Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice

Cai, Weibo; Ebrahimnejad, Alireza; Chen, Kai; Cao, Qizhen; Li, Zibo; Tice, David A.; Chen, Xiaoyuan

doi:10.1007/s00259-007-0503-5

Cited by 78 publications

(86 citation statements)

References 33 publications

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“…The results for 89 Zr-Df-Bz-NCS-DS8895a were superior to those of a prior study of anti-EphA2 64 Cu-DOTA-1C1, particularly at later time points, when maximal uptake in human tumors is anticipated and when 89 Zr half-life is better suited to human trials (18). These results were comparable to uptake of other 89 Zr-labeled antibodies in animal models, including trastuzumab (Herceptin; Genentech), although expression of ErbB2 on tumor cell surfaces is much higher than that of EphA2 (19)(20)(21)(22).…”

Section: Discussionsupporting

confidence: 57%

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with ⁸⁹Zr-DS-8895a

et al. 2016

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Subtype A2 of the erythropoietin-producing hepatocellular tyrosine kinase (EphA2) cell surface receptor is expressed in a range of epithelial cancers. This study evaluated the molecular imaging of EphA2 expression in vivo in mouse tumor models using SPECT/MR and PET/MR and a humanized anti-EphA2 antibody, DS-8895a. Methods: DS-8895a was labeled with 111 In, 125 I, and 89 Zr and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen-binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution, imaging, and pharmacokinetic studies were performed with SPECT/MR and PET/MR. A dose-escalation study was also performed to determine EphA2 receptor saturability through tissue and imaging quantitative analysis. Results: All conjugates demonstrated good serum stability and specific binding to EphA2-expressing cells in vitro. In vivo biodistribution studies showed high uptake of 111 In-CHX-A″-DTPA-DS8895a and 89 Zr-Df-Bz-NCS-DS-8895a in EphA2-expressing xenograft models, with no specific uptake in normal tissues. In comparison, retention of 125 I-DS-8895a in tumors was lower because of internalization of the radioconjugate and dehalogenation. These results were confirmed by SPECT/MR and PET/MR. EphA2 receptor saturation was observed at the 30 mg/kg dose. Conclusion: Molecular imaging of tumor uptake of DS-8895a allows noninvasive measurement of EphA2 expression in tumors in vivo and determination of receptor saturation. 89 Zr-Df-Bz-NCS-DS-8895a is suited for human bioimaging trials on the basis of superior imaging characteristics and will inform DS-8895a dose assessment and patient response evaluation in clinical trials.

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Section: Discussionsupporting

confidence: 57%

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with ⁸⁹Zr-DS-8895a

et al. 2016

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“…However, mRNA levels do not always predict protein levels of EphA2 (13,36). Imaging analysis using a radiolabeled version of the highly selective antibody 1C1, which binds both human and rodent EphA2, revealed preferential distribution to tumors with no accumulation in any normal mouse or rat tissues (32). The in vivo data presented herein show that effective tumor cell killing can be achieved with 1C1-mcMMAF without any observable side effects to the animals, suggesting that targeting of the conjugate to normal mouse and rat tissues is minimal.…”

Section: Discussionmentioning

confidence: 71%

“…Previous positron emission tomography imaging studies of radiolabeled 1C1 confirmed that the antibody was accumulating in EphA2-expressing tumor xenografts, but not in normal mouse or rat organs (32). To determine if 1C1-mcMMAF penetrated the tumor and degraded EphA2 in vivo, receptor levels were monitored from tumor homogenates at various times after i.v.…”

