US2008166295A1PendingUtilityA1
Antibodies, polypeptides and uses thereof
Est. expiryNov 20, 2022(expired)· nominal 20-yr term from priority
A61P 9/00A61P 9/10A61P 35/00A61P 43/00A61P 3/04A61P 29/00A61P 27/02C07K 2317/76A61K 31/70A61K 2039/505A61K 2039/53C07K 16/18A61P 19/02C07K 16/2803A61P 15/00A61P 17/06
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Claims
Abstract
Provided are methods of inhibiting angiogenesis in an individual in need thereof comprising administering an antibody that selectively binds to the extracellular region of human magic roundabout (MR) to the individual. Also provided are antibodies that have the amino acid sequences i) to iii), iv) to vi), or i) to vi): i) SEQ ID NO:9, ii) SEQ ID NO:10, iii) SEQ ID NO:11, iv) SEQ ID NO:13, v) SEQ ID NO:14, vi) SEQ ID NO:15. Further provided are methods of inhibiting angiogenesis in an individual in need thereof comprising administering the extracellular domain (residues 1-467) of MR, or a fragment thereof, that inhibits angiogenesis, to the individual. Methods of inhibiting endothelial cell migration and/or proliferation comprising administering the extracellular domain of MR, or a fragment thereof, that inhibits endothelial cell migration and/or proliferation are also provided.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting angiogenesis in an individual in need thereof comprising administering an antibody that selectively binds to the extracellular region (residues 1-467, SEQ ID NO: 3) of human magic roundabout (MR) to the individual.
2 . Use of an antibody that selectively binds to the extracellular region of MR in the preparation of a medicament for inhibiting angiogenesis.
3 . An in vitro method of inhibiting angiogenesis comprising administering an antibody that selectively binds to the extracellular region of MR to tissue or cells in vitro.
4 . A method or a use according to any of claims 1 to 3 wherein the antibody selectively binds to the Ig region of MR (residues 46-209, SEQ ID NO: 4).
5 . A method or a use according to claim 4 wherein the antibody selectively binds to the IgA region of MR (residues 46-116, SEQ ID NO: 5).
6 . A method or a use according to claim 4 wherein the antibody selectively binds to the IgB region of MR (residues 151-209, SEQ ID NO: 6).
7 . A method or a use according to any of claims 1 to 6 wherein the antibody has at least one light chain variable region incorporating the following CDRs:
CDR1:
SASSSVSYMY
(SEQ ID NO: 9)
CDR2:
LTSNLAS
(SEQ ID NO: 10)
CDR3:
QQWSSNPLT
(SEQ ID NO: 11)
8 . A method or a use according to claim 7 wherein the antibody has at least one light chain variable region comprising the amino acid sequence Q I
(SEQ ID NO: 12)
VLTQSPALMSASPGEKVTMTC SAS S
SVSYMYWYQQKPRSSPKPWIYLTSNLASGVPARFSGSGSGTSYS
LTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK.
9 . A method or a use according to any of claims 1 to 6 wherein the antibody has at least one heavy chain variable region incorporating the following CDRs:
CDR1:
DYNLN
(SEQ ID NO: 13)
CDR2:
VINPNYGTTSYNQKFKG
(SEQ ID NO: 14)
CDR3:
GRDYFGY
(SEQ ID NO: 15)
10 . A method or a use according to claim 9 wherein the antibody has at least one heavy chain variable region comprising the amino acid sequence Q
(SEQ ID NOs: 16-17)
VK/QLQESGPELVKPGASVKISCKASGYSLTDYNLNWVKQNKGKSLEWIG
VINPNYGTTSYNQKFKGKATLTVDQSSSTTYMQLNSLTSEDSAVYYCARG
RDYFGYWGQGTTVTVSS.
11 . A method or a use according to any of claims 1 to 6 wherein the antibody has at least one light chain variable region as defined in claim 7 or 8 and at least one heavy chain variable region as defined in claim 9 or 10 .
12 . A method of inhibiting angiogenesis in an individual in need thereof comprising administering a polynucleotide encoding an antibody as defined in any of claims 1 to 11 to the individual.
13 . Use of a polynucleotide encoding an antibody as defined in any of claims 1 to 11 in the preparation of a medicament for inhibiting angiogenesis.
