WO2008119356A1 - The use of a type ii transmembrane protein designated fibcd1 as an endocytosis receptor of acetylated compounds - Google Patents
The use of a type ii transmembrane protein designated fibcd1 as an endocytosis receptor of acetylated compounds Download PDFInfo
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- WO2008119356A1 WO2008119356A1 PCT/DK2008/000127 DK2008000127W WO2008119356A1 WO 2008119356 A1 WO2008119356 A1 WO 2008119356A1 DK 2008000127 W DK2008000127 W DK 2008000127W WO 2008119356 A1 WO2008119356 A1 WO 2008119356A1
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- fibcd1
- acetylated
- compound
- small intestine
- transmembrane protein
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
Definitions
- FIBCD1 a type Il transmembrane protein designated FIBCD1 as an endocytosis receptor of acetylated compounds
- the present invention relates to the use of a type Il transmembrane protein designated FIBCD1 as an endocytosis receptor of acetylated compounds. More specifically the invention concerns the use of FIBCD1 in a method of transporting a compound, especially a drug, over the epithelium of the small intestine.
- a novel member of the fibrinogen domain superfamily in the form of a transmembrane protein has recently been identified and given the designation
- FIBCD1 The cDNA of FIBCD1 encodes a protein consisting of 461 amino acid residues.
- the deduced amino acid sequence predicts that FIBCD1 is a type Il transmembrane protein with a coiled coil region, a polycationic region and a C- terminal fibrinogen related domain (FReD). It is present as a complex of four FIBCD1 polypeptide chains and has been identified during a search for proteins with a homology to microfibril-associated protein 4 (MFAP4); see Schlosser, A.:
- MFAP4 microfibril-associated protein 4
- Microfibril-associated protein 4 [MF AP 4) and FRe D-1 Two members of the fibrinogen domain superfamily; ph.d. thesis, Syddansk Universitet (September
- the protein was characterised as a novel scavenger receptor involved in the inherited immune defense and/or in cell-cell or cell-extracellular matrix interactions. The initial characterization has also been disclosed in
- FIBCD1 is located in the epithelium membrane of the small intestine, more specifically on the luminal side of the enterocyte. Moreover it has been demonstrated that FIBCD1 binds to any known molecule to which an acetyl group is bound. This discovery is essential to the present invention. Brief description of the invention
- the small intestine is the site where the majority of drug substances are taken up by the body. No receptors with characteristics similar to FIBCD1 are located exactly at this site. Novel complex drug substances, such as the peptide/protein based drugs, cannot be transported passively across the small intestine wall. It would therefore be desirable to provide a method of increasing the bioavailability of complex hydrophilic drug substances by facilitating their passage through the wall of the small intestine. It has now been found that
- FIBCD1 can be used for that purpose.
- Fig. 1 illustrates the binding of the FIBCD1 ectodomain to acetylated BSA in the presence or absence of various divalent ions as well as the inhibition of said binding
- Fig. 2 illustrates the FIBCD1 -mediated endocytosis of 125 I acetylated BSA.
- FIBCD1 can be used to transport a compound, such as a drug substance, over the epithelium of the small intestine. Therefore the present invention concerns a method of transporting a compound over the epithelium of the small intestine with the aid of the FIBCD1 receptor, said method comprising:
- the compound is preferably a drug substance, but in principle it can be selected broadly from the group consisting of molecules, such as peptides and proteins, microspheres etc. It is especially preferred that the drug substance is selected among complex hydrophilic drug substances.
- the compound is a compound used for oral mucosal immunization.
- the invention is based on the idea of utilizing FIBCD1 to transport a compound over the epithelium of the small intestine.
- FIBCD1 The ability of the FIBCD1 molecule to exert a transport function is due to the fact that - unlike other receptors with characteristics similar to FIBCD1 - it is specifically located in the epithelium membrane of the small intestine.
- Highly conserved homologues of FIBCD1 are found in rat and mouse.
- a recombinant form of the extracellular part of FIBCD1 expressed in 293 cells in a mammalian expression system forms a disulfide linked homotetramer of 60 kDa polypeptides.