Section: Resultsmentioning

confidence: 99%

A Human Antibody–Drug Conjugate Targeting EphA2 Inhibits Tumor GrowthIn vivo

Jackson¹,

Gooya²,

Mao³

et al. 2008

Cancer Research

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The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by EphA2 monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. In this report, we describe the isolation and characterization of a fully human monoclonal antibody (1C1) that selectively binds both the human and rodent EphA2 receptor. After cell binding, the antibody induces rapid tyrosine phosphorylation, internalization, and degradation of the EphA2 receptor. Because monoclonal antibodies that selectively bind tumor cells and internalize provide a vehicle for targeted delivery of cytotoxics, 1C1 was conjugated to the microtubule inhibitor monomethylauristatin phenylalanine using a stable maleimidocaproyl linker. The anti-EphA2 antibody-drug conjugate [1C1-maleimidocaproyl-MMAF (mcMMAF)] stimulated the activation of caspase-3/caspase-7 and the death of EphA2-expressing cells with IC 50 values as low as 3 ng/mL. Similarly, the conjugate induced degradation of the EphA2 receptor and inhibited tumor growth in vivo. Administration of 1C1-mcMMAF at doses as low as 1 mg/kg once weekly resulted in significant growth inhibition of EphA2-expressing tumors without any observable adverse effects in mouse xenograft and rat syngeneic tumor models. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of EphA2-expressing tumors. [Cancer Res 2008;68(22):9367-74]

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“…Projected radiation absorbed doses for humans were made by assuming that the metabolism rates and pharmacokinetics of 99m Tc-anti-MT1-MMP mAb in humans and rodents are equivalent, as previously reported. 15) Absorbed doses and effective dose were estimated with a standard quantitation platform Organ Level Internal Dose Assessment (OLINDA; Vanderbilt University). 16) …”

Section: Preparation Of 99mmentioning

confidence: 99%

Development of a Radiolabeled Probe for Detecting Membrane Type-1 Matrix Metalloproteinase on Malignant Tumors

Temma

Sano

Kuge

et al. 2009

Biological & Pharmaceutical Bulletin

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Membrane type-1 matrix metalloproteinase (MT1-MMP) expressed on the tumor cell surface activates pro-MMP-2 and pro-MMP-13 to exacerbate the malignancy, suggesting its suitability as a target molecule for diagnosis by in vivo molecular imaging. Thus, we prepared radiolabeled anti-MT1-MMP monoclonal antibody (mAb) as a novel radiolabeled probe for detecting MT1-MMP in vivo and evaluated its usefulness in breast tumor-bearing rodents. Tc-anti-MT1-MMP mAb was prepared using HYNIC as a bifunctional chelating agent and immunoreactivity was evaluated by flow cytometry. MT1-MMP expression in breast carcinoma cells (rat: Walker-256 and MRMT-1, mouse: FM3A) was measured by Western blotting. In vivo biodistribution was examined for 48 h using tumor-implanted rodents followed by estimation of radiation absorbed by a standard quantitation platform Organ Level Internal Dose Assessment (OLINDA).

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Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice

Abstract: The tumor uptake of (64)Cu-DOTA-1C1 measured by microPET imaging reflects tumor EphA2 expression level in vivo. This is, to our knowledge, the first report of quantitative radioimmunoPET imaging of EphA2 in living subjects. Future clinical investigation of (64)Cu-DOTA-1C1 is warranted.

Cited by 78 publications

References 33 publications

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with ⁸⁹Zr-DS-8895a

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with ⁸⁹Zr-DS-8895a

A Human Antibody–Drug Conjugate Targeting EphA2 Inhibits Tumor GrowthIn vivo

Development of a Radiolabeled Probe for Detecting Membrane Type-1 Matrix Metalloproteinase on Malignant Tumors

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Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice

Abstract: The tumor uptake of (64)Cu-DOTA-1C1 measured by microPET imaging reflects tumor EphA2 expression level in vivo. This is, to our knowledge, the first report of quantitative radioimmunoPET imaging of EphA2 in living subjects. Future clinical investigation of (64)Cu-DOTA-1C1 is warranted.

Cited by 78 publications

References 33 publications

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a

A Human Antibody–Drug Conjugate Targeting EphA2 Inhibits Tumor GrowthIn vivo

Development of a Radiolabeled Probe for Detecting Membrane Type-1 Matrix Metalloproteinase on Malignant Tumors

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Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with ⁸⁹Zr-DS-8895a

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with ⁸⁹Zr-DS-8895a