Evaluation of backbone-cyclized HER2-binding 2-helix Affibody molecule for In Vivo molecular imaging

Honarvar, Hadis; Jokilaakso, Nima; Andersson, Karl; Malmberg, Jennie; Rosik, Daniel; Orlova, Anna; Karlström, Amelie Eriksson; Tolmachev, Vladimir; Järver, Peter

doi:10.1016/j.nucmedbio.2012.12.009

Cited by 14 publications

(22 citation statements)

References 46 publications

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“…First, anti-C5b-9 is a biological macromolecule with a large molecular weight, complex structure and immunogenicity and may not be appropriate for use in humans. Recent reports [26,27] have shown that an affibody may be a potential substitute in future studies because affibodies are functionally similar to antibodies but display certain advantages, including a small molecular weight, weak immunogenicity, strong tissue penetration and high affinity. Due to the higher affinity towards specific molecular targets than peptides and smaller size compared to antibodies, affibody molecules are attractive candidates as a promising platform for targeting imaging and therapy applications [28,29,30].…”

Section: Discussionmentioning

confidence: 99%

C5b-9-Targeted Molecular MR Imaging in Rats with Heymann Nephritis: A New Approach in the Evaluation of Nephrotic Syndrome

Huang

Wang

et al. 2015

PLoS ONE

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Membranous nephropathy (MN) is the major cause of adult nephrotic syndrome, which severely affects patients’ quality of life. Currently, percutaneous renal biopsy is required to definitively diagnose MN. However, this technique is invasive and may cause severe complications. Therefore, an urgent clinical need exists for dynamic noninvasive monitoring of the renal state. In-depth molecular imaging studies could assist in finding a solution. Membrane attack complex C5b-9 is the key factor in the development of MN, and this protein primarily deposits in the glomerulus. The present study bound polyclonal antibodies to C5b-9 with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to obtain C5b-9-targeted magnetic resonance molecular imaging probes. The probes were injected intravenously into rats with Heymann nephritis, a classic disease model of MN. The signal intensity in the T2*-weighted imaging of kidneys in vivo using 7.0 Tesla magnetic resonance imaging decreased significantly 24 hours after injection compared to the untargeted and control groups. This signal change was consistent with the finding of nanoparticle deposits in pathological glomeruli. This study demonstrated a novel molecular imaging technique for the assessment of MN.

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Section: Discussionmentioning

confidence: 99%

C5b-9-Targeted Molecular MR Imaging in Rats with Heymann Nephritis: A New Approach in the Evaluation of Nephrotic Syndrome

Huang

Wang

et al. 2015

PLoS ONE

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“…Euthanasia was performed under Ropmpun/Ketalar anesthesia, and all efforts were made to minimize suffering. 68 Ga and 111 In labeled conjugates were compared using a dual label study was performed to improve the statistical power and to minimize the number of tumor-bearing animals, as it was described by Honarvar and co-workers [29].…”

Section: Methodsmentioning

confidence: 99%

Influence of Macrocyclic Chelators on the Targeting Properties of 68Ga-Labeled Synthetic Affibody Molecules: Comparison with 111In-Labeled Counterparts

