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Plexin d1 as a target for tumor diagnosis and therapy

a tumor and plexin technology, applied in the direction of dna/rna fragmentation, peptide/protein ingredients, depsipeptides, etc., can solve the problems of secondary tumor cell death, inhibit the growth of infiltrative cells, and the translation to clinical level has so far been less successful, so as to inhibit the migration of tumor cells and inhibit the migration of macrophages

Inactive Publication Date: 2010-05-13
STICHTING KATHOLIEKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0032]Advantageously, plexin D1 can be targeted with specific binding molecules upon intravenous administration since plexin D1 is expressed on the luminal side of endothelial cells in tumor blood vessels. Therapeutic compounds for damaging or killing tumor cells that are coupled to the binding molecule can reach the tumor from within and compounds that induce thrombosis are easily delivered to their site of action.

Problems solved by technology

Although such anti-angiogenic therapies have been effective in animal tumor models, translation to the clinical level has so far proven to be less successful (Eichhorn, M E et al., Drug Resist Update 7:125-138 (2004)).
Furthermore, patients that are candidates for anti-angiogenic therapy are typically patients with disseminated, uncontrollable cancer and growth of metastases may not always be strictly dependent on angiogenesis.
Indeed, an angiogenesis inhibitor that very effectively inhibits tumor growth in a number of subcutaneous tumor models (Wedge, S R et al., Cancer Res 62:4645-4655 (2002)) does not inhibit growth of infiltrative tumors in mouse brain.
These results imply that anti-angiogenic therapy should be supplemented by vascular targeting therapies in which the existing tumor vascular bed is attacked, resulting in secondary tumor cell death due to disruption of the tumor's blood supply.

Method used

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  • Plexin d1 as a target for tumor diagnosis and therapy
  • Plexin d1 as a target for tumor diagnosis and therapy
  • Plexin d1 as a target for tumor diagnosis and therapy

Examples

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example 1

Specific Expression of Plexin D1 on Tumor-Associated Blood Vessels

[0110]Plexin D1 is expressed on neurons but also endothelial cells in angiogenic vessels during embryogenesis. The present invention demonstrates that plexin D1 is expressed on tumor-associated blood vessels but not on normal blood vessels. This has been shown by in situ hybridization of mouse brains, containing angiogenic human melanoma lesions (FIG. 2). The animal tumor model is described in (Kusters, B et al., Cancer Res 63:5408-5413 (2003)). In short, tumor cells are injected via a microsurgical procedure in the right carotid artery, resulting in tumor growth in the parenchyma of the right brain hemisphere. After three weeks, at the onset of neurological symptoms, mice are sacrificed and brains removed and fixed in formalin.

[0111]Sections of 4μm were subjected to in situ hybridization with digoxigenin-labeled sense and antisense RNA fragments. RNA probes were generated by transcription using T3 and T7 RNA polymera...

example 2

Expression of Plexin D1 in Tumors

[0114]To investigate plexin D1 RNA expression in human tumor samples, we performed in situ hybridizations with a human-specific plexin D1 RNA probe. High plexin D1 RNA expression levels were found in a number of human tumors, of which (glioblastoma multiforme, brain metastases of sarcoma, renal cell carcinoma, adenocarcinoma of the colon and of the breast), both in tumor vasculature and tumor cells. A summary of plexin D1-expressing tumor types is given in Table 1. FIG. 3 shows some examples of in situ hybridizations, e.g. a glioblastoma, a brain metastasis of melanoma and a brain metastasis of colon carcinoma. Plexin D1 RNA was found not only on the tumor vasculature, but also excessively on the tumor cells themselves. Importantly as in FIG. 4A, no plexin D1 RNA expression is observed in normal brain vasculature. In FIG. 4B a CD31 staining is shown, demonstrating that abundant vessels are present in these sections.

example 3

Preparation of Antibodies Against Plexin D1

[0115]To detect plexin D1 protein, antibodies were selected with affinity towards plexin D1. To this end, a M13 pHENIX phage library was constructed expressing Llama single domain V-H antibodies, constructed by RT-PCR from Llama B-lymphocytes as described (van Koningsbruggen, S et al., J Immunol Methods 279:149-161 (2003)). The population of resulting cDNAs encoding V-H-single domain antibody (sdab) fragments was ligated into phagemid vector pHENIXHis8VSV (results not shown), resulting in a fusion product with a 8*His-tag and a VSV-G-tag at the C-terminus. After electroporation in E. coli TG1 cells, ampicillin-resistant colonies were collected and pooled.

[0116]The resulting library had a complexity of 8×108 clones. Eighty percent of plasmids contained full-length sdab insert as determined by PCR analysis and immunological dot-blot-detection of the VSV-G-tag in sdabs (see below). The phage library was propagated as phagemids in E. coli TG1 b...

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Abstract

The present invention relates to plexin D1 for use as a targetable protein in the treatment or diagnosis of disorders that involve expression of plexin D1. Diagnosis is suitably effected by detecting the presence of plexin D1 in the body or a bodily tissue or fluid, whereas treatment is effected by targeting plexin D1 for delivery of therapeutics to the site where treatment is needed. The invention further relates to the use of molecules that bind plexin D1, a nucleic acid encoding plexine D1 or a ligand of plexin D1 for the preparation of a therapeutical composition for the treatment or diagnosis of disorders that involve expression of plexin D1. The disorders comprise disorders in which plexin D1 is expressed on tumor cells, tumor blood vessels or activated macrophages.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the identification of a novel targetable protein that can be used in the treatment and diagnosis of tumors, in particular solid tumors, and disorders that involve inflammation, in particular rheumatoid arthritis, atherosclerosis and multiple sclerosis.BACKGROUND OF THE INVENTION[0002]To grow beyond a size of 2-3 mm3, tumors have to recruit a neovasculature via angiogenesis. Tumors accomplish this via expression of Vascular Endothelial Growth Factor-A (VEGF-A), either induced by hypoxia in the tumor centre or as a result of malfunctioning tumor suppressor gene products or activated proto-oncogenes. A number of compounds that target the VEGF-A signaling pathway has been developed with the aim to inhibit angiogenesis and, consequently, tumor growth. Although such anti-angiogenic therapies have been effective in animal tumor models, translation to the clinical level has so far proven to be less successful (Eichhorn, M E et al....

Claims

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Application Information

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IPC IPC(8): A61K51/00A61K9/127A61K39/395C12Q1/68G01N33/53A61K38/00A61K38/16A61K31/7088A01N57/00C07K14/00C07K16/00
CPCC07K14/705C07K2317/569C07K2317/22C07K16/28A61K47/6817A61K47/6849A61P25/00A61P25/28A61P29/00A61P35/00A61P37/00A61P37/08A61P9/10A61K39/39558A61K9/0019A61K51/1018
Inventor LEENDERS, WILHELMUS PETRUS JOHANNESROODINK, ILSERAATS, JOZEF MARIA HENDRIK
Owner STICHTING KATHOLIEKE UNIV
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