Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature

Halin, Cornelia; Rondini, Simona; Nilsson, Fred; Berndt, Alexander; Kosmehl, Hartwig; Zardi, Luciano; Neri, Dario

doi:10.1038/nbt0302-264

Cited by 239 publications

(219 citation statements)

References 27 publications

Supporting

Mentioning

209

Contrasting

Unclassified

Order By: Relevance

“…30 Subsequently, similar approaches have been employed to target cytotoxic or antiangiogenic proteins to tumor vasculature, including targeting tumor necrosis factor alpha and interleukin-12 to ED-B domain of fibronectin. 31,32 In addition, chemotherapeutic agents and proapoptotic peptides have been directed to tumor endothelium using short targeting peptides. 33,34 The specificity of direct targeting can be further enhanced by using vectors capable of gene delivery, where therapeutic genes can be placed also under transcriptional control.…”

Section: Discussionmentioning

confidence: 99%

Efficient infection of tumor endothelial cells by a capsid-modified adenovirus

et al. 2005

View full text Add to dashboard Cite

Targeted antiangiogenic gene therapy is an attractive approach to treat metastatic cancer. However, the relative paucity of the receptors of the commonly used adenovirus serotype 5 in endothelial cells as compared with liver cells undermines the use of this vector for targeting the endothelial cells in tumors. To overcome this problem, we analyzed the ability of a hybrid Ad5/35 virus, where the serotype 5 fiber has been replaced with the fiber from serotype 35, to target tumor vasculature. Infection of human umbilical vein endothelial cells (HUVECs) with Ad5/35 at MOI 120 infected 100% of cells. In contrast, infection with Ad5 at the same MOI infected only 10% HUVECs. Ad5/35 was even more effective in transducing human aortic endothelial cells (HAECs), as infection with Ad5/35 at MOI 3.6 was sufficient to transduce 95% of cells. Gene expression analyses demonstrated that infection of HUVECs and HAECs with Ad5/35 resulted in between 1 and 3 orders of magnitude higher gene expression than infection with Ad5. Furthermore, various liver-derived cells were less infectable with Ad5/35 than Ad5, indicating a favorable toxicity profile for this virus. In a rat colon carcinoma tumor model, Ad5 was located mainly in the liver parenchyma after hepatic artery administration. In contrast, Ad5/35 was found only in the angiogenesis-rich border region of the tumor. Double immunostaining revealed that Ad5/35 colocalized with CD31 and Flk-1 positive endothelial cells. These results indicate that Ad5/ 35 may be useful in anticancer strategies targeting tumor endothelial cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Efficient infection of tumor endothelial cells by a capsid-modified adenovirus

et al. 2005

View full text Add to dashboard Cite

show abstract

“…105 The administered IL-12 was found to activate myeloid cells by increasing the expression of Fas and cross-presentation, leading to the stimulation of tumor antigen-specific CD8 T cells and regression of established tumors 102,106 (Figure 1). More recently, the development of novel approaches that direct IL-12 activity to the tumor site focus on immunocytokines, for example, the fusion of the cytokine to an antibody that binds specifically to the tumor vasculature, 107,108 or to exposed deoxyribonucleic acid (DNA) in the necrotic core of a tumor. 109 The targeting of necrotic areas within the tumor is of special interest due to the lack of perfusion of solid tumors and subsequent cell death.…”

Section: Therapeutic Effects Of Il-12 In Preclinical Modelsmentioning

confidence: 99%

New insights into IL-12-mediated tumor suppression

et al. 2014

View full text Add to dashboard Cite

During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

show abstract

“…Several fusion proteins based on the L19 antibody have been produced and characterised (Birchler et al, 1999;Nilsson et al, 2001;Halin et al, 2002;Halin et al, 2003;Ebbinghaus et al, 2005;Fabbrini et al, 2006). Furthermore, several radiolabelled derivatives of the L19 antibody have been studied in biodistribution experiments as well as being evaluated in clinical radioimmunscintigraphy studies (Santimaria et al, 2003).…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature

Cited by 239 publications

References 27 publications

Efficient infection of tumor endothelial cells by a capsid-modified adenovirus

Efficient infection of tumor endothelial cells by a capsid-modified adenovirus

New insights into IL-12-mediated tumor suppression

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

Contact Info

Product

Resources

About