14 . An in vitro method of inhibiting angiogenesis comprising administering a polynucleotide encoding an antibody as defined in any of claims 1 to 11 to tissue or cells in vitro.
15 . An antibody that contains the amino acid sequences i) to iii), the amino acid sequences iv) to vi), or preferably the amino acid sequences i) to vi):
i)
SASSSVSYMY
(SEQ ID NO: 9)
ii)
LTSNLAS
(SEQ ID NO: 10)
iii)
QQWSSNPLT
(SEQ ID NO: 11)
iv)
DYNLN
(SEQ ID NO: 13)
v)
VINPNYGTTSYNQKFKG
(SEQ ID NO: 14)
vi)
GRDYFGY.
(SEQ ID NO: 15)
16 . An antibody according to claim 15 having at least one light chain variable region incorporating the following CDRs:
CDR1:
SASSSVSYMY
(SEQ ID NO: 9)
CDR2:
LTSNLAS
(SEQ ID NO: 10)
CDR3:
QQWSSNPLT
(SEQ ID NO: 11)
17 . An antibody according to claim 16 having at least one light chain variable region comprising the amino acid sequence Q I V L T Q S P A L M S ASPGEKVTMTCSASSSVSYMYWYQQKPRSSPKPWIYLTSNLASGVPARFSGSGSGTSYS LTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELK (SEQ ID NO: 12).
18 . An antibody according to claim 15 having at least one heavy chain variable region incorporating the following CDRs:
CDR1:
DYNLN
(SEQ ID NO: 13)
CDR2:
VINPNYGTTSYNQKFKG
(SEQ ID NO: 14)
CDR3:
GRDYFGY
(SEQ ID NO: 15)
19 . An antibody according to claim 18 having at least one heavy chain variable region comprising the amino acid sequence Q V K/Q L Q E S G P E LVKPGASVKISCKASGYSLTDYNLNWVKQNKGKS LEWIGVINPNYGTTSYNQKFKGKATLTVDQSSSTT YMQLNSLTSEDSAVYYCARGRDYFGYWGQGTTV T V S S (SEQ ID NOs: 16-17).
20 . An antibody according to claim 15 having at least one light chain variable region according to claim 16 or 17 and at least one heavy chain variable region according to claim 18 or 19 .
21 . An antibody that selectively binds to the MR epitope bound by an antibody having at least one kappa light chain variable region according to claim 17 and at least one heavy chain variable region according to claim 19 .
22 . A polynucleotide encoding an antibody according to any of claims 15 to 21 .
23 . A polynucleotide according to claim 22 comprising one or more of the nucleotide sequences:
i)
(SEQ ID NO: 18)
AGT GCC AGC TCA AGT GTA AGT TAC ATG TAC
ii)
(SEQ ID NO: 19)
TCT CAC ATC CAA CCT GGC TTC T
iii)
(SEQ ID NO: 20)
CAG CAG TGG AGT AGT AAC CCA CTC ACG
iv)
(SEQ ID NO: 22)
GAC TAC AAC CTG AAC
v)
(SEQ ID NO: 23)
GTA ATT AAT CCA AAC TAT GGT ACT AGT TAC AAT CAG
AAG TTC AAG GGC,
and
vi)
(SEQ ID NO: 24)
GGG AGG GAT TAC TTC GGC TAC
24 . A polynucleotide according to claim 22 or 23 comprising the nucleotide sequence CAA ATT GTT CTC ACC CAG TCT CCA GCA CTC ATG TCT GCA TCT CCA GGG GAG AAG GTC ACC ATG ACC TGC AGT GCC AGC TCA AGT GTA AGT TAC ATG TAC TGG TAC CAG CAG AAG CCA AGA TCC TCC CCC AAA CCC TGG ATT TAT CTC ACA TCC AAC CTG GCT TCT GGA GTC CCT GCT CGC TTC AGT GGC AGT GGG TCT GGG ACC TCT TAC TCT CTC ACA ATC AGC AGC ATG GAG GCT GAA GAT GCT GCC ACT TAT TAC TGC CAG CAG TGG AGT AGT AAC CCA CTC ACG TTC GGT GCT GGG ACC AAG CTG GAG CTG AAA (SEQ ID NO: 21).
