CA3011824A1 - Endothelin-1 receptor based endothelin-1 sponge - Google Patents
Endothelin-1 receptor based endothelin-1 sponge Download PDFInfo
- Publication number
- CA3011824A1 CA3011824A1 CA3011824A CA3011824A CA3011824A1 CA 3011824 A1 CA3011824 A1 CA 3011824A1 CA 3011824 A CA3011824 A CA 3011824A CA 3011824 A CA3011824 A CA 3011824A CA 3011824 A1 CA3011824 A1 CA 3011824A1
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- Prior art keywords
- endothelin
- fusion polypeptide
- polypeptide
- binding
- nucleic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
- C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2318/00—Antibody mimetics or scaffolds
- C07K2318/10—Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Fusion polypeptides capable of binding endothelin-1 to form a non-functional complex are provided, including amino acid sequences of the fusion polypeptides. The fusion polypeptides will be linked to the Fc portion of human IgG1 to form dimers that will function as endothelin-1 antagonists (endothelin-1 sponge).
Description
DESCRIPTION OF THE INVENTION
Background:
Endothelin-1 is a vasoactive peptide synthesized and secreted by a diverse range of cells, and thus implicated in signalling events in a wide variety of target tissues (Nelson et al. 2003). Endothelin-1 plays a key role in physiological functions.
However, under elevated levels, endothelin-1 induces pathology and as such is implicated in a host of different diseases, including neurodegenerative disorders, cardiovascular diseases, as well as pregnancy disorders like preeclampsia (Jain 2013, Jain et al. 2012). Given that a key feature of these diseases is elevated endothelin-1 levels, one proposed strategy of therapeutic intervention is targeting the increased levels of endothelin-1, To this end, fusion polypeptides capable of binding endothelin-1 to form a non-functional complex would serve as endothelin-1 antagonists. The construction of these endothelin-1 antagonists, termed endothelin-1 sponge, would require fusing the endothelin-1 receptor(s) ligand-binding domains to the Fc portion of human IgGl.
Endothelin-1 exerts its effects by binding to the endothelin A (ETA) and endothelin B
(ETB) receptors, two highly homologous cell-surface proteins that belong to the G-protein- coupled receptor superfamily (Karet and Davenport 1994). The two receptors share about 60% similarity in the primary structure (Nelson et al.
2003), i.e.
both receptors exhibit a high polypeptide sequence identity with each other.
Nevertheless, the two receptors show a clear distinction in ligand binding selectivity based on their ligand-binding domains.
Endothelin-1 binding to the ETA receptor:
Endothelin-1 binding to the ETA receptor is thought to require the ETA
receptor N-terminus loop, extracellular loop 1 (ECL1), extracellular loop 2 (ECL2), intracellular loop 3 (ICL3), extracellular loop 3 (ECL3) and the C-terminal domain (Adachi et al.
1993). Amino acid sequences of these ETA receptor ligand-binding domains are given in Figure 1.
A 5 amino acid sequence (140 ¨ Lys Leu Leu Ala Gly ¨ 144) in ECL1 has been implicated as the most important element required for ligand binding. In addition, both ECL2 and ECL3, including the flanking transmembrane regions, were found to play an important role in ligand selection.
Orry et al. (2000) also constructed a model of interaction of the ET-1 peptide with the ETA receptor, where ET-1 makes contacts with both the N-terminal receptor domain and 2 different extracellular loops.
Further, the C-terminal 8 amino acid residues located in close proximity to the seventh transmembrane region and the C-terminal 16 amino acid residues in the third intracellular loop are important for endothelin-1 binding (Adachi et al.
1993).
SUBSTITUTE SHEET (RULE 26) Endothelin-1 binding to the ETB receptor:
Endothelin-1 binding to the ETB receptor requires the 39 amino acids between Pro93 in the N-terminal domain and Cys131 in the first intracellular loop of the ETB
receptor (Klammt et al. 2007). In addition, the 12 amino acids from Ser390 to Leu401 in the proximal cytoplasmic tail are necessary to maintain the ligand-binding site in an active form (Wada et al. 1994).
Further, it has been suggested that the 60 amino acids sequence from 11e138 to 11e197 located in transmembrane domains 2 and 3 (TM2+3) might also be important for ligand binding. Amino acid sequences of these ETB receptor ligand-binding domains are given in Figure 2.
