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Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.

ABSTRACT: PURPOSE:ABY-029, a synthetic Affibody peptide, Z03115-Cys, labeled with a near-infrared fluorophore, IRDye® 800CW, targeting epidermal growth factor receptor (EGFR) has been produced under good manufacturing practices for a US Food and Drug Administration-approved first-in-use human study during surgical resection of glioma, as well as other tumors. Here, the pharmacology, phototoxicity, receptor activity, and biodistribution studies of ABY-029 were completed in rats, prior to the intended human use. PROCEDURES:Male and female Sprague Dawley rats were administered a single intravenous dose of varying concentrations (0, 245, 2449, and 24,490 ?g/kg corresponding to 10×, 100×, and 1000× an equivalent human microdose level) of ABY-029 and observed for up to 14 days. Histopathological assessment of organs and tissues, clinical chemistry, and hematology were performed. In addition, pharmacokinetic clearance and biodistribution of ABY-029 were studied in subgroups of the animals. Phototoxicity and ABY-029 binding to human and rat EGFR were assessed in cell culture and on immobilized receptors, respectively. RESULTS:Histopathological assessment and hematological and clinical chemistry analysis demonstrated that single-dose ABY-029 produced no pathological evidence of toxicity at any dose level. No phototoxicity was observed in EGFR-positive and EGFR-negative glioma cell lines. Binding strength and pharmacokinetics of the anti-EGFR Affibody molecules were retained after labeling with the dye. CONCLUSION:Based on the successful safety profile of ABY-029, the 1000× human microdose 24.5 mg/kg was identified as the no observed adverse effect level following intravenous administration. Conserved binding strength and no observed light toxicity also demonstrated ABY-029 safety for human use.

SUBMITTER: Samkoe KS

PROVIDER: S-EPMC5648591 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.

Samkoe Kimberley S KS Gunn Jason R JR Marra Kayla K Hull Sally M SM Moodie Karen L KL Feldwisch Joachim J Strong Theresa V TV Draney Daniel R DR Hoopes P Jack PJ Roberts David W DW Paulsen Keith K Pogue Brian W BW

Molecular imaging and biology 20170801 4

<h4>Purpose</h4>ABY-029, a synthetic Affibody peptide, Z03115-Cys, labeled with a near-infrared fluorophore, IRDye® 800CW, targeting epidermal growth factor receptor (EGFR) has been produced under good manufacturing practices for a US Food and Drug Administration-approved first-in-use human study during surgical resection of glioma, as well as other tumors. Here, the pharmacology, phototoxicity, receptor activity, and biodistribution studies of ABY-029 were completed in rats, prior to the intend ...[more]

PMID: 27909986

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Project description:BACKGROUND:High expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with 68Ga-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between 68Ga-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of 68Ga-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs. METHODS:Dynamic 68Ga-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K1) and irreversible binding (Ki) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to Ki. RESULTS:Characterization of HER2 expression in smaller liver metastases was improved using parametric images. Ki values from parametric images agreed very well with VOI-based gold standard (R2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with Ki values from both the two-tissue compartment model and Patlak method (R2 = 0.87 and 0.95, both p < 0.001). 68Ga-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%). CONCLUSION:68Ga-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein Ki highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.

Project description:UnlabelledEpidermal growth factor receptor (EGFR) is often overexpressed in a variety of human cancers, and its expression is associated with poor prognosis for many cancer types. However, an accurate technique to noninvasively image EGFR expression in vivo is not available in the clinical setting. In this research, an Affibody analog, anti-EGFR Ac-Cys-Z(EGFR:1907), was successfully site-specifically (18)F-labeled for PET of EGFR expression.MethodsThe prosthetic group N-[2-(4-(18)F-fluorobenzamido) ethyl] maleimide ((18)F-FBEM) was conjugated to Ac-Cys-Z(EGFR:1907) under mild conditions (pH 7) to produce the probe (18)F-FBEM-Cys-Z(EGFR:1907). The binding affinity and specificity tests of (18)F-FBEM-Cys-Z(EGFR:1907) to EGFR were conducted using A431 cancer cells. Small-animal PET and biodistribution studies were conducted on various mice tumor xenograft models with EGFR overexpression (6 types) after injection of approximately 2.0 MBq of (18)F-FBEM-Cys-Z(EGFR:1907) with or without coinjection of unlabeled Ac-Cys-Z(EGFR:1907) for up to 3 h after injection. A correlation study between (18)F-FBEM-Cys-Z(EGFR:1907) small- animal PET quantification and ex vivo Western blot analysis of tumor EGFR expression was conducted in those 6 types of tumor models.Results(18)F-FBEM-Cys-Z(EGFR:1907) binds to EGFR with low nanomolar affinity (37 nM) in A431 cells. (18)F-FBEM-Cys-Z(EGFR:1907) rapidly accumulated in the tumor and cleared from most of the normal organs except the liver and kidneys at 3 h after injection, allowing excellent tumor-to-normal tissue contrast to be obtained. In the A431 tumor xenograft model, coinjection of the PET probe with 45 μg of Ac-Cys-Z(EGFR:1907) was able to improve the tumor uptake (3.9 vs. 8.1 percentage of the injected radioactive dose per gram of tissue, at 3 h after injection) and tumor imaging contrast, whereas coinjection with 500 μg of Ac-Cys-Z(EGFR:1907) successfully blocked the tumor uptake significantly (8.1 vs. 1.0 percentage of the injected radioactive dose per gram of tissue, at 3 h after injection, 88% inhibition, P < 0.05). Moderate correlation was found between the tumor tracer uptake at 3 h after injection quantified by PET and EGFR expression levels measured by Western blot assay (P = 0.007, R = 0.59).Conclusion(18)F-FBEM-Cys-Z(EGFR:1907) is a novel protein scaffold-based PET probe for imaging EGFR overexpression of tumors, and its ability to differentiate tumors with high and low EGFR expression in vivo holds promise for future clinical translation.

Dataset Information

Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.

Publications

Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.

Similar Datasets

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