Re-186-maSGS-Z(HER2:342), a potential Affibody conjugate for systemic therapy of HER2-expressing tumours

• Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z(HER2:342) has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for Tc-99m-labelling, we have found that synthetic Z(HER2:342) conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. maGGG-Z(HER2:342) and maGSG-Z(HER2:342) were labelled with Re-186 and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by Re-186-maGSG-Z(HER2:342) were studied. Gluconate-mediated labelling of maGGG-Z(HER2:342) and maGSG-Z(HER2:342) with Re-186 provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both Re-186-maGGG-Z(HER2:342) and Re-186-maGSG-Z(HER2:342) demonstrated lower renal uptake than their Tc-99m-labelled counterparts. Re-186-maGSG-Z(HER2:342) provided the lowest uptake in healthy tissues. Biodistribution of Re-186-maGSG-Z(HER2:342) in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84 +/- 0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.

Ämnesord

TEKNIK OCH TEKNOLOGIER  -- Medicinteknik -- Medicinsk laboratorie- och mätteknik (hsv//swe)

ENGINEERING AND TECHNOLOGY  -- Medical Engineering -- Medical Laboratory and Measurements Technologies (hsv//eng)

Nyckelord

Rhenium

Affibody molecules

Chelator

Mercaptoacetyl

HER2

renal-cell carcinoma

monoclonal-antibody

malignant-tumors

binding-proteins

her2 expression

nude-mice

in-vitro

molecule

tc-99m

cancer

Medical engineering

Medicinsk teknik

MEDICINE

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