25 . A polynucleotide according to claim 22 or 23 comprising the nucleotide sequence CAG GTC AAG (or A/CAA) CTG CAG GAG TCA GGA CCT GAG CTG GTG AAG CCT GGC GCT TCA GTG AAG ATA TCC TGC AAG GCT TCT GGT TAC TCA CTC ACT GAC TAC AAC CTG AAC TGG GTG AAG CAG AAC AAA GGA AAG AGC CTT GAG TGG ATT GGA GTA ATT AAT CCA AAC TAT GGT ACT AGT TAC AAT CAG AAG TTC AAG GGC AAG GCC ACA TTG ACT GTA GAC CAA TCT TCC AGC ACA ACC TAC ATG CAG CTC AAC AGC CTG ACA TCT GAG GAC TCT GCA GTC TAT TAC TGT GCA AGA GGG AGG GAT TAC TTC GGC TAC TGG GGC CAA GGG ACC ACG GTC ACC GTC TCC TCA (SEQ ID NOs: 25-27).
26 . A polynucleotide according to claim 22 or 23 comprising the nucleotide sequence as defined in claim 24 and the nucleotide sequence as defined in claim 25 .
27 . An antibody that selectively binds the Ig region of MR (residues 46-209, SEQ ID NO: 4) but does not selectively bind to the peptides LLQPPARGHAHDGQALSTDL (SEQ ID NO: 28) or LSQSPGAVPQALVAWRA (SEQ ID NO: 29).
28 . An antibody according to claim 27 that selectively binds the IgA region of MR (residues 46-116, SEQ ID NO: 5) but does not selectively bind to the peptide LLQPPARGHAHDGQALSTDL (SEQ ID NO: 28), or that selectively binds the IgB region of MR (residues 151-209, SEQ ID NO: 6) but does not selectively bind to the peptide LSQSPGAVPQALVAWRA (SEQ ID NO: 29).
29 . A polynucleotide that encodes an antibody according to claim 27 or 28 .
30 . A compound comprising an antibody according to any of claims 15 to 21 or 27 to 28 and a directly or indirectly cytotoxic moiety.
31 . A compound according to claim 30 wherein the cytotoxic moiety is selected from a directly cytotoxic chemotherapeutic agent, a directly cytotoxic polypeptide, a moiety which is able to convert a relatively non-toxic prodrug into a cytotoxic drug, a radiosensitizer, a directly cytotoxic nucleic acid, a nucleic acid molecule that encodes a directly or indirectly cytotoxic polypeptide, a nucleic acid molecule that encodes a therapeutic polypeptide, or a radioactive atom.
32 . A compound according to claim 31 wherein the radioactive atom is any one of phosphorus-32, iodine-125, iodine-131, indium-111, rhenium-186, rhenium-188 or yttrium-90.
33 . A compound according to claim 30 or 31 wherein the antibody and the cytotoxic moiety are polypeptides which are fused.
34 . A polynucleotide encoding a compound according to claim 33 .
35 . A compound comprising an antibody according to any of claims 15 to 21 or 27 to 28 and a readily detectable moiety.
36 . A compound according to claim 35 wherein the readily detectable moiety comprises a suitable amount of any one of iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, technitium-99m, gadolinium, manganese or iron.
37 . A vector comprising the polynucleotide of any of claims 22 to 26 , 29 or 34 .
38 . A host cell comprising the polynucleotide of any of claims 22 to 26 , 29 or 34 , or the vector of claim 37 .
39 . A stable host cell line producing an antibody according to any of claims 15 to 21 or 27 to 28 or a compound according to claim 33 resulting from incorporation in the cell line an exogenous polynucleotide according to any of claims 22 to 26 , 29 or 34 , or a vector according to claim 37 .
40 . A pharmaceutical composition comprising an antibody according to any of claims 15 to 21 or 27 to 28 , or a polynucleotide according to any of claims 22 to 26 , 29 or 34 , or a compound according to any of claims 30 to 33 or 35 to 36 , and a pharmaceutically acceptable carrier.
41 . A pharmaceutical composition according to claim 40 suitable for administration to a patient by injection.
42 . An antibody according to any of claims 15 to 21 or 27 to 28 , or a polynucleotide according to any of claims 22 to 26 , 29 or 34 , or a compound according to any of claims 30 to 33 or 35 to 36 , for use in medicine.
43 . Use of an antibody according to any of claims 15 to 21 or 27 to 28 , or a polynucleotide according to any of claims 22 to 26 , 29 or 34 , or a compound according to any of claims 30 to 33 or 35 to 36 , in the preparation of a medicament for inhibiting angiogenesis.
44 . A method of inhibiting angiogenesis in an individual in need thereof comprising administering an antibody according to any of claims 15 to 21 or 27 to 28 , or a polynucleotide according to any of claims 22 to 26 , 29 or 34 , or a compound according to any of claims 30 to 33 or 35 to 36 , to the individual.
45 . An in vitro method of inhibiting angiogenesis comprising administering an antibody according to any of claims 15 to 21 or 27 to 28 , or a polynucleotide according to any of claims 22 to 26 , 29 or 34 , or a compound according to any of claims 30 to 33 or 35 to 36 , to tissue or cells in vitro.
46 . A method of producing an antibody according to any of claims 15 to 21 or 26 to 28 , or a compound according to any of claims 33 , the method comprising expressing a polynucleotide according to any one of claims 22 to 26 , 29 or 34 , or culturing a stable host cell line according to claim 39 .
47 . A method of combating a disease or condition selected from tumours/cancer, psoriasis, atherosclerosis, menorrhagia, endometriosis, arthritis (both inflammatory and rheumatoid), macular degeneration, Paget's disease, retinopathy and its vascular complications (including proliferative and of prematurity, and diabetic retinopathy), benign vascular proliferations, fibroses, obesity and inflammation in an individual in need thereof comprising administering an antibody that selectively binds to the extracellular region of MR to the individual.
48 . Use of an antibody that selectively binds to the extracellular region of MR in the preparation of a medicament for combating a disease or condition selected from tumours/cancer, psoriasis, atherosclerosis, menorrhagia, endometriosis, arthritis (both inflammatory and rheumatoid), macular degeneration, Paget's disease, retinopathy and its vascular complications (including proliferative and of prematurity, and diabetic retinopathy), benign vascular proliferations, fibroses, obesity and inflammation.
49 . The MR ectodomain (SEQ ID NO: 3), or a fragment thereof that inhibits endothelial cell migration and/or proliferation.
50 . The MR ectodomain or a fragment thereof that inhibits endothelial cell migration and/or proliferation, or a polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits endothelial cell migration and/or proliferation, for use in medicine.
51 . A pharmaceutical composition comprising the MR ectodomain, or a fragment thereof that inhibits endothelial cell migration and/or proliferation, or a polynucleotide encoding the MR ectodomain or fragment thereof, and a pharmaceutically acceptable carrier.
52 . A pharmaceutical composition according to claim 51 suitable for intravenous administration to a patient.
53 . A method of combating a disease or condition involving unwanted, undesirable or inappropriate endothelial cell migration and/or proliferation in an individual, the method comprising administering the MR ectodomain or a fragment thereof that inhibits endothelial cell migration and/or proliferation, or a polynucleotide encoding the MR ectodomain or a fragment thereof that inhibits endothelial cell migration and/or proliferation, to the individual.
54 . Use of the MR ectodomain or a fragment thereof that inhibits endothelial cell migration and/or proliferation, or a polynucleotide encoding the MR ectodomain or a fragment thereof that inhibits endothelial cell migration and/or proliferation, in the preparation of a medicament for combating a disease or condition involving unwanted, undesirable or inappropriate endothelial cell migration and/or proliferation.
55 . A method or a use according to claim 53 or 54 wherein the disease or condition involving unwanted, undesirable or inappropriate endothelial cell migration and/or proliferation is selected from tumours/cancer, psoriasis, atherosclerosis, menorrhagia, endometriosis, arthritis (both inflammatory and rheumatoid), macular degeneration, Paget's disease, retinopathy and its vascular complications (including proliferative and of prematurity, and diabetic retinopathy), benign vascular proliferations, fibroses, obesity and inflammation.
56 . An in vitro method of inhibiting endothelial cell migration and/or proliferation comprising administering the MR ectodomain or a fragment thereof that inhibits endothelial cell migration and/or proliferation, a polynucleotide encoding the MR ectodomain or a fragment thereof that inhibits endothelial cell migration and/or proliferation, to tissue or cells in vitro.
