Site-specifically 89Zr-labeled monoclonal antibodies for ImmunoPET

Tinianow, Jeff N.; Gill, Herman; Ogasawara, Annie; Flores, Judith E.; Vanderbilt, Alexander; Luis, Elizabeth; Vandlen, Richard; Darwish, Martine; Junutula, Jagath R.; Williams, Simon-P.; Mařı́k, Jan

doi:10.1016/j.nucmedbio.2009.11.010

Cited by 99 publications

(113 citation statements)

References 30 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…The fast metabolism of mice most likely was responsible for the degradation or demetalation of 89 ZrÁDf-Fab-PAS 200 in the liver (18). Interestingly, no overt accumulation in bones was detected here, although this was previously observed with 89 ZrÁDf-trastuzumab in mice (19,20).…”

Section: Biodistribution Studiessupporting

confidence: 52%

“…Notably, maximal contrast for 89 ZrÁDf-Bz-SCN-trastuzumab in mice with HER2-positive BT474M1 xenografts was reached only 96-144 h after injection (20), in accordance with its long-lasting circulation in blood.…”

Section: Discussionmentioning

confidence: 74%

“…Besides biodistribution studies in mice (20), 89 Zr-labeled trastuzumab has already been tested in human patients with metastatic breast cancer (10), thus demonstrating potential for the noninvasive monitoring of HER2 status during cancer progression. Consequently, the clinical application of a protein tracer based on the corresponding Fab fragment should not be too difficult to achieve.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

⁸⁹Zr-Labeled Versus ¹²⁴I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo

et al. 2015

View full text Add to dashboard Cite

Immuno-PET imaging of the tumor antigen HER2/neu allows for the noninvasive detection and monitoring of oncogene expression; such detection and monitoring are of prognostic value in patients with breast cancer. Compared with the full-size antibody trastuzumab, smaller protein tracers with more rapid blood clearance permit higher imaging contrast at earlier time points. Antigen-binding fragments (Fabs) of antibodies with moderately prolonged circulation achieved through the genetic fusion with a long, conformationally disordered chain of the natural amino acids Pro, Ala, and Ser (PASylation)-a biologic alternative to chemical conjugation with polyethylene glycol, PEG-offer a promising tracer format with improved pharmacokinetics for in vivo imaging. Recently, the transition metal radionuclide 89 Zr has attracted increasing interest for immuno-PET studies, complementing the conventional halogen radionuclide 124 I. Methods: To allow direct comparison of these 2 radioactive labels for the same protein tracer, the recombinant aHER2 Fab fused with 200 Pro, Ala, and Ser (PAS 200 ) residues was either conjugated with 124 I via an iodination reagent or coupled with deferoxamine (Df) and complexed with 89 Zr. After confirmation of the stability of both radioconjugates and quality control in vitro, immuno-PET and biodistribution studies were performed with CD1-Foxn1 nu mice bearing HER2-positive human tumor xenografts. Results: 89 Zr⋅Df-Fab-PAS 200 and 124 I-Fab-PAS 200 showed specific tumor uptake of 11 and 2.3 percentage injected dose per gram 24 h after injection, respectively; both led to high tumor-to-blood (3.6 and 4.4, respectively) and tumor-to-muscle (20 and 43, respectively) ratios. With regard to off-target accumulation, overt 124 I activity was seen in the thyroid, as expected, whereas high kidney uptake was evident for 89 Zr; the latter was probably due to glomerular filtration and reabsorption of the protein tracer in proximal tubular cells. Conclusion: Both 89 Zr-and 124 I-labeled versions of aHER2 Fab-PAS 200 allowed PET tumor imaging with high contrast. With its residualizing radiometal, the tracer 89 Zr⋅Df-Fab-PAS 200 showed better in vivo stability and higher tumor uptake.

show abstract

Section: Biodistribution Studiessupporting

confidence: 52%

Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

⁸⁹Zr-Labeled Versus ¹²⁴I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo

et al. 2015

View full text Add to dashboard Cite

show abstract

“…This has been a major barrier to the adoption of many otherwise excellent fluorescent labels. Controlling the labeling sites and limiting the stoichiometry (19,20) should minimize the risk of immunogenicity and the problems of batch-to-batch heterogeneity, helping the validation of fluorescent labels in clinical and other critical settings (4). With optical and radioactive labels alike, incorporating more labels per protein [up to 10 of each in Sampath et al (21)] gives rise to a temptingly "brighter" protein with higher specific activity or fluorescent yield, but this is a siren call risking compromised behavior in vivo (4) and would require even more cautious validation.…”

Section: Topics Labeling: First Do No Harmmentioning

confidence: 99%

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

Williams¹

2012

AAPS J

View full text Add to dashboard Cite

Abstract. Molecular imaging techniques for protein therapeutics rely on reporter labels, especially radionuclides or sometimes near-infrared fluorescent moieties, which must be introduced with minimal perturbation of the protein's function in vivo and are detected non-invasively during whole-body imaging. PET is the most sensitive whole-body imaging technique available, making it possible to perform biodistribution studies in humans with as little as 1 mg of injected antibody carrying 1 mCi (37 MBq) of zirconium-89 radiolabel. Different labeling chemistries facilitate a variety of optical and radionuclide methods that offer complementary information from microscopy and autoradiography and offer some trade-offs in whole-body imaging between cost and logistic difficulty and image quality and sensitivity (how much protein needs to be injected). Interpretation of tissue uptake requires consideration of label that has been catabolized and possibly residualized. Image contrast depends as much on background signal as it does on tissue uptake, and so the choice of injected dose and scan timing guides the selection of a suitable label and helps to optimize image quality. Although only recently developed, zirconium-89 PET techniques allow for the most quantitative tomographic imaging at millimeter resolution in small animals and they translate very well into clinical use as exemplified by studies of radiolabeled antibodies, including trastuzumab in breast cancer patients, in The Netherlands.

show abstract

“…4 On the other hand, the 78.4 h half-life of Zirconium-89 is ideal for labeling intact monoclonal antibodies. 5 Future clinical applications of these tracers will require them to be produced reliably and efficiently without increasing radiation exposure to personnel. To carry out this task, a semi-automated module is under development using commercially available components.…”

Section: Introductionmentioning

confidence: 99%

Design and development of a semi-automated module for the preparation of metallic PET radionuclides

Trejo-Ballado¹,

López‐Rodríguez²,

Gaspar-Carcamo³

et al. 2012

AIP Conference Proceedings

View full text Add to dashboard Cite

Site-specifically 89Zr-labeled monoclonal antibodies for ImmunoPET

Cited by 99 publications

References 30 publications

⁸⁹Zr-Labeled Versus ¹²⁴I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo

⁸⁹Zr-Labeled Versus ¹²⁴I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

Design and development of a semi-automated module for the preparation of metallic PET radionuclides

Contact Info

Product

Resources

About

Site-specifically 89Zr-labeled monoclonal antibodies for ImmunoPET

Cited by 99 publications

References 30 publications

89Zr-Labeled Versus 124I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo

89Zr-Labeled Versus 124I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

Design and development of a semi-automated module for the preparation of metallic PET radionuclides

Contact Info

Product

Resources

About

⁸⁹Zr-Labeled Versus ¹²⁴I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo

⁸⁹Zr-Labeled Versus ¹²⁴I-Labeled αHER2 Fab with Optimized Plasma Half-Life for High-Contrast Tumor Imaging In Vivo