Identification of a Novel Prostate Tumor Target, Mindin/RG-1, for Antibody-Based Radiotherapy of Prostate Cancer

Parry, Renate; Schneider, Doug; Hudson, Debra L.; Parkes, Debbie; Xuan, Jian-Ai; Newton, Alicia; Toy, Pam; Lin, Rick Y; Harkins, Rick; Alicke, Bruno; Biroc, Sandra L.; Kretschmer, Peter J.; Halks-Miller, Meredith; Klocker, Helmut; Zhu, Ying; Larsen, Brent; Cobb, Ronald R.; Bringmann, Peter; Roth, Georg A.; Lewis, Jason S.; Dinter, Harald; Parry, Gordon

doi:10.1158/0008-5472.can-05-1203

Cited by 41 publications

(34 citation statements)

References 24 publications

(20 reference statements)

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“…In addition, Simon et al (2007) reported that B7-H4, spondin 2, and DcR3 are potential ovarian cancer markers that may improve early detection of cancer. The human spondin 2 homolog, spondin 2/RG-1, is a prostate-associated protein, and its expression is maintained in primary prostate tumors and in metastases to lymph nodes and bone tissues (Parry et al 2005). In this study, we reported that the spondin 2 protein was detected in most of the HCCs analyzed.…”

Section: Discussionmentioning

confidence: 80%

Positive regulation of spondin 2 by thyroid hormone is associated with cell migration and invasion

Liao¹,

Yeh²,

Huang³

et al. 2010

Endocrine-Related Cancer

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The thyroid hormone 3,3 0 ,5-triiodo-L-thyronine (T 3 ) regulates growth, development, and differentiation processes in animals. These activities are mediated by the nuclear thyroid hormone receptors (TRs). Microarray analyses were performed previously to study the mechanism of regulation triggered by T 3 treatment in hepatoma cell lines. The results showed that spondin 2 was regulated positively by T 3 . However, the underlying mechanism and the physiological role of T 3 in the regulation of spondin 2 are not clear. To verify the microarray results, spondin 2 was further investigated using semi-quantitative reverse transcription-PCR and western blotting. After 48 h of T 3 treatment in the HepG2-TRa1#1 cell line, spondin 2 mRNA and protein levels increased by 3.9-to 5.7-fold. Similar results were observed in thyroidectomized rats. To localize the regulatory region in spondin 2, we performed serial deletions of the promoter and chromatin immunoprecipitation assays. The T 3 response element on the spondin 2 promoter was localized in the K1104/K1034 or K984/K925 regions. To explore the effect of spondin 2 on cellular function, spondin 2 knockdown cell lines were established from Huh7 cells. Knockdown cells had higher migration ability and invasiveness compared with control cells. Conversely, spondin 2 overexpression in J7 cells led to lower migration ability and invasiveness compared with control cells. Furthermore, this study demonstrated that spondin 2 overexpression in some types of hepatocellular carcinomas is TR dependent. Together, these experimental findings suggest that spondin 2, which is regulated by T 3 , has an important role in cell invasion, cell migration, and tumor progression.

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Section: Discussionmentioning

confidence: 80%

Positive regulation of spondin 2 by thyroid hormone is associated with cell migration and invasion

Liao¹,

Yeh²,

Huang³

et al. 2010

Endocrine-Related Cancer

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“…In the context of tumor growth, spondin-2 exerts different effects depending on the cell type: in ovarian cancer, spondin-2 was overexpressed and deployed as a new serum diagnostic biomarker (169); analogously, in prostate cancer, spondin-2 was found to be overexpressed in Ͼ 80% of the prostate cancers metastatic to bone or the lymph nodes, as well as in locally recurrent tumors in androgen-unresponsive patients. Prominent antitumor effects were achieved with a single administration of radiolabeled spondin-2-antibodies to animals (170). In contrast, overexpression of spondin-2 was shown to moderate the invasiveness of hepatocellular carcinoma by attenuating cell migration (171).…”

Section: Discussionmentioning

confidence: 99%

Identification of Differentially Regulated Secretome Components During Skeletal Myogenesis

Chan

Masui

Krakovska

et al. 2011

Molecular & Cellular Proteomics

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Myogenesis is a well-characterized program of cellular differentiation that is exquisitely sensitive to the extracellular milieu. Systematic characterization of the myogenic secretome (i.e. the ensemble of secreted proteins) is, therefore, warranted for the identification of novel secretome components that regulate both the pluripotency of these progenitor mesenchymal cells, and also their commitment and passage through the differentiation program. Previously, we have successfully identified 26 secreted proteins in the mouse skeletal muscle cell line C2C12 (1). In an effort to attain a more comprehensive picture of the regulation of myogenesis by its extracellular milieu, quantitative profiling employing stable isotope labeling by amino acids in cell culture was implemented in conjunction with two parallel high throughput online reverse phase liquid chromatography-tandem mass spectrometry systems.In summary, 34 secreted proteins were quantified, 30 of which were shown to be differentially expressed during muscle development. Intriguingly, our analysis has revealed several novel up-and down-regulated secretome components that may have critical biological relevance for both the maintenance of pluripotency and the passage of cells through the differentiation program. In particular, the altered regulation of secretome components, including follistatin-like protein-1, osteoglycin, spondin-2, and cytokine-induced apoptosis inhibitor-1, along with consti-

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“…The mammalian cell expression vector pIE (Medarex), previously described to express 19G9 IgG antibody (2), was used to construct a bacterial vector for expression of the single-chain antibody 19G9 scFv by published methods (7). The resultant 19G9 scFv construct was then used to create a second bacterial vector to express the 19G9 diabody (dimeric single-chain antibody) and a mammalian vector to express the 19G9 miniantibody expression vector.…”

Section: Methodsmentioning

confidence: 99%

“…The human mindin homolog, mindin/RG-1, is a member of the mindin/F-spondin family of extracellular matrix proteins (1) and is expressed in normal human prostate and prostate tumor tissues, including androgen-independent tissue and metastases to lymph node and bone (2). The human antimindin/RG-1 mAb (19G9) IgG is a promising format for PET imaging in mindin/RG-1–expressing tumor xenografts in mice, after conjugation with [( R )-2-amino-3-(4-isothiocyanatophenyl) propyl]- trans ( S , S )-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA) and 86 Y labeling (2).…”

mentioning

confidence: 99%

“…The human antimindin/RG-1 mAb (19G9) IgG is a promising format for PET imaging in mindin/RG-1–expressing tumor xenografts in mice, after conjugation with [( R )-2-amino-3-(4-isothiocyanatophenyl) propyl]- trans ( S , S )-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA) and 86 Y labeling (2). This conjugate is efficacious in radioimmunotherapy in the same tumor model after 90 Y labeling.…”

mentioning

confidence: 99%

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In Vivo Biodistribution, PET Imaging, and Tumor Accumulation of ⁸⁶Y- and ¹¹¹In-Antimindin/RG-1, Engineered Antibody Fragments in LNCaP Tumor–Bearing Nude Mice

Schneider¹,

Heitner²,

Alicke³

et al. 2009

J Nucl Med

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To optimize in vivo tissue uptake kinetics and clearance of engineered monoclonal antibody (mAb) fragments for radiotherapeutic and radiodiagnostic applications, we compared the biodistribution and tumor localization of four 111In- and 86Y-labeled antibody formats, derived from a single antimindin/RG-1 mAb, in a prostate tumor model. The IgG, diabody, single-chain variable domain (scFv), and novel miniantibody formats, composed of the human IgE-CH4 and a modified IgG1 hinge linked to scFv domains, were compared. Methods Antibodies were first derivatized with the bifunctional chelator CHX-A″-diethylenetriamine pentaacetic acid and then bound to the radiometal to create radiolabeled immunoconjugates. Human LNCaP xenografts were grown in nude mice, and 111In- or 86Y-labeled antibodies were administered intravenously. Tissues were harvested at different times, and the level of antibody deposition was determined by measuring radioactivity. Whole-body small-animal PET of mice receiving 86Y-labeled antibodies was performed at 6 time points and colocalized with simultaneous micro-CT imaging. Results The biodistributions of 111In and 86Y antibodies were quite similar. The blood, tumor, kidney, and liver tissues contained varying levels of radioactivity. The antibody accumulation in the tumor correlated with molecular size. The IgG steadily increased with time to 24.1 percentage injected dose per gram (%ID/g) at 48 h. The miniantibody accumulated at a similar rate to reach a lower level (14.2 %ID/g) at 48 h but with a higher tumor-to-blood ratio than the IgG. Tumor accumulation of the diabody peaked at 3 h, reaching a much lower level (3.7 %ID/g). A combination of rapid clearance and lower relative affinity of the scFv precluded deposition in the tumor. Small-animal PET results correlated well with the biodistribution results, with similar tumor localization patterns. Conclusion The larger antibody formats (IgG and miniantibody) gave higher tumor uptake levels than did the smaller formats (diabody and scFv). These larger formats may be more suitable for radioimmunotherapy applications, evidenced by the preclinical efficacy previously shown by a report on the IgG format. The smaller formats were rapidly cleared from circulation, and the diabody, which accumulated in the tumor, may be more suitable for radiodiagnostic applications.

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Identification of a Novel Prostate Tumor Target, Mindin/RG-1, for Antibody-Based Radiotherapy of Prostate Cancer

Cited by 41 publications

References 24 publications

Positive regulation of spondin 2 by thyroid hormone is associated with cell migration and invasion

Positive regulation of spondin 2 by thyroid hormone is associated with cell migration and invasion

Identification of Differentially Regulated Secretome Components During Skeletal Myogenesis

In Vivo Biodistribution, PET Imaging, and Tumor Accumulation of ⁸⁶Y- and ¹¹¹In-Antimindin/RG-1, Engineered Antibody Fragments in LNCaP Tumor–Bearing Nude Mice

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Identification of a Novel Prostate Tumor Target, Mindin/RG-1, for Antibody-Based Radiotherapy of Prostate Cancer

Cited by 41 publications

References 24 publications

Positive regulation of spondin 2 by thyroid hormone is associated with cell migration and invasion

Positive regulation of spondin 2 by thyroid hormone is associated with cell migration and invasion

Identification of Differentially Regulated Secretome Components During Skeletal Myogenesis

In Vivo Biodistribution, PET Imaging, and Tumor Accumulation of 86Y- and 111In-Antimindin/RG-1, Engineered Antibody Fragments in LNCaP Tumor–Bearing Nude Mice

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In Vivo Biodistribution, PET Imaging, and Tumor Accumulation of ⁸⁶Y- and ¹¹¹In-Antimindin/RG-1, Engineered Antibody Fragments in LNCaP Tumor–Bearing Nude Mice