochemical purity of greater than 95%. Ex vivo biodistribution showed protein dose-and time-dependent distribution of 89 Zr-MSB0010853 in all organs. Uptake of 89 Zr-MSB0010853 in H441 tumors was only time-dependent. Tumor could be visualized up to at least 96 h after injection. The highest mean SUV of 0.6 6 0.2 was observed at 24 h after injection of 25 mg of 89 Zr-MSB0010853. 89 Zr-MSB0010853 tumor uptake correlated with HER3 expression and was highest in H441 (6.2 6 1.1 percentage injected dose per gram [%ID/g]) and lowest in Calu-1 (2.3 6 0.3 %ID/g) xenografts. Conclusion: 89 Zr-MSB0010853 organ distribution and tumor uptake in mice are time-dependent, and tumor uptake correlates with HER3 expression. In contrast to tumor uptake except for kidney uptake, organ distribution of 89 Zr-MSB0010853 is protein dose-dependent for the tested doses. 89 Zr-MSB0010853 PET imaging gives insight into the in vivo behavior of MSB0010853.

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“…Clinical imaging studies generally start with determination of the optimal protein dose and time point for exploring tumor-tobackground ratios and image quality (12). Especially for dosedependent pharmacokinetics, the optimal protein dose may have to be high.…”

Section: Pharmacokinetics and Target Visualization Of Radiolabeled Mabsmentioning

confidence: 99%

Theranostics Using Antibodies and Antibody-Related Therapeutics

et al. 2017

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In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment. In addition, these drugs are relatively easy to radiolabel. Noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibodyrelated therapeutics. Molecular antibody imaging can potentially elucidate drug target expression, tracer uptake in the tumor, tumor saturation, and heterogeneity for these parameters within the tumor. These data can support drug development and may aid in patient stratification and monitoring of the treatment response. Selecting a radionuclide for theranostic purposes generally starts by matching the serum half-life of the mAb or antibody-related therapeutic and the physical half-life of the radionuclide. Furthermore, PET imaging allows better quantification than the SPECT technique. This information has increased interest in theranostics using PET radionuclides with a relatively long physical half-life, such as 89 Zr. In this review, we provide an overview of ongoing research on mAbs and antibodyrelated theranostics in preclinical and clinical oncologic settings. We identified 24 antibodies or antibody-related therapeutics labeled with PET radionuclides for theranostic purposes in patients. For this approach to become integrated in standard care, further standardization with respect to the procedures involved is required.

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Antibody Positron Emission Tomography Imaging in Anticancer Drug Development

Cited by 96 publications

References 95 publications

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

Human Epidermal Growth Factor Receptor 3–Specific Tumor Uptake and Biodistribution of⁸⁹Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging

Theranostics Using Antibodies and Antibody-Related Therapeutics

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Antibody Positron Emission Tomography Imaging in Anticancer Drug Development

Cited by 96 publications

References 95 publications

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

Human Epidermal Growth Factor Receptor 3–Specific Tumor Uptake and Biodistribution of89Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging

Theranostics Using Antibodies and Antibody-Related Therapeutics

Contact Info

Product

Resources

About

Human Epidermal Growth Factor Receptor 3–Specific Tumor Uptake and Biodistribution of⁸⁹Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging