N-succinimidyl 3-[211At]astato-4-guanidinomethylbenzoate: an acylation agent for labeling internalizing antibodies with α-particle emitting 211At

Vaidyanathan, Ganesan; Affleck, Donna J.; Bigner, Darell D.; Zalutsky, Michael R.

doi:10.1016/s0969-8051(03)00005-2

Cited by 45 publications

(35 citation statements)

References 20 publications

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“…4). These results are similar to results seen with the anti-EGFRvIII mAb L8A4 radioiodinated with this prosthetic group and other cell lines [41], suggesting that NZ-1 does indeed become internalized once it binds to podoplanin.…”

Section: Discussionsupporting

confidence: 87%

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas

Kato

Vaidyanathan

Kaneko

et al. 2010

Nuclear Medicine and Biology

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Introduction-Podoplanin/Aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study is to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas. Results-The dissociation constant (K D ) of NZ-1 was determined to be 1.2 × 10 -10 M by surface plasmon resonance, and 9.8 × 10 -10 M for D397MG glioblastoma cells by Scatchard analysis. Pairedlabel internalization assays in LN319 glioblastoma cells indicated that [ 131 I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3 ± 0.8% of initially bound radioactivity at 8 hr) compared to that from the 125 I-NZ-1(Iodogen) (10.0 ± 0.1% of initially bound radioactivity at 8 hr). Likewise, tumor uptake of [ 131 I]SGMIB-NZ-1 (39.9 ± 8.8%ID/g at 24 hr) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of 125 I-NZ-1(Iodogen) (29.7 ± 6.1% ID/g at 24 hr). Methods-TheConclusions-The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma.

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Section: Discussionsupporting

confidence: 87%

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas

Kato

Vaidyanathan

Kaneko

et al. 2010

Nuclear Medicine and Biology

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“…Moreover, a particularly appealing strategy would be to label this Nanobody with the 7.2-h α-particle–emitting radiohalogen 211 At via the SGMIB analog N -succinimidyl 3- 211 At-astato-4-guanidino-methylbenzoate ( 211 At-SAGMB). Using an intact anti-EGFRvIII mAb, the in vitro and in vivo targeting characteristics obtained with 131 I-SGMIB and 211 At-SAGMB labeling were nearly identical (40). …”

Section: Discussionmentioning

confidence: 99%

Improved Tumor Targeting of Anti-HER2 Nanobody Through N-Succinimidyl 4-Guanidinomethyl-3-Iodobenzoate Radiolabeling

et al. 2014

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Nanobodies are approximately 15-kDa proteins based on the smallest functional fragments of naturally occurring heavy chain–only antibodies and represent an attractive platform for the development of molecularly targeted agents for cancer diagnosis and therapy. Because the human epidermal growth factor receptor type 2 (HER2) is overexpressed in breast and ovarian carcinoma, as well as in other malignancies, HER2-specific Nanobodies may be valuable radiodiagnostics and therapeutics for these diseases. The aim of the present study was to evaluate the tumor-targeting potential of anti-HER2 5F7GGC Nanobody after radioiodination with the residualizing agent N-succinimidyl 4-guanidinomethyl 3-125/131I-iodobenzoate (*I-SGMIB). Methods The 5F7GGC Nanobody was radiolabeled using *I-SGMIBand, for comparison, withNε-(3-*I-iodobenzoyl)-Lys5-Nα-maleimido-Gly1-GEEEK (*I-IB-Mal-D-GEEEK), another residualizing agent, and by direct radioiodination using IODO-GEN (125I-Nanobody). The 3 labeled Nanobodies were evaluated in affinity measurements, and paired-label internalization assays were performed on HER2-expressing BT474M1 breast carcinoma cells and in paired-label tissue distribution measurements in mice bearing subcutaneous BT474M1 xenografts. Results *I-SGMIB-Nanobody was produced in 50.4% ± 3.6% radiochemical yield and exhibited a dissociation constant of 1.5 ± 0.5 nM. Internalization assays demonstrated that intracellular retention of radioactivity was up to 1.5-fold higher for *I-SGMIB-Nanobody than for coincubated 125I-Nanobody or *I-IB-Mal-D-GEEEK-Nanobody. Peak tumor uptake for *I-SGMIB-Nanobody was 24.50% ± 9.89% injected dose/g at 2 h, 2- to 4-fold higher than observed with other labeling methods, and was reduced by 90% with trastuzumab blocking, confirming the HER2 specificity of localization. Moreover, normal-organ clearance was fastest for *I-SGMIB-Nanobody, such that tumor–to–normal-organ ratios greater than 50:1 were reached by 24 h in all tissues except lungs and kidneys, for which the values were 10.4 ± 4.5 and 5.2 ± 1.5, respectively. Conclusion Labeling anti-HER2 Nanobody 5F7GGC with *I-SGMIB yields a promising new conjugate for targeting HER2-expressing malignancies. Further research is needed to determine the potential utility of *I-SGMIB-5F7GGC labeled with 124I, 123I, and 131I for PET and SPECT imaging and for targeted radiotherapy, respectively.

