Selective targeting of tumour neovasculature by a radiohalogenated human antibody fragment specific for the ED-B domain of fibronectin

Demartis, Salvatore; Tarli, Lorenzo; Borsi, Laura; Zardi, Luciano; Neri, Dario

doi:10.1007/s002590100480

Cited by 88 publications

(54 citation statements)

References 15 publications

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“…These antibodies display comparable in vivo biodistribution results and can target a broad variety of tumours. However, their uptake within the solid tumour mass is confined to the subendothelial extracellular matrix (Demartis et al, 2001;Borsi et al, 2002;El-Emir et al, 2007b;Villa et al, 2008). The human anti-CA IX antibodies appear to target a similarly broad spectrum of cancers, yet with a four-times lower tumour uptake and a broader tissue distribution within the lesion.…”

Section: Discussionmentioning

confidence: 99%

Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours

et al. 2009

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BACKGROUND: Hypoxia, which is commonly observed in areas of primary tumours and of metastases, influences response to treatment. However, its characterisation has so far mainly been restricted to the ex vivo analysis of tumour sections using monoclonal antibodies specific to carbonic anhydrase IX (CA IX) or by pimonidazole staining, after the intravenous administration of this 2-nitroimidazole compound in experimental animal models. METHODS: In this study, we describe the generation of high-affinity human monoclonal antibodies (A3 and CC7) specific to human CA IX, using phage technology. RESULTS: These antibodies were able to stain CA IX ex vivo and to target the cognate antigen in vivo. In one of the two animal models of colorectal cancer studied (LS174T), CA IX imaging closely matched pimonidazole staining, with a preferential staining of tumour areas characterised by little vascularity and low perfusion. In contrast, in a second animal model (SW1222), distinct staining patterns were observed for pimonidazole and CA IX targeting. We observed a complementary pattern of tumour regions targeted in vivo by the clinical-stage vascular-targeting antibody L19 and the anti-CA IX antibody A3, indicating that a homogenous pattern of in vivo tumour targeting could be achieved by a combination of the two antibodies. CONCLUSION: The new human anti-CA IX antibodies are expected to be non-immunogenic in patients with cancer and may serve as broadly applicable reagents for the non-invasive imaging of hypoxia and for pharmacodelivery applications.

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Section: Discussionmentioning

confidence: 99%

Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours

et al. 2009

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“…2) and quantitative biodistribution analysis with radiolabeled protein preparations. 59,[61][62][63] Such studies allowed the comparison of different antibody formats, like the scFv fragment (both monomer and noncovalent homodimer) and larger homobivalent formats, such as miniantibody (or ''SIP'') and full IgG.…”

