US2008254021A1PendingUtilityA1
Tie1-binding ligands
Est. expiryAug 12, 2023(expired)· nominal 20-yr term from priority
A61P 35/04A61P 9/00A61P 37/06A61P 35/02A61P 35/00A61P 27/02A61P 25/00A61P 29/00C07K 16/2863C07K 2319/00C07K 16/005C07K 2317/565C07K 2317/73A61P 19/02C07K 2317/75C07K 2317/55A61P 17/02A61P 17/06C07K 2317/76
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Claims
Abstract
Tie1 is a receptor tyrosine kinase protein that includes a transmembrane domain. Tie1 is present on endothelial cells. This disclosure described antibodies that bind to Tie1, including ones that inhibit endothelial cell activity.
Claims
exact text as granted — not AI-modified1 . An isolated protein comprising a heavy chain immunoglobulin variable domain sequence and a light chain immunoglobulin variable domain sequence, wherein the protein binds to Tie1 ectodomain and the heavy chain immunoglobulin variable domain sequence comprises one or more of the following properties:
i) a HC CDR1 that includes an amino acid sequence as follows:
(SEQ ID NO:117)
(AGSR)-Y-(GVK)-M-(GSVF),
(SEQ ID NO:118)
(AGSIMRH)-Y-(GVMK)-M-(GSVMFH),
or
(SEQ ID NO:119)
(AGSIMRNH)-Y-(AGTVMKPQ)-M-(AGSTVMYWFKH);
ii) a HC CDR2 that includes an amino acid sequence as follows:
(SEQ ID NO:120)
X-I-Y-P-S-G-G-X-T-X-Y-A-D-S-V-K-G,
wherein X is any amino acid,
(SEQ ID NO:121)
(GSV)-I-(SY)-P-S-G-G-(WQ)-T-(GY),
(SEQ ID NO:160)
(GSV)-I-(SY)-P-S-G-G-(WNQ)-T-(GY),
(SEQ ID NO:122)
(GSV)-I-(SY)-P-S-G-G-(WQ)-T-(GY)-Y-A-D-S-V-K-G,
or
(SEQ ID NO:123)
(GSVW)-I-(SY)-P-S-G-G-(AGVMYWPQH)-T-(AGSTLVMYFKH);
iii) a HC CDR3 that includes an amino acid
sequence as follows:
(SEQ ID NO:124)
V-(four or five residues)-F-D-(I/Y),
(SEQ ID NO:125)
G-Y-G-P-I-A-P-G-L-D-Y,
(SEQ ID NO:126)
(GV)-N-Y-Y-(GYD)-S-(SD)-G-Y-G-P-I-A-P-G-L-D-Y,
(SEQ ID NO:127)
(GVD)-(AGLN)-(LYR)-(GSTLYH)-(GYD)-(AGSYFP)-(SFD)-
(AGYD)-(IY)-(GFD)-(YDP)-(IP)-A-P-G-L-D-Y,
or
(SEQ ID NO:128)
VNYYDSSGYGPIAPGLDY.
2 . The protein of claim 1 wherein the light chain immunoglobulin variable domain sequence comprises one or more of the following properties
i) a LC CDR1 that includes an amino acid sequence as follows:
(SEQ ID NO:129)
R-A-S-Q-S-(IV)-S-(SR)-X1-Y-L-(AN),
(SEQ ID NO:130)
R-A-S-Q-S-V-S-S-X-L,
(SEQ ID NO:131)
R-A-S-Q-S-(IV)-S-(SR)-(SY)-(LY)-(ALN),
or
R-A-S-(REQ)-(GSTRN)-(IV)-(GSTIRN)-(STIRH)-X1-
(SYWNH)-(LV)-(ASN)
(SEQ ID NO:132), wherein X1 can be serine or absent;
ii) a LC CDR2 that includes an amino acid sequence as follows:
X-A-S-X-R-A-T (SEQ ID NO:133), wherein X can be any amino acid,
(AGD)-A-S-(STN)-R-A-T (SEQ ID NO:134),
(AGD)-A-S-(STN)-(LR)-(AEQ)-(ST) (SEQ ID NO:135), or
(AGTKDEH)-A-S-(STN)-(LR)-(AVEQ)-(ST) (SEQ ID NO:136); and
iii) a LC CDR3 that includes an amino acid sequence as follows:
(SEQ ID NO:137)
Q-Q-(SYFR)-(GSYN)-S-(STYW)-(RP)-(LWR)-(TIY)-T,
(SEQ ID NO:161)
Q-Q-(SYFR)-(GSYN)-S-(STYW)-(RP)-(LWRH)-(TIY),
(SEQ ID NO:138)
(LQ)-Q-(SYFR)-(GSYN)-(SKN)-(STYW)-(RP)-(LWR)-
(TIY)-T,
(SEQ ID NO:139)
Q-Q-(YR)-(GS)-S-(SW)-P-R-X1-T,
wherein X1 is any amino acid or absent,
(SEQ ID NO:140)
(LQ)-(LQ)-(SYFRD)-(GSYN)-(STRKN)-(STYWF)-(RP)-
(ILMWRH)-(TIY)-(TI),
and
(SEQ ID NO:141)
(LQ)-(LRQ)-(SYFRD)-(GSYN)-(ASTRKN)-(STYWF)-(SVRP)-
(STILMWRH)-(TIY)-(STI).