- Three conserved cysteines found in the proximal extracellular part of the membrane may facilitate this oligomerization.
- One potential N-linked glycosylation site is found in the FReD.
- Real-time PCR on 22 different human tissues showed the highest levels of FIBCD1 expression in testis, adrenal gland, brain, mammary gland, retina, placenta, colon and lung.
- FIBCD1 like L-ficolin (Krarup, A et ai, J. Biol. Chem. 279; 47513 (2004)), M-ficolin (Frederiksen, P.D. et ai, Scand. J. Immunol. 62; 462 (2005)) and tachylectin 5's (Gokudan, S. et ai, Proc. Natl. Acad. Sci. USA 96; 10086 (1999)), may recognize acetyl group containing substances, including acetylated carbohydrates. The acetyl group has now been shown to be sufficient for the recognition of these proteins.
- the region between the coiled coil and the FReD domain was found to be highly cationic with a very high density of arginine residues.
- This cationic region is similar to cationic regions found in scavenger receptors like SR-A, CD36 and CL-P1 , where this region binds polyanionic ligands as oxLDL, bacterial products, extracellular matrix, apoptotic cells and polyanionic polysaccharide (Platt, N. and Gordon, S., J. CHn. Invest. 108; 649 (2001); Ohtani, K. et ai, J. Biol. Chem. 276; 44222 (2001); Kunjathoor, V.V. et ai, J. Biol. Chem. 277; 49982 (2002)).
- FIBCD1 may share the acetyl group binding properties of the tachylectin 5's
- the purified FIBCD1 ectodomain bind to acetylated BSA coated microtiter plates.
- This example describes an ELISA based approach for screening of the ability of acetylated compounds to bind FIBCD1.
- Microtiter plates are coated with acetylated BSA followed by inbubation with soluble FIBCD1 and the acetylated compound.
- the amount of soluble FIBCD1 bound to the solid phase acetylated BSA is detected using a chicken anti-FIBCD1 antibody followed by incubation with an anti-chicken antibody labeled with alkaline phosphatase.
- the ligand selectivity of FIBCD1 was investigated by inhibiting the binding of the FIBCD1 ectodomain to acetylated BSA coated microtiter plates.
- N-acetylated carbohydrates but not their corresponding non-acetylated counterparts, were capable of inhibiting the binding.
- Other acetylated compounds like acetylcholine and N-acetyl alanine, could also inhibit the binding to acetylated BSA.
- Fig. 1 A-D.
- the legends to the figure are as follows: A) Binding of FIBCD1 ectodomain to acetylated BSA. B) Binding of FIBCD1 to acetylated BSA with calcium from 0-1 mM. C) Binding between FIBCD1 and acetylated BSA in the presense of various divalent ions. D) Inhibition of the binding of FIBCD1 ectodomain to acetylated BSA.
- HEK293 cell line and a CHO cell line that stably express the FIBCD1 full-length protein. These cells bind and internalize acetylated compounds, e.g. acetylated BSA, while BSA is not bound and internalized by the FIBCD1 transfected cells. Non-transfected cells do not bind acetylated compounds.
- FIBCD1 transfected cells The binding of acetylated compounds to FIBCD1 transfected cells can be inhibited by monoclonal antibodies directed against FIBCD1 and also by acetate. Any cell line transfected with FIBCD1 can be used to screen the cellular uptake and internalization of a substance that contains an acetyl group.
- FIBCD1 FIBCD1 mediated endocytosis of 125 I acetylated BSA.
- a time course for cell asscociated ( ⁇ ) and degraded ( ⁇ ) 125 I acetylated BSA in CHO/CHOFIBCD1 cells Confluent cell layers were incubated with 125 I acetylated BSA at 37°C for various time intervals. Degradation was measured as the cell-mediated increase in of TCA-soluble radioactivity in the growth medium and cell-associated was determined by counting the radioactivity of the cell lysate.