et al. 2013

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Affibody molecules are a class of small (7 kDa) non-immunoglobulin scaffold-based affinity proteins, which have demonstrated substantial potential as probes for radionuclide molecular imaging. The use of positron emission tomography (PET) would further increase the resolution and quantification accuracy of Affibody-based imaging. The rapid in vivo kinetics of Affibody molecules permit the use of the generator-produced radionuclide 68Ga (T1/2 = 67.6 min). Earlier studies have demonstrated that the chemical nature of chelators has a substantial influence on the biodistribution properties of Affibody molecules. To determine an optimal labeling approach, the macrocyclic chelators 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1-(1,3-carboxypropyl)-1,4,7- triazacyclononane-4,7-diacetic acid (NODAGA) were conjugated to the N-terminus of the synthetic Affibody molecule ZHER2:S1 targeting HER2. Affibody molecules were labeled with 68Ga, and their binding specificity and cellular processing were evaluated. The biodistribution of 68Ga-DOTA-ZHER2:S1, 68Ga-NOTA-ZHER2:S1 and 68Ga-NODAGA-ZHER2:S1, as well as that of their 111In-labeled counterparts, was evaluated in BALB/C nu/nu mice bearing HER2-expressing SKOV3 xenografts. The tumor uptake for 68Ga-DOTA-ZHER2:S1 (17.9±0.7%IA/g) was significantly higher than for both 68Ga-NODAGA-ZHER2:S1 (16.13±0.67%IA/g) and 68Ga-NOTA-ZHER2:S1 (13±3%IA/g) at 2 h after injection. 68Ga-NODAGA-ZHER2:S1 had the highest tumor-to-blood ratio (60±10) in comparison with both 68Ga-DOTA-ZHER2:S1 (28±4) and 68Ga-NOTA-ZHER2:S1 (42±11). The tumor-to-liver ratio was also higher for 68Ga-NODAGA-ZHER2:S1 (7±2) than the DOTA and NOTA conjugates (5.5±0.6 vs.3.3±0.6). The influence of chelator on the biodistribution and targeting properties was less pronounced for 68Ga than for 111In. The results of this study demonstrate that macrocyclic chelators conjugated to the N-terminus have a substantial influence on the biodistribution of HER2-targeting Affibody molecules labeled with 68Ga.This can be utilized to enhance the imaging contrast of PET imaging using Affibody molecules and improve the sensitivity of molecular imaging. The study demonstrated an appreciable difference of chelator influence for 68Ga and 111In.

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Section: Protein-based Molecular Imaging Agentsmentioning

confidence: 99%

“…The resulting destabilization was partially compensated by stabilizing mutations and disulfide bonding [21,22]. The two-helix affibody has only been able to achieve low nanomolar affinity to date [21]. The two-helix affibody has been applied to molecular imaging in HER2-expressing tumor xenograft models successfully when labeled with 68 Ga [23], 18 F [24], and 111 In [25].…”

Section: Protein-based Molecular Imaging Agentsmentioning

confidence: 99%

Alternative non-antibody protein scaffolds for molecular imaging of cancer

Stern

Case

Hackel

2013

Current Opinion in Chemical Engineering

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The development of improved methods for early detection and characterization of cancer presents a major clinical challenge. One approach that has shown excellent potential in preclinical and clinical evaluation is molecular imaging with small-scaffold, non-antibody based, engineered proteins. These novel diagnostic agents produce high contrast images due to their fast clearance from the bloodstream and healthy tissues, can be evolved to bind a multitude of cancer biomarkers, and are easily functionalized by site-specific bioconjugation methods. Several small protein scaffolds have been verified for in vivo molecular imaging including affibodies and their two-helix variants, knottins, fibronectins, DARPins, and several natural ligands. Further, the biodistribution of these engineered ligands can be optimized through rational mutation of the conserved regions, careful selection and placement of chelator, and modification of molecular size.

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Evaluation of backbone-cyclized HER2-binding 2-helix Affibody molecule for In Vivo molecular imaging

Abstract: Evaluation of backbone-cyclized HER2-binding 2-helix Affibody molecule for In Vivo molecular imaging. Nuclear Medicine and Biology

Cited by 14 publications

References 46 publications

C5b-9-Targeted Molecular MR Imaging in Rats with Heymann Nephritis: A New Approach in the Evaluation of Nephrotic Syndrome

C5b-9-Targeted Molecular MR Imaging in Rats with Heymann Nephritis: A New Approach in the Evaluation of Nephrotic Syndrome

Influence of Macrocyclic Chelators on the Targeting Properties of 68Ga-Labeled Synthetic Affibody Molecules: Comparison with 111In-Labeled Counterparts

Alternative non-antibody protein scaffolds for molecular imaging of cancer

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