Section: Tumor Targeting With L19 Antibody Derivativesmentioning

confidence: 99%

Fibronectin as target for tumor therapy

2005

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During cancer progression, the extracellular matrix (ECM) of the tissue in which the tumor grows is extensively remodeled, both by degradation of preexisting ECM molecules and by the neosynthesis of ECM components, which in many cases are not present in the ECM of normal tissues. Fibronectin (FN), a class of highmolecular-weight adhesive glycoproteins, plays a prominent role in mediating ECM function, because of its high abundance and its interaction with cellular components. Furthermore, the generation of tumor-associated FN isoforms allows the development of specific ligands (e.g., antibodies), which can be used for the selective delivery of therapeutic agents to the tumor environment. In view of these considerations, it is not surprising that FN is being used as a target for biomolecular intervention, both for the development of inhibitory molecules that block the interaction of FN with integrins and other receptors on the cell surface, and for the development of ligand-based targeted imaging and therapeutic strategies. In this review, we briefly present the essential properties of FN, and we then focus on the therapeutic strategies that are currently in preclinical or clinical development and feature FN as a target, or that are based on FN fragments so as to promote tumor-growth inhibition. ' 2005 Wiley-Liss, Inc.Key words: fibronectin; ECM; angiogenesis; EDB; vascular tumor targeting Tumor-associated extracellular matrix components Neoplastic cells are obviously the most important component of solid tumors, and it is not surprising that most efforts in cancer research focus on the characterization of the properties of tumor cells and of their molecules. However, the role of the tumor stroma (and in particular of its extracellular matrix (ECM) components) is becoming increasingly recognized as an important determinant for the growth and progression of solid tumors.1,2 The extensive remodeling of the normal ECM in tumors proceeds through 2 main processes: (i) degradation of preexisting ECM molecules by a number of hydrolytic enzymes (e.g., proteases) that are produced, activated and/or induced by neoplastic cells, and (ii) neosynthesis of ECM components, which in many cases, are not present (or present at low concentration) in the normal tissues. This tumor ECM may generate a more suitable and possibly more permissive and/or instructive environment for tumor growth and progression. Furthermore, tumor-associated ECM components, which may be produced by tumor cells, stromal cells and/or endothelial cells, often represent ideal targets for biomolecular intervention, as will be illustrated in this review. ECM tumor antigens are in general more abundant and possibly more stable than tumor-associated antigens of the tumor cell surface, thus facilitating tumor imaging and targeted therapeutic applications.Among the most abundant ECM components (such as collagens, tenascins, proteoglycans, glycosaminoglycans and laminin), 1 fibronectins (FNs) play a special role both in terms of their functional properties and becau...

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“…However, it is overexpressed during active tissue remodelling, for example, angiogenesis in tumours, wound healing and embryogenesis Kaspar et al, 2006). It has been shown to accumulate specifically around neovasculature in studies of many different tumour types, making it a good marker for angiogenesis (Carnemolla et al, 1989;Kaczmarek et al, 1994;Neri et al, 1997;Kosmehl et al, 1999;Tarli et al, 1999;Viti et al, 1999;Demartis et al, 2001;Castellani et al, 2002;Birchler et al, 2003;Ebbinghaus et al, 2004).…”

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confidence: 99%

Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models

et al. 2007

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Angiogenesis is a characteristic feature of tumours and other disorders. The human monoclonal antibody L19-SIP targets the extra domain B of fibronectin, a marker of angiogenesis expressed in a range of tumours. The aim of this study was to investigate whole body distribution, tumour localisation and the potential of radioimmunotherapy with the L19-small immunoprotein (SIP) in colorectal tumours. Two colorectal tumour models with highly different morphologies, the SW1222 and LS174T xenografts, were used in this study. Localisation and retention of the L19-SIP antibody at tumour vessels was demonstrated using immunohistochemistry and Cy3-labelled L19-SIP. Whole body biodistribution studies in both tumour models were carried out with 125 I-labelled L19-SIP. Finally, 131 I-labelled antibody was used to investigate the potential of radioimmunotherapy in SW1222 tumours. Using immunohistochemistry, we confirmed extra domain B expression in the tumour vasculature. Immunofluorescence demonstrated localisation and retention of injected Cy3-labelled L19-SIP at the abluminal side of tumour vessels. Biodistribution studies using a 125 I-labelled antibody showed selective tumour uptake in both models. Higher recorded values for localisation were found in the SW1222 tumours than in the LS174T (7.9 vs 6.6 %ID g À1 ), with comparable blood clearance for both models. Based on these results, a radioimmunotherapy study was performed in the SW1222 xenograft using 131 I-Labelled L19-SIP (55.5 MBq), which showed selective tumour uptake, tumour growth inhibition and improved survival. Radio-and fluorescence-labelled L19-SIP showed selective localisation and retention at vessels of two colorectal xenografts. Furthermore, 131 I-L19-SIP shows potential as a novel treatment of colorectal tumours, and provides the foundation to investigate combined therapies in the same tumour models.

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Selective targeting of tumour neovasculature by a radiohalogenated human antibody fragment specific for the ED-B domain of fibronectin

Cited by 88 publications

References 15 publications

Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours

Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours

Fibronectin as target for tumor therapy

Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models

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