- FReD C-terminal fibrinogen related domain
Abstract
A type II transmembrane protein designated FIBCD1 is used as an endocytosis receptor of acetylated compounds. More specifically the FIBCD1 is used in a method of transporting a compound, especially a drug, over the epithelium of the small intestine. Thereby the uptake of acetylated drug compounds through the wall of the small intestine is improved. Since the small intestine is the site where the majority of drug substances are taken up by the body, the method of the invention is useful in the future administration of pharmaceuticals to humans.
Description
The use of a type Il transmembrane protein designated FIBCD1 as an endocytosis receptor of acetylated compounds
Field of the invention
The present invention relates to the use of a type Il transmembrane protein designated FIBCD1 as an endocytosis receptor of acetylated compounds. More specifically the invention concerns the use of FIBCD1 in a method of transporting a compound, especially a drug, over the epithelium of the small intestine.
Background of the invention
A novel member of the fibrinogen domain superfamily in the form of a transmembrane protein has recently been identified and given the designation
FIBCD1. The cDNA of FIBCD1 encodes a protein consisting of 461 amino acid residues. The deduced amino acid sequence predicts that FIBCD1 is a type Il transmembrane protein with a coiled coil region, a polycationic region and a C- terminal fibrinogen related domain (FReD). It is present as a complex of four FIBCD1 polypeptide chains and has been identified during a search for proteins with a homology to microfibril-associated protein 4 (MFAP4); see Schlosser, A.:
Microfibril-associated protein 4 [MF AP 4) and FRe D-1: Two members of the fibrinogen domain superfamily; ph.d. thesis, Syddansk Universitet (September
2004). Potentially the protein was characterised as a novel scavenger receptor involved in the inherited immune defense and/or in cell-cell or cell-extracellular matrix interactions. The initial characterization has also been disclosed in
Connective Tissue Research vol. 47(1), pp 39-52 (January-February 2006).
Using a specific antibody it has now been shown that FIBCD1 is located in the epithelium membrane of the small intestine, more specifically on the luminal side of the enterocyte. Moreover it has been demonstrated that FIBCD1 binds to any known molecule to which an acetyl group is bound. This discovery is essential to the present invention.
Brief description of the invention
The small intestine is the site where the majority of drug substances are taken up by the body. No receptors with characteristics similar to FIBCD1 are located exactly at this site. Novel complex drug substances, such as the peptide/protein based drugs, cannot be transported passively across the small intestine wall. It would therefore be desirable to provide a method of increasing the bioavailability of complex hydrophilic drug substances by facilitating their passage through the wall of the small intestine. It has now been found that
FIBCD1 can be used for that purpose.
Brief description of the drawings
The invention is explained in detail below with reference to the drawings, in which
Fig. 1 illustrates the binding of the FIBCD1 ectodomain to acetylated BSA in the presence or absence of various divalent ions as well as the inhibition of said binding, and
Fig. 2 illustrates the FIBCD1 -mediated endocytosis of 125I acetylated BSA.
Detailed description of the invention
It has now surprisingly been found that FIBCD1 can be used to transport a compound, such as a drug substance, over the epithelium of the small intestine. Therefore the present invention concerns a method of transporting a compound over the epithelium of the small intestine with the aid of the FIBCD1 receptor, said method comprising:
a) acetylation of the compound and
b) binding of the acetylated compound to the FIBCD1 receptor.
According to the invention the compound is preferably a drug substance, but in principle it can be selected broadly from the group consisting of molecules, such as peptides and proteins, microspheres etc. It is especially preferred that the drug substance is selected among complex hydrophilic drug substances.
In a preferred embodiment of the invention the compound is a compound used for oral mucosal immunization.
The FIBCD1 protein
As already mentioned, the invention is based on the idea of utilizing FIBCD1 to transport a compound over the epithelium of the small intestine.
The ability of the FIBCD1 molecule to exert a transport function is due to the fact that - unlike other receptors with characteristics similar to FIBCD1 - it is specifically located in the epithelium membrane of the small intestine. Highly conserved homologues of FIBCD1 are found in rat and mouse. A recombinant form of the extracellular part of FIBCD1 expressed in 293 cells in a mammalian expression system forms a disulfide linked homotetramer of 60 kDa polypeptides. Three conserved cysteines found in the proximal extracellular part of the membrane may facilitate this oligomerization. One potential N-linked glycosylation site is found in the FReD. Real-time PCR on 22 different human tissues showed the highest levels of FIBCD1 expression in testis, adrenal gland, brain, mammary gland, retina, placenta, colon and lung.