3 . The protein of claim 1 wherein the light chain immunoglobulin variable domain sequence comprises one or more of the following properties
i) a LC CDR1 that includes an amino acid sequence as follows:
(SEQ ID NO:142)
S-X-(ND)-(IV)-(AG)-X1-X2-X3,
or
(SEQ ID NO:143)
T-(GR)-(ST)-S-X5-(ND)-(IV)-(AG)-X1-X2-X3-Y-X4-S,
wherein X1 is any amino acid (e.g., G or R), X2 is any amino acid (e.g., Y or N), X3 is any amino acid (e.g., F, N, or K), X4 is any amino acid (e.g., aliphatic, e.g., V or A);
ii) a LC CDR2 that includes an amino acid sequence as follows:
(DE)-V-N-N-R-P-S (SEQ ID NO:144), or
(DE)-(VD)-(STDN)-(YRDN)-R-P-S (SEQ ID NO:145); and
iii) a LC CDR3 that includes an amino acid sequence as follows:
(SEQ ID NO:146)
(SQ)-S-(SY)-(ASID)-(GSR)-(ST)-(STRN)-(STYR)-
(ATLY)-(SVWQ).
4 . The protein of claim 1 wherein the HC variable domain sequence comprises SEQ ID NO:118 and SEQ ID NO:160.
5 . The protein of claim 1 wherein the LC variable domain sequence comprises SEQ ID NO:132, SEQ ID NO:136, and SEQ ID NO:161.
6 . The protein of claim 1 wherein the amino acid sequence of the HC variable domain sequence is at least 85% identical to the amino acid sequence of the HC variable domain of clone E3, G2, p-A1, p-A10, p-B1, p-B3, p-C6, p-D12, p-F3, p-F4, p-G3, s-A10, s-H1, s-A2, s-B2, s-B9, s-C10, s-C2, s-C7, s-D11, s-E11, s-G10, or s-H4.
7 . The protein of claim 1 wherein the amino acid sequence of the LC variable domain sequence is at least 85% identical to the amino acid sequence of the LC variable domain of clone E3, G2, p-A1, p-A10, p-B1, p-B3, p-C6, p-D12, p-F3, p-F4, p-G3, s-A10, s-H1, s-A2, s-B2, s-B9, s-C10, s-C2, s-C7, s-D11, s-E11, s-G10, or s-H4.
8 . The protein of claim 1 wherein the amino acid sequences of the HC variable domain sequence comprises CDR1, CDR2, and CDR3 sequences from the E3 clone, and the LC variable domain sequence comprises CDR1, CDR2, and CDR3 sequences from the E3 clone.
9 . The protein of claim 8 wherein the LC variable domain sequence comprises SEQ ID NO:159.
10 . The protein of claim 8 wherein the HC variable domain sequence comprises SEQ ID NO:114.
11 . The protein of claim 1 wherein the HC and LC framework regions are human.
12 . The protein of claim 1 further comprising an Fc domain.
13 . The protein of claim 12 that comprises the constant domains of a human IgG1, IgG2, IgG3, or IgG4.
14 . An isolated protein comprising a heavy chain immunoglobulin variable domain sequence and a light chain immunoglobulin variable domain sequence, wherein the protein binds to a Tie1 ectodomain and to endothelial cells, but does not substantially bind to platelets.
15 . The protein of claim 14 that binds to Tie1 with a K d of less than 5 nM.
16 . The isolated protein of claim 14 that comprises the HC and LC immunoglobulin variable domains of the E3 antibody or domains that are at least 85% identical to the HC and LC immunoglobulin variable domains of the E3 antibody, respectively.
17 . The protein of claim 14 that inhibits tube formation by HUVEC cells in vitro.
18 . The protein of claim 14 that recognizes melanoma-associated structures in a histological section.
19 . An isolated protein comprising a heavy chain immunoglobulin variable domain sequence and a light chain immunoglobulin variable domain sequence, wherein the protein binds to a Tie1 ectodomain and competes with E3 for binding to Tie1 or binds to an epitope that overlaps an epitope that is recognized by E3 or that has at least one, two or three residues in common with an epitope that is recognized by E3.