57 . A vector comprising a polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits endothelial cell migration and/or proliferation.
58 . A host cell comprising a polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits endothelial cell migration and/or proliferation, or the vector of claim 57 .
59 . The MR ectodomain, or a fragment thereof that inhibits angiogenesis.
60 . A method of inhibiting angiogenesis in an individual in need thereof comprising administering the MR ectodomain, or a fragment thereof that inhibits angiogenesis, to the individual.
61 . A method of combating a disease or condition selected from tumours/cancer, psoriasis, atherosclerosis, menorrhagia, endometriosis, arthritis (both inflammatory and rheumatoid), macular degeneration, Paget's disease, retinopathy and its vascular complications (including proliferative and of prematurity, and diabetic retinopathy), benign vascular proliferations, fibroses, obesity and inflammation in an individual in need thereof comprising administering the MR ectodomain, or a fragment thereof that inhibits angiogenesis, to the individual.
62 . The MR ectodomain, or a fragment thereof that inhibits angiogenesis, for use in medicine.
63 . Use of the MR ectodomain, or a fragment thereof that inhibits angiogenesis, in the preparation of a medicament for inhibiting angiogenesis.
64 . Use of the MR ectodomain, or a fragment thereof that inhibits angiogenesis, in the preparation of a medicament for combating a disease or condition selected from tumours/cancer, psoriasis, atherosclerosis, menorrhagia, endometriosis, arthritis (both inflammatory and rheumatoid), macular degeneration, Paget's disease, retinopathy and its vascular complications (including proliferative and of prematurity, and diabetic retinopathy), benign vascular proliferations, fibroses, obesity and inflammation.
65 . An in vitro method of inhibiting angiogenesis comprising administering the MR ectodomain, or a fragment thereof that inhibits angiogenesis, to tissue or cells in vitro.
66 . A method of inhibiting angiogenesis in an individual in need thereof comprising administering a polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits angiogenesis.
67 . A polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits angiogenesis, for use in medicine.
68 . Use of a polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits angiogenesis, in the preparation of a medicament for inhibiting angiogenesis.
69 . An in vitro method of inhibiting angiogenesis comprising administering a polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits angiogenesis, to tissue or cells in vitro.
70 . A vector comprising a polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits angiogenesis.
71 . A host cell comprising a polynucleotide encoding the MR ectodomain, or a fragment thereof that inhibits angiogenesis, or the vector of claim 60 .
72 . A pharmaceutical composition comprising the MR ectodomain, or a fragment thereof that inhibits angiogenesis, or a polynucleotide encoding the MR ectodomain or fragment thereof, and a pharmaceutically acceptable carrier.
73 . A pharmaceutical composition according to claim 72 suitable for intravenous administration to a patient.
74 . A method according to claim 12 , wherein the antibody selectively binds to the Ig region of MR (residues 46-209, SEQ ID NO:4).
75 . A method according to claim 74 , wherein the antibody selectively binds to the IgA region of MR (residues 46-116, SEQ ID NO:5).
76 . A method according to claim 74 , wherein the antibody selectively binds to the IgB region of MR (residues 151-209, SEQ ID NO:6).
77 . A vector comprising the polynucleotide of claim 34 .
78 . A host cell comprising the polynucleotide of claim 34 .
79 . A host cell comprising the vector of claim 37 .
80 . A host cell comprising the vector of claim 77 .
81 . A stable host cell line producing a compound resulting from incorporation in the cell line of an exogenous polynucleotide according to claim 34 .
82 . A stable host cell line producing an antibody resulting from incorporation in the cell line of a vector according to claim 37 .
83 . A stable host cell line producing a compound resulting from incorporation in the cell line of a vector according to claim 77 .
84 . A method of producing a compound, the method comprising expressing a polynucleotide according to claim 34 .
85 . A method of producing an antibody, the method comprising culturing a stable host cell line according to claim 39 .
86 . A method of producing a compound, the method comprising culturing a stable host cell line according to claim 81 .
87 . A method of producing an antibody, the method comprising culturing a stable host cell line according to claim 82 .
88 . A method of producing a compound, the method comprising culturing a stable host cell line according to claim 83 .Cited by (0)
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