Structure based alignment suggests that FIBCD1 , like L-ficolin (Krarup, A et ai, J. Biol. Chem. 279; 47513 (2004)), M-ficolin (Frederiksen, P.D. et ai, Scand. J. Immunol. 62; 462 (2005)) and tachylectin 5's (Gokudan, S. et ai, Proc. Natl. Acad. Sci. USA 96; 10086 (1999)), may recognize acetyl group containing substances, including acetylated carbohydrates. The acetyl group has now been shown to be sufficient for the recognition of these proteins.
The region between the coiled coil and the FReD domain was found to be highly cationic with a very high density of arginine residues. This cationic region is similar to cationic regions found in scavenger receptors like SR-A, CD36 and CL-P1 , where this region binds polyanionic ligands as oxLDL, bacterial products, extracellular matrix, apoptotic cells and polyanionic polysaccharide (Platt, N. and Gordon, S., J. CHn. Invest. 108; 649 (2001); Ohtani, K. et ai, J. Biol. Chem. 276; 44222 (2001); Kunjathoor, V.V. et ai, J. Biol. Chem. 277; 49982 (2002)).
Since structure based alignment has suggested that FIBCD1 may share the acetyl group binding properties of the tachylectin 5's, it has been attempted to purify the FIBCD1 ectodomain by means of affinity chromatography on acetylated Toyopearls, essentially as described in Godukan, S. et al. (supra). It appears that the FIBCD1 ectodomain forms a tetrameric structure of approximately 250 kDa in the unreduced state. The ability of FIBCD1 to bind acetylated molecules was tested in an ELISA based approach. The purified FIBCD1 ectodomain bind to acetylated BSA coated microtiter plates.
The invention is illustrated in more details in the following examples.
Example 1
An In vitro screening assay to identify acetylated FIBCD1 ligands
This example describes an ELISA based approach for screening of the ability of acetylated compounds to bind FIBCD1. Microtiter plates are coated with acetylated BSA followed by inbubation with soluble FIBCD1 and the acetylated compound. The amount of soluble FIBCD1 bound to the solid phase acetylated BSA is detected using a chicken anti-FIBCD1 antibody followed by incubation with an anti-chicken antibody labeled with alkaline phosphatase.
More specifically, the ligand selectivity of FIBCD1 was investigated by inhibiting the binding of the FIBCD1 ectodomain to acetylated BSA coated microtiter plates. The inhibition experiments demonstrated that N-acetylated carbohydrates, but not their corresponding non-acetylated counterparts, were capable of inhibiting the binding. Other acetylated compounds, like acetylcholine and N-acetyl alanine, could also inhibit the binding to acetylated BSA. Furthermore, one of the simplest compounds containing an acetyl group, namely sodium acetate, strongly inhibited the binding, even at millimolar levels, whereas sodium propionate was non-inhibitory at a concentration of 50 mM. In addition, the interaction between FIBCD1 and acetylated BSA and the presence of FIBCD1 on the cell surface was demonstrated using fluorescent labelled acetylated BSA and FIBCD1 overexpressing CHO cells in microscopy and FACS analysis. The results appear from the following Table 1 :
Inhibitor l5o (mM) l5o relative
Sialic acid 2 1
Glucose NI
Glucosamine NI
N-acetylglucosamine 4 0.5 Mannose NI
Mannosamine NI
N-acetylmannosamine 2 1
Galactose NI
Galactosamine NI N-acetylgalactosamine 5 0.4
Alanine NI
N-acetylalanine 4 0.5
Acetylcholine 10 0.2
Acetate 3 0.7 Butyrate N.I
Propionate N.I
Table 1. I50 values of the binding between FIBCD1 and acetylated BSA. I50 calculated from inhibition curves as shown in Fig 1 B). The relative inhibitor potential ("relative") was determined by dividing the I50 of the best inhibitor with the I50 of the desired compound. Nl, not inhibitory (i.e. resulting in less than 50% inhibition at 50 mM).