Constructing endothelin-1 sponge:
1. Endothelin-1 sponge could be constructed by fusing the above mentioned ETA
receptor ligand-binding domains into a fusion polypeptide that can then be fused to the Fc portion of human IgG1 (Figure 3).
Background:
Endothelin-1 is a vasoactive peptide synthesized and secreted by a diverse range of cells, and thus implicated in signalling events in a wide variety of target tissues (Nelson et al. 2003). Endothelin-1 plays a key role in physiological functions.
However, under elevated levels, endothelin-1 induces pathology and as such is implicated in a host of different diseases, including neurodegenerative disorders, cardiovascular diseases, as well as pregnancy disorders like preeclampsia (Jain 2013, Jain et al. 2012). Given that a key feature of these diseases is elevated endothelin-1 levels, one proposed strategy of therapeutic intervention is targeting the increased levels of endothelin-1, To this end, fusion polypeptides capable of binding endothelin-1 to form a non-functional complex would serve as endothelin-1 antagonists. The construction of these endothelin-1 antagonists, termed endothelin-1 sponge, would require fusing the endothelin-1 receptor(s) ligand-binding domains to the Fc portion of human IgGl.
Endothelin-1 exerts its effects by binding to the endothelin A (ETA) and endothelin B
(ETB) receptors, two highly homologous cell-surface proteins that belong to the G-protein- coupled receptor superfamily (Karet and Davenport 1994). The two receptors share about 60% similarity in the primary structure (Nelson et al.
2003), i.e.
both receptors exhibit a high polypeptide sequence identity with each other.
Nevertheless, the two receptors show a clear distinction in ligand binding selectivity based on their ligand-binding domains.
Endothelin-1 binding to the ETA receptor:
Endothelin-1 binding to the ETA receptor is thought to require the ETA
receptor N-terminus loop, extracellular loop 1 (ECL1), extracellular loop 2 (ECL2), intracellular loop 3 (ICL3), extracellular loop 3 (ECL3) and the C-terminal domain (Adachi et al.
1993). Amino acid sequences of these ETA receptor ligand-binding domains are given in Figure 1.
A 5 amino acid sequence (140 ¨ Lys Leu Leu Ala Gly ¨ 144) in ECL1 has been implicated as the most important element required for ligand binding. In addition, both ECL2 and ECL3, including the flanking transmembrane regions, were found to play an important role in ligand selection.
Orry et al. (2000) also constructed a model of interaction of the ET-1 peptide with the ETA receptor, where ET-1 makes contacts with both the N-terminal receptor domain and 2 different extracellular loops.
Further, the C-terminal 8 amino acid residues located in close proximity to the seventh transmembrane region and the C-terminal 16 amino acid residues in the third intracellular loop are important for endothelin-1 binding (Adachi et al.
1993).
SUBSTITUTE SHEET (RULE 26) Endothelin-1 binding to the ETB receptor:
Endothelin-1 binding to the ETB receptor requires the 39 amino acids between Pro93 in the N-terminal domain and Cys131 in the first intracellular loop of the ETB
receptor (Klammt et al. 2007). In addition, the 12 amino acids from Ser390 to Leu401 in the proximal cytoplasmic tail are necessary to maintain the ligand-binding site in an active form (Wada et al. 1994).
Further, it has been suggested that the 60 amino acids sequence from 11e138 to 11e197 located in transmembrane domains 2 and 3 (TM2+3) might also be important for ligand binding. Amino acid sequences of these ETB receptor ligand-binding domains are given in Figure 2.
Constructing endothelin-1 sponge:
1. Endothelin-1 sponge could be constructed by fusing the above mentioned ETA
receptor ligand-binding domains into a fusion polypeptide that can then be fused to the Fc portion of human IgG1 (Figure 3).
2. Endothelin-1 sponge could be constructed by fusing the above mentioned ETB
receptor ligand-binding domains into a fusion polypeptide that can then be fused to the Fc portion of human IgG1 (Figure 4).
receptor ligand-binding domains into a fusion polypeptide that can then be fused to the Fc portion of human IgG1 (Figure 4).
3. Endothelin-1 sponge could be constructed by fusing the ETB receptor ligand-binding domains inline with the ETA receptor ligand-binding domains into a fusion polypeptide that can then be fused to the Fc potion of human IgG1 (Figure 5).
The present invention provides amino acid sequences of fusion polypeptides capable of binding endothelin-1 to form a nonfunctional complex comprising:
a) ETA receptor ligand-binding domains b) ETB receptor ligand-binding domains fused to the Fc portion of human IgG1.