20 . An isolated nucleic acid comprising a coding sequence that encodes a polypeptide comprising an immunoglobulin HC variable domain sequence, wherein the coding sequence is at least 85% identical to a reference sequence that encodes the HC variable domain of clone E3, G2, p-A1, p-A10, p-B1, p-B3, p-C6, p-D12, p-F3, p-F4, p-G3, s-A10, s-H1, s-A2, s-B2, s-B9, s-C10, s-C2, s-C7, s-D11, s-E11, s-G10, or s-H4, or the coding sequence hybridizes to the reference sequence or a complement thereof.
21 . The nucleic acid of claim 20 that further comprises a second coding sequence that encodes a polypeptide comprising an immunoglobulin LC variable domain.
22 . An isolated nucleic acid comprising a coding sequence that encodes a polypeptide comprising an immunoglobulin LC variable domain sequence, wherein the coding sequence is at least 85% identical to a reference sequence that encodes the LC variable domain of clone E3, G2, p-A1, p-A10, p-B1, p-B3, p-C6, p-D12, p-F3, p-F4, p-G3, s-A10, s-H1, s-A2, s-B2, s-B9, s-C10, s-C2, s-C7, s-D11, s-E11, s-G10, or s-H4, or the coding sequence hybridizes to the reference sequence or a complement thereof.
23 . The nucleic acid of claim 22 that further comprises a second coding sequence that encodes a polypeptide comprising an immunoglobulin HC variable domain.
24 . A host cell that contains a first nucleic acid sequence encoding a polypeptide comprising a HC variable domain of an antibody and a second nucleic acid sequence encoding a polypeptide comprising a LC variable domain of the antibody, wherein the antibody is a protein according to claim 1 or 14 .
25 . A host cell that contains a first nucleic acid encoding a polypeptide comprising a HC variable region and a second nucleic acid encoding a polypeptide comprising a LC variable region, wherein the HC and the LC variable regions each comprise a sequence at least 85% identical to respective amino acid sequences of the HC and LC variable domains of a clone selected from the group consisting of E3, G2, p-A1, p-A10, p-B1, p-B3, p-C6, p-D12, p-F3, p-F4, p-G3, s-A10, s-H1, s-A2, s-B2, s-B9, s-C10, s-C2, s-C7, s-D11, s-E11, s-G10, and s-H4.
26 . A pharmaceutical composition comprising a protein of any of claims 1 - 19 and a pharmaceutically acceptable carrier.
27 . A method of modulating angiogenesis, the method comprising:
administering a composition that comprises the protein of claim 1 or 14 to a subject in an amount effective to modulate angiogenesis in the subject.
28 . The method of claim 27 wherein the protein antagonizes Tie1 activity.
29 . The method of claim 27 wherein the subject has an angiogenesis-related disorder.
30 . The method of claim 27 wherein the subject has a neoplastic disorder.
31 . The method of claim 27 wherein the subject has a metastatic cancer.
32 . The method of claim 27 wherein the subject has an angiogenesis-dependent cancer or tumor.
33 . The method of claim 27 wherein the subject has an inflammatory disorder.
34 . The method of claim 33 wherein the subject has rheumatoid arthritis.
35 . The method of claim 33 wherein the subject has psoriasis.
36 . The method of claim 27 wherein the protein is delivered systemically.
37 . The method of claim 27 wherein the protein is administered in an amount effective to reduce one or more of the following activities: sprouting, splitting and remodeling of blood vessels.
38 . The method of claim 27 wherein the protein is administered in an amount effective to reduce vasculogenesis or tubule formation.
39 . A method of modulating endothelial cell activity in the subject, the method comprising:
administering a composition that comprises the protein of claim 14 to a subject in an amount effective to modulate endothelial cell activity in the subject.
40 . A method for detecting the presence of a Tie1 protein, in a sample, in vitro, the method comprising:
(i) contacting the sample with an Tie1-binding protein according to claim 1 , under conditions that allow interaction of the Tie1-binding protein and the Tie1 protein to occur; and (ii) detecting formation of a complex between the Tie1-binding protein and the sample.
41 . A method for detecting the presence of Tie1 in vivo, the method comprising:
(i) administering to a human subject an Tie1-binding protein, under conditions that allow interaction of the Tie1-binding ligand and the Tie1 protein to occur; and (ii) detecting formation of a complex between the Tie1-binding protein and a Tie1 molecule of the subject or detecting distribution of Tie1-binding protein or at least one location of the Tie1-binding protein in the subject.Join the waitlist — get patent alerts
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