The results are shown graphically in Fig. 1 (A-D). The legends to the figure are as follows:
A) Binding of FIBCD1 ectodomain to acetylated BSA. B) Binding of FIBCD1 to acetylated BSA with calcium from 0-1 mM. C) Binding between FIBCD1 and acetylated BSA in the presense of various divalent ions. D) Inhibition of the binding of FIBCD1 ectodomain to acetylated BSA.
Example 2
An in vitro screening assay to measure uptake of acetylated compounds
We have produced an HEK293 cell line and a CHO cell line that stably express the FIBCD1 full-length protein. These cells bind and internalize acetylated compounds, e.g. acetylated BSA, while BSA is not bound and internalized by the FIBCD1 transfected cells. Non-transfected cells do not bind acetylated compounds.
The binding of acetylated compounds to FIBCD1 transfected cells can be inhibited by monoclonal antibodies directed against FIBCD1 and also by acetate. Any cell line transfected with FIBCD1 can be used to screen the cellular uptake and internalization of a substance that contains an acetyl group.
More specifically, the possible internalization of FIBCD1 was demonstrated using CHO cells expressing FIBCD1 and I125 labelled acetylated BSA as ligand. The uptake of I125 labelled acetylated BSA was inhibited by GIcNAc, by unlabelled acetylated BSA and by the anti-FIBCD1 monoclonal antibody HG- HYB-12-1. The results are shown graphically in Fig. 2. The legends to the figure, which illustrates FIBCD1 mediated endocytosis of 125I acetylated BSA, are as follows:. A time course for cell asscociated (■ ) and degraded (♦) 125I acetylated BSA in CHO/CHOFIBCD1 cells. Confluent cell layers were incubated with 125I acetylated BSA at 37°C for various time intervals. Degradation was measured as the cell-mediated increase in of TCA-soluble radioactivity in the growth medium and cell-associated was determined by counting the radioactivity of the cell lysate. A) CHO cells and B) CHOFIBCD1 cells.C) Effect
of lysosomal inhibitors chloquine and leupeptin (both 100 μM) on endocytosis of acetylated BSA. Values are mean +/- 1 SD of triplicate samples. D) Inhibition of 125I acetylated BSA uptake. E) and F) Fluorescense microscopy of CHO (E) and CHO-FReD (F) after incubation with Alexa488 acetylated BSA.
Monoclonal antibodies against FIBCD1 have been produced for detection of
FIBCD1 in FACS analysis, immunohistochemistry and Western blotting, lmmunohistochemistry performed on formalin-fixed, paraffin-embedded human tissues showed FIBCD1 expression in enterocytes with a highly polarized localization to the apical surface
In order to establish the three-dimensional structure of the C-terminal fibrinogen related domain (FReD) of FIBCD1 a recombinant 25 kDa fragment of the C- terminal of FIBCD1 was produced in a Baculovirus insect expression system. The expressed FReDs were purified using an acetylated TSK column followed by ion exchange chromatography. The yield of the recombinant FReDs was estimated to be approximately 2.5 μg/ml culture supernatant. The structure has now been solved with and without acetylated ligand.
As already mentioned, no receptors are known to exist with characteristics similar to FIBCD1 , which are located in the epithelium membrane of the small intestine, more specifically on the luminal side of the enterocyte. The proposed technology according to the invention will improve the uptake of acetylated drug compounds through the wall of the small intestine. Since the small intestine is the site where the majority of drug substances are taken up by the body, the present invention has a great potential regarding the future administration of pharmaceuticals to humans.
Claims
1. A method of transporting a compound over the epithelium of the small intestine with the aid of the type Il transmembrane protein designated FIBCD1 as a receptor of acetylated compounds, said method comprising:
a) acetylation of the compound and
b) binding of the acetylated compound to the FIBCD1 receptor.
2. A method according to claim 1 , wherein the compound is selected from the group consisting of molecules, such as peptides and proteins, microspheres and the like.