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“…Elevated uptake of 211 At has been noted in targeted a-radioimmunotherapy in several organs, for example, thyroid, lung, spleen, and stomach (20)(21)(22). As a wider mapping of the distribution of free astatide, we used whole-body sectioning in combination with a-camera imaging.…”

Section: Applications Of Imaging Systemmentioning

confidence: 99%

The α-Camera: A Quantitative Digital Autoradiography Technique Using a Charge-Coupled Device for Ex Vivo High-Resolution Bioimaging of α-Particles

2010

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Bioconjugates used in internal radiotherapy exhibit heterogeneous distributions in organs and tumors, implying a risk of nonuniform dose distribution in therapeutic applications using a-particle emitters. Tools are required that provide data on the activity distribution for estimation of absorbed dose on a suborgan level. The a-camera is a quantitative imaging technique developed to detect a-particles in tissues ex vivo. The aim of this study was to evaluate the characteristics of this imaging system and to exemplify its potential use in the development of a-radioimmunotherapy. Methods: The a-camera combines autoradiography with a scintillating technique and optical registration by a charge-coupled device (CCD). The imaging system characteristics were evaluated by measurements of linearity, uniformity, and spatial resolution. The technique was applied for quantitative imaging of 211 At activity distribution in cryosections of tumors, kidney, and whole body. Intratumoral activity distributions of tumor-specific 211 At-MX35-F(ab9) 2 were studied at various times after injection. The postinjection activity distributions in the renal cortex and whole kidneys were compared for 211 At-F(ab9) 2 and 211 At-IgG trastuzumab. Results: Quantitative analysis of a-camera images demonstrated that the pixel intensity increased linearly with activity in the imaged specimen. The spatial resolution was 35 6 11 mm (mean 6 SD) and the uniformity better than 2%. Kidney cryosections revealed a higher cortex-to-whole kidney ratio for 211 At-F(ab9) 2 than for 211 At-IgG (1.38 6 0.03 and 0.77 6 0.04, respectively) at 2 h after injection. Nonuniform intratumoral activity distributions were found for tumor-specific 211 At-MX35-F(ab9) 2 at 10 min and 7 h after injection; after 21 h, the distribution was more uniform. Conclusion: The characteristics of the a-camera are promising, suggesting that this bioimaging system can assist the development, evaluation, and refinement of future targeted radiotherapy approaches using a-emitters. The a-camera provides quantitative data on the activity distribution in tissues on a near-cellular scale and can therefore be used for small-scale dosimetry, improving the prediction of biologic outcomes with a-particles with short path length and high linear energy transfer. Promi sing results from preclinical studies (1-6) and pilot clinical trials (7,8) have increased the interest in clinical applications using a-emitting radionuclides for the treatment of cancer. The high linear energy transfer (LET) of a-particles yields a potent method of killing cancer cells. The short path length of a-particles in tissues (50-70 mm) is an advantage if the bioconjugate can be targeted specifically to tumor cells. In combination, the high LET and the short path length can make a-particle therapy an effective treatment of micrometastases and small tumors.Because of the short range of a-particles and the heterogeneous distributions of the targeting molecules, the resulting dose distributions within organs and tumor tissues can...

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N-succinimidyl 3-[211At]astato-4-guanidinomethylbenzoate: an acylation agent for labeling internalizing antibodies with α-particle emitting 211At

Cited by 45 publications

References 20 publications

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas

Improved Tumor Targeting of Anti-HER2 Nanobody Through N-Succinimidyl 4-Guanidinomethyl-3-Iodobenzoate Radiolabeling

The α-Camera: A Quantitative Digital Autoradiography Technique Using a Charge-Coupled Device for Ex Vivo High-Resolution Bioimaging of α-Particles

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