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ABSTRACT: Conference code: 88259, Export Date: 7 August 2012, Source: Scopus, Language of Original Document: English, Correspondence Address: Iqbal, U.; Institute for Biological Science (IBS), National Research Council (NRC) Canada, Ottawa, ON, Canada, References: De Schepper, A.M., Bloem, J.L., Soft tissue tumors: Grading, staging, and tissue-specific diagnosis (2007) Top Magn. Reson. Imaging, 18, pp. 431-433;
AIChE Annual Meeting, Conference Proceedings, Minneapolis, MN; 01/2011
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AIChE Annual Meeting, Conference Proceedings; 01/2011
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ABSTRACT: Insulin-like growth factor-binding protein 7 (IGFBP7) is an abundant, selective and accessible biomarker of glioblastoma multiforme (GBM) tumour vessels. In this study, an anti-IGFBP7 single-domain antibody (sdAb) was developed to target GBM vessels for molecular imaging applications.
Human GBM was modelled in mice by intracranial implantation of U87MG.EGFRvIII cells. An anti-IGFBP7 sdAb, isolated from an immune llama library by panning, was assessed in vitro for its binding affinity using surface plasmon resonance and by ex vivo immunobinding on mouse and human GBM tissue. Tumour targeting by Cy5.5-labelled anti-IGFBP7 sdAb as well as by anti-IGFBP7 sdAb conjugated to PEGylated Fe₃O₄ nanoparticles (NPs)-Cy5.5 were assessed in U87MG.EGFRvIII tumour-bearing mice in vivo using optical imaging and in brain sections using fluorescent microscopy.
Surface plasmon resonance analyses revealed a medium affinity (K(D)=40-50 nM) binding of the anti-IGFBP7 sdAb to the purified antigen. The anti-IGFBP7 sdAb also selectively bound to both mouse and human GBM vessels, but not normal brain vessels in tissue sections. In vivo, intravenously injected anti-IGFBP7 sdAb-Cy5.5 bound to GBM vessels creating high imaging signal in the intracranial tumour. Similarly, the anti-IGFBP7 sdAb-functionalised PEGylated Fe₃O₄ NP-Cy5.5 demonstrated enhanced tumour signal compared with non-targeted NPs. Fluorescent microscopy confirmed the presence of anti-IGFBP7 sdAb and anti-IGFBP7 sdAb-PEGylated Fe₃O₄ NPs selectively in GBM vessels.
Anti-IGFBP7 sdAbs are novel GBM vessel-targeting moieties suitable for molecular imaging.
British Journal of Cancer 10/2010; 103(10):1606-16. · 5.04 Impact Factor
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U Iqbal,
U. Trojahn, H Albaghdadi,
J Zhang,
M. O’Connor-McCourt,
D Stanimirovic,
B. Tomanek,
G Sutherland,
A Abulrob,
Umar Iqbal,
Ulrike Trojahn,
Homam Albaghdadi,
Jianbing Zhang,
Danica B Stanimirovic,
Abedelnasser Abulrob
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ABSTRACT: Background and purpose: The overexpression of epidermal growth factor receptor (EGFR) and its mutated variant EGFRvIII occurs in 50% of glioblastoma multiforme. We developed antibody fragments against EGFR/EGFRvIII for molecular imaging and/or therapeutic targeting applications. Experimental approach: An anti–EGFR/EGFRvIII llama single-domain antibody (EG2) and two higher valency format constructs, bivalent EG2-hFc and pentavalent V2C-EG2 sdAbs, were analysed in vitro for their binding affinities using surface plasmon resonance and cell binding studies, and in vivo using pharmacokinetic, biodistribution, optical imaging and fluorescent microscopy studies. Key results: Kinetic binding analyses by surface plasmon resonance revealed intrinsic affinities of 55 nM and 97 nM for the monovalent EG2 to immobilized extracellular domains of EGFR and EGFRvIII, respectively, and a 10- to 600-fold increases in apparent affinities for the multivalent binders, V2C-EG2 and EG2-hFc, respectively. In vivo pharmacokinetic and biodistribution studies in mice revealed plasma half-lives for EG2, V2C-EG2 and EG2-hFc of 41 min, 80 min and 12.5 h, respectively, as well as a significantly higher retention of EG2-hFc compared to the other two constructs in EGFR/EGFRvIII-expressing orthotopic brain tumours, resulting in the highest signal in the tumour region in optical imaging studies. Time domain volumetric optical imaging fusion with high-resolution micro-computed tomography of microvascular brain network confirmed EG2-hFc selective accumulation/retention in anatomically defined tumour regions. Conclusions: Single domain antibodies can be optimized for molecular imaging applications by methods that improve their apparent affinity and prolong plasma half-life and, at the same time, preserve their ability to penetrate tumour parenchyma. yes yes
British Journal of Pharmacology 06/2010; · 4.41 Impact Factor