3. A method according to claim 1 or 2, wherein the compound is a drug substance.
4. A method according to claim 3, wherein the compound is a compound used for oral mucosal immunization.
5. A method according to claim 3, wherein the drug substance is selected among complex hydrophilic drug substances.
6. The use of the type Il transmembrane protein designated FIBCD1 as an endocytosis receptor in a method of transporting a compound, especially a drug, over the epithelium of the small intestine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010075891A1 (en) * | 2008-12-30 | 2010-07-08 | Syddansk Universitet | Fibcd1 for the prevention and treatment of diseases |
| CN107881240A (en) * | 2017-12-27 | 2018-04-06 | 北京泱深生物信息技术有限公司 | The diagnosis and treatment mark of osteosarcoma |
| WO2021173616A1 (en) * | 2020-02-28 | 2021-09-02 | St. Jude Children's Research Hospital, Inc. | Recombinant fibcd1 and use thereof in the treatment of muscle atrophy |
Citations (1)
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| JP2681700B2 (en) * | 1989-09-29 | 1997-11-26 | ヒゲタ醤油株式会社 | Anticancer drug |
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2008
- 2008-04-03 WO PCT/DK2008/000127 patent/WO2008119356A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2681700B2 (en) * | 1989-09-29 | 1997-11-26 | ヒゲタ醤油株式会社 | Anticancer drug |
Non-Patent Citations (6)
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| "6th Pan Pacific Connective Tissue Societies Symposium", CONNECTIVE TISSUE RESEARCH, vol. 47, 2006, pages 39 - 52, XP002488194 * |
| ANDER GRONNEGAARD SCHLOSSER: "Microfibril-Associated Protein 4 (MFAP4) and FRED-1. Two Members of the Fibrinogen Domain SUperfamily", 1 March 2004, THESIS,, PAGE(S) 67PP, XP009103147 * |
| ENDO Y ET AL: "Carbohydrate-binding specificities of mouse ficolin A, a splicing variant of ficolin A and ficolin B and their complex formation with MASP-2 and sMAP", IMMUNOGENETICS, vol. 57, no. 11, December 2005 (2005-12-01), pages 837 - 844, XP002488196, ISSN: 0093-7711 * |
| GOKUDAN S ET AL: "Horseshoe crab acetyl group-recognizing lectins involved in innate immunity are structurally related to fibrinogen.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 31 AUG 1999, vol. 96, no. 18, 31 August 1999 (1999-08-31), pages 10086 - 10091, XP002488195, ISSN: 0027-8424 * |
| KRARUP ANDERS ET AL: "L-ficolin is a pattern recognition molecule specific for acetyl groups.", THE JOURNAL OF BIOLOGICAL CHEMISTRY 12 NOV 2004, vol. 279, no. 46, 12 November 2004 (2004-11-12), pages 47513 - 47519, XP002488197, ISSN: 0021-9258 * |
| ZHAO ZHAOYANG ET AL: "THE GENE FOR A HUMAN MICROFIBRIL-ASSOCIATED GLYCOPROTEIN IS COMMONLY DELETED IN SMITH-MAGENIS SYNDROME PATIENTS", HUMAN MOLECULAR GENETICS, OXFORD UNIVERSITY PRESS, SURREY, vol. 4, no. 4, 1 January 1995 (1995-01-01), pages 589 - 597, XP009075115, ISSN: 0964-6906 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010075891A1 (en) * | 2008-12-30 | 2010-07-08 | Syddansk Universitet | Fibcd1 for the prevention and treatment of diseases |
| CN107881240A (en) * | 2017-12-27 | 2018-04-06 | 北京泱深生物信息技术有限公司 | The diagnosis and treatment mark of osteosarcoma |
| CN107881240B (en) * | 2017-12-27 | 2018-10-02 | 北京泱深生物信息技术有限公司 | The diagnosis and treatment marker of osteosarcoma |
| WO2021173616A1 (en) * | 2020-02-28 | 2021-09-02 | St. Jude Children's Research Hospital, Inc. | Recombinant fibcd1 and use thereof in the treatment of muscle atrophy |
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