SUMMARY OF THE INVENTION
An object of the present invention is the production of endothelin-1 antagonists that are useful in the treatment of endothelin-1 -related diseases or disorders.
Another object of the invention is the use of the disclosed endothelin-1 antagonists for the treatment of endothelin-1 -related diseases or disorders. For example, an endothelin-1 antagonist described herein may be used for the treatment of preeclampsia, cardiovascular diseases or neurodegenerative disorders.
Another object of the invention is the construction of several specific endothelin-1 antagonists, termed endothelin-1 sponge, each having different sequences but all being capable of blocking the binding of endothelin-1 to its receptor/s, thus functioning as endothelin-1 antagonists SUBSTITUTE SHEET (RULE 26) DESCRIPTION OF THE FIGURES
Figure 1. ETA receptor ligand-binding domains Figure 2. ETB receptor ligand-binding domains Figure 3, Proposed design of ET-1 sponge based on ETA receptor ligand-binding domains Figure 4. Proposed design of ET-1 sponge based on ETB receptor ligand-binding domains Figure 5. Proposed design of ET-1 sponge based on ETA and ETB receptors' ligand-binding domains Figure 6A-C. SEQ ID NO: 1, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3, ECL3 and C-terminus, fused to the Fc portion of human IgG1 Figure 7A-C, SEQ ID NO: 2, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 (16 amino acids), ECL3 and C-terminus (8 amino acids), fused to the Fc portion of human IgG1 Figure 8A-C. SEQ ID NO: 3, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 and C-terminus, fused to the Fc portion of human IgG1 Figure 9A-C. SEQ ID NO: 4, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 (16 amino acids) and C-terminus (8 amino acids), fused to the Fc portion of human IgG1 Figure 10A-C. SEQ ID NO: 5, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ICL3, ECL3 and C-terminus, fused to the Fc portion of human IgG1 Figure 11A-C, SEQ ID NO: 6, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ICL3 (16 amino acids), ECL3 and C-terminus (8 amino acids), fused to the Fc portion of human IgG1 Figure 12A-B. SEQ ID NO: 7, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus, ICL1 and C-terminus, fused to the Fc portion of human IgG1 Figure 13A-C. SEQ ID NO: 8, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus, ICL1, TM2 + 3 and C-terminus, fused to the Fc portion of human IgG1 Figure 14A-B. SEQ ID NO: 9, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus and ICL1, fused to the Fc portion of human IgG1 SUBSTITUTE SHEET (RULE 26)
The present invention provides amino acid sequences of fusion polypeptides capable of binding endothelin-1 to form a nonfunctional complex comprising:
a) ETA receptor ligand-binding domains b) ETB receptor ligand-binding domains fused to the Fc portion of human IgG1.
SUMMARY OF THE INVENTION
An object of the present invention is the production of endothelin-1 antagonists that are useful in the treatment of endothelin-1 -related diseases or disorders.
Another object of the invention is the use of the disclosed endothelin-1 antagonists for the treatment of endothelin-1 -related diseases or disorders. For example, an endothelin-1 antagonist described herein may be used for the treatment of preeclampsia, cardiovascular diseases or neurodegenerative disorders.
Another object of the invention is the construction of several specific endothelin-1 antagonists, termed endothelin-1 sponge, each having different sequences but all being capable of blocking the binding of endothelin-1 to its receptor/s, thus functioning as endothelin-1 antagonists SUBSTITUTE SHEET (RULE 26) DESCRIPTION OF THE FIGURES
Figure 1. ETA receptor ligand-binding domains Figure 2. ETB receptor ligand-binding domains Figure 3, Proposed design of ET-1 sponge based on ETA receptor ligand-binding domains Figure 4. Proposed design of ET-1 sponge based on ETB receptor ligand-binding domains Figure 5. Proposed design of ET-1 sponge based on ETA and ETB receptors' ligand-binding domains Figure 6A-C. SEQ ID NO: 1, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3, ECL3 and C-terminus, fused to the Fc portion of human IgG1 Figure 7A-C, SEQ ID NO: 2, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 (16 amino acids), ECL3 and C-terminus (8 amino acids), fused to the Fc portion of human IgG1 Figure 8A-C. SEQ ID NO: 3, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 and C-terminus, fused to the Fc portion of human IgG1 Figure 9A-C. SEQ ID NO: 4, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 (16 amino acids) and C-terminus (8 amino acids), fused to the Fc portion of human IgG1 Figure 10A-C. SEQ ID NO: 5, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ICL3, ECL3 and C-terminus, fused to the Fc portion of human IgG1 Figure 11A-C, SEQ ID NO: 6, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ICL3 (16 amino acids), ECL3 and C-terminus (8 amino acids), fused to the Fc portion of human IgG1 Figure 12A-B. SEQ ID NO: 7, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus, ICL1 and C-terminus, fused to the Fc portion of human IgG1 Figure 13A-C. SEQ ID NO: 8, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus, ICL1, TM2 + 3 and C-terminus, fused to the Fc portion of human IgG1 Figure 14A-B. SEQ ID NO: 9, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus and ICL1, fused to the Fc portion of human IgG1 SUBSTITUTE SHEET (RULE 26)
Claims (24)
1. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 6A-C.
2. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim 1.
3. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 7A-C.
4. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim 3.
5. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 8A-C.
6. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim 5.
7. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 9A-C.
8. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim 7.
9. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 10A-C.
10. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim 9.
11. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 11A-C.
12. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim11.
13. A fusion polypeptide capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises one or more of the ETA
receptor ligand-binding domains, or part thereof, of claim 1.
receptor ligand-binding domains, or part thereof, of claim 1.
14. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 12A-B.
15. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim14.
16. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 13A-C.
17. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim16.
18. A fusion polypeptide which forms a multimer capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises the amino acid sequence of Figure 14A-B.
19. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim18.
20. A fusion polypeptide capable of binding endothelin-1 to form a non-functional complex, wherein the polypeptide molecule comprises one or more of the ETB
receptor ligand-binding domains, or part thereof, of claim 16.
receptor ligand-binding domains, or part thereof, of claim 16.
21. A composition capable of binding endothelin-1 to form a non-functional complex comprising a multimer of the fusion polypeptide of any of claims 1, 3, 5, 7, 9, 11, 14, 16 or 18.
22. The composition of claim 21, wherein the multimer is a dimer.
23. A vector comprising the nucleic acid molecule of any of claims 2, 4, 6, 8, 10, 12, 15, 17 or 19.
24. An expression vector comprising the nucleic acid molecule of any of claims 2, 4, 6, 8, 10, 12, 15, 17 or 19 operatively linked to an expression control sequence.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB201503453A GB201503453D0 (en) | 2015-03-01 | 2015-03-01 | Endothelin-1"sponge" |
| GB1503453.1 | 2015-03-01 | ||
| GBGB1507043.6A GB201507043D0 (en) | 2015-03-01 | 2015-04-24 | Endothelin-1 receptor(s) based endothelin-1 sponge |
| GB1507043.6 | 2015-04-24 | ||
| PCT/IB2016/050337 WO2016139543A1 (en) | 2015-03-01 | 2016-01-22 | Endothelin-1 receptor based endothelin-1 sponge |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3011824A1 true CA3011824A1 (en) | 2016-09-09 |
Family
ID=63865744
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3011824A Abandoned CA3011824A1 (en) | 2015-03-01 | 2016-01-22 | Endothelin-1 receptor based endothelin-1 sponge |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU2016227458A1 (en) |
| CA (1) | CA3011824A1 (en) |
| SG (1) | SG11201806168PA (en) |
| WO (1) | WO2016139543A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6927044B2 (en) * | 1998-09-25 | 2005-08-09 | Regeneron Pharmaceuticals, Inc. | IL-1 receptor based cytokine traps |
| US6811780B2 (en) * | 2002-05-01 | 2004-11-02 | Regeneron Pharmaceuticals, Inc. | Methods of using cytokine antagonists to treat HIV infection and AIDS |
-
2016
- 2016-01-22 CA CA3011824A patent/CA3011824A1/en not_active Abandoned
- 2016-01-22 SG SG11201806168PA patent/SG11201806168PA/en unknown
- 2016-01-22 WO PCT/IB2016/050337 patent/WO2016139543A1/en active Application Filing
- 2016-01-22 AU AU2016227458A patent/AU2016227458A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| SG11201806168PA (en) | 2018-08-30 |
| AU2016227458A1 (en) | 2018-08-02 |
| WO2016139543A1 (en) | 2016-09-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20220412 |
|
| FZDE | Discontinued |
Effective date: 20220412 |