<sup>188</sup>Re-Z<sub>HER2:V2</sub>, a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment

Altai, Mohamed; Wållberg, Helena; Honarvar, Hadis; Strand, Joanna; Orlova, Anna; Varasteh, Zohreh; Sandström, Mattias; Löfblom, John; Larsson, Erik; Strand, Sven‐Erik; Lubberink, Mark; Ståhl, Stefan; Tolmachev, Vladimir

doi:10.2967/jnumed.114.140194

Cited by 24 publications

(15 citation statements)

References 33 publications

(39 reference statements)

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“…Of course, an extended study is required to assess absorbed doses in tumors and in normal tissues. The use of a GGGC peptide-based chelator for labeling of Affibody molecules with a b-emitting radionuclide, 188 Re (half-life, 17.0 h), provided a nonresidualizing radiometal label with good retention in tumors and low retention in the kidneys (26). It would be interesting to evaluate such labeling chemistry for ADAPT as well.…”

Section: Discussionmentioning

confidence: 99%

Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label

et al. 2017

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Visualization of cancer-associated alterations of molecular phenotype using radionuclide imaging is a noninvasive approach to stratifying patients for targeted therapies. The engineered albumin-binding domain-derived affinity protein (ADAPT) is a promising tracer for radionuclide molecular imaging because of its small size (6.5 kDa), which satisfies the precondition for efficient tumor penetration and rapid clearance. Previous studies demonstrated that the human epidermal growth factor receptor type 2 (HER2)-targeting ADAPT6 labeled with radiometals at the N terminus is able to image HER2 expression in xenografts a few hours after injection. The aim of this study was to evaluate whether the use of a nonresidualizing label or placement of the labels at the C terminus would further improve the targeting properties of ADAPT6. Two constructs, Cys-ADAPT6 and Cys-ADAPT6, having the (HE)DANS sequence at the N terminus were produced and site-specifically labeled using In-DOTA orI-iodo-((4-hydroxyphenyl)ethyl) maleimide (HPEM). The conjugates were compared in vitro and in vivo. HER2-targeting properties and biodistribution were evaluated in BALB/C mice bearing ovarian carcinoma cell (SKOV-3) xenografts. Specific HER2 binding and high affinity were preserved after labeling. Both Cys-ADAPT6 and Cys-ADAPT6 were internalized slowly by HER2-expressing cancer cells. Depending on the label position, uptake at 4 h after injection varied from 10% to 22% of the injected dose per gram of tumor tissue. Regardless of terminus position, the I-HPEM label provided more than 140-fold lower renal uptake than theIn-DOTA label at 4 after injection. The tumor-to-organ ratios were, in contrast, higher for both of the In-DOTA-labeled ADAPT variants in other organs. Tumor-to-blood ratios forIn-labeled Cys-ADAPT6 and Cys-ADAPT6 did not differ significantly (250-280), but In-DOTA-Cys-ADAPT6 provided significantly higher tumor-to-lung, tumor-to-liver, tumor-to-spleen, and tumor-to-muscle ratios. Radioiodinated variants had similar tumor-to-organ ratios, but I-HPEM-Cys-ADAPT6 had significantly higher tumor uptake and a higher tumor-to-kidney ratio. Residualizing properties of the label strongly influence the targeting properties of ADAPT6. The position of the radiolabel influences targeting as well, although to a lesser extent. Placement of a label at the C terminus yields the best biodistribution features for both radiometal and radiohalogen labels. Low renal retention of the radioiodine label creates a precondition for radionuclide therapy usingI-labeled HPEM-Cys-ADAPT6.

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Section: Discussionmentioning

confidence: 99%

Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label

et al. 2017

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“…However, internalization of anti-HER2 Affibody molecules is slow after binding to malignant cells but rapid in proximal tubuli. The peptidebased chelator GGGC provides nonresidualizing 188 Re labeling, thereby resulting in good tumor retention but rapid washout from kidneys (24). Extrapolation to humans suggests that the absorbed dose to tumors would exceed that to the kidney by approximately 3.4-fold.…”

Section: Affibody Molecules In Radionuclide Imagingmentioning

confidence: 99%

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

Krasniqi¹,

D’Huyvetter²,

Devoogdt³

et al. 2018

J Nucl Med

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Imaging of expression of therapeutic targets may enable stratification of patients for targeted treatments. The use of small radiolabeled probes based on the heavy-chain variable region of heavy-chain-only immunoglobulins or nonimmunoglobulin scaffolds permits rapid localization of radiotracers in tumors and rapid clearance from normal tissues. This makes high-contrast imaging possible on the day of injection. This mini review focuses on small proteins for radionuclide-based imaging that would allow same-day imaging, with the emphasis on clinical applications and promising preclinical developments within the field of oncology.

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“…Affibody molecules have been successfully labelled with radionuclides including 111 In, 99m Tc, 68 Ga, 124 I, and 18 F (26,(29)(30)(31)(32) or fluorophores (33,34) for in vivo imaging. The β-emitting nuclides, 177 Lu and 188 Re (35)(36)(37), and toxins (8,9) were conjugated to Affibody molecules for therapeutic applications. The radiolabelled anti-HER2 Affibody molecule Z HER2:2891 , showed specific tumour accumulation and high-contrast imaging in clinics (38,39).…”

Section: Introductionmentioning

confidence: 99%

Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin

Altai

Líu

Orlova

et al. 2016

International Journal of Oncology

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Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide 111In. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)3 purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, 111In-(HE)3-ZHER2-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

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¹⁸⁸Re-Z_HER2:V2, a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment

Cited by 24 publications

References 33 publications

Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label

Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin

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188Re-ZHER2:V2, a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment

Cited by 24 publications

References 33 publications

Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label

Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin

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¹⁸⁸Re-Z_HER2:V2, a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment