US2023279088A1PendingUtilityA1
Fusion protein comprising a blood-brain barrier (bbb)-crossing single domain antibody fc5, an immunoglobulin fc fragment and a beta-amyloid binding polypeptide (abp)
Est. expiryJan 30, 2037(~10.5 yrs left)· nominal 20-yr term from priority
C07K 2317/622C07K 16/2863C07K 14/4711C07K 16/28C07K 16/18A61K 9/0019C07K 2317/569C07K 2317/24C07K 2319/70C07K 2319/33C07K 2317/565C07K 2319/10C07K 2319/30A61P 25/28A61K 47/68A61K 2039/505C07K 2317/94C07K 16/1282C07K 14/001
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Claims
Abstract
A brain-penetrating composition of amyloid-β binding peptide is disclosed. This may be useful in the treatment of Alzheimer's disease, for example as a bifunctional molecule, comprising a blood-brain barrier crossing antibody and an amyloid-β targeting peptide linked via an Fc fragment that is able to transmigrate across the blood-brain barrier into the brain, and compositions comprising same. Methods of using this composition for treating Alzheimer's disease are disclosed.
Claims
exact text as granted — not AI-modified1 . A compound comprising a fusion protein, comprising an antibody or fragment thereof that transmigrates the blood brain barrier (BBB) a polypeptide that binds β-amyloid.
2 . The compound of claim 1 further comprising a Fc fragment.
3 . The compound of claim 1 or 2 , wherein the polypeptide that binds β-amyloid comprises a sequence
(SEQ ID NO: 31)
X 1 TFX 2 TX 3 X 4 ASAQASLASKDKTPKSKSKKX 5 X 6 STQLX 7 SX 8 VX 9 NI
wherein X 1 = G or A, X 2 = G or V, X 3 = G or A,
X 4 = G or A, X 5 = G or V, X 6 = G or V, X 7 =
G or V, X 8 = G or A, X 9 = G or A.
3 . The compound of claim 2 , wherein the polypeptide that binds β-amyloid comprises a sequence selected from the group consisting of:
(SEQ ID NO:27)
SGKTEYMAFPKPFESSSSIGAEKPRNKKLPEEEVESSRTPWLYEQEGEVE
KPFIKTGFSVSVEKSTSSNRKNQLDTNGRRRQFDEESLESFSSMPDPVDP
TTVTKTFKTRKASAQASLASKDKTPKSKSKKRNSTQLKSRVKNITHARRI
LQQSNRNACNEAPETGSDFSMFEA;
(SEQ ID NO: 28)
FSSMPDPVDPTTVTKTFKTRKASAQASLASKDKTPKSKSK;
(SEQ ID NO: 29)
KDKTPKSKSKKRNSTQLKSRVKNITHARRILQQSNRNACN;
(SEQ ID NO: 30)
KTFKTRKASAQASLASKDKTPKSKSKKRNSTQLKSRVKNI;
(SEQ ID NO: 32)
KTFKTRKASAQASLASKDKTPKSKSKKRGSTQLKSRVKNI;
(SEQ ID NO: 33)
KTFKTRKASAQASLASKDKTPKSKSKKGGSTQLKSRVKNI;
(SEQ ID NO: 34)
KTFKTRGASAQASLASKDKTPKSKSKKRGSTQLKSRVKNI;
(SEQ ID NO: 35)
KTFKTGGASAQASLASKDKTPKSKSKKRGSTQLKSRVKNI;
(SEQ ID NO: 36)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKSRVKNI;
(SEQ ID NO: 37)
KTFKTRKASAQASLASKDKTPKSKSKKGGSTVKNI;
(SEQ ID NO: 38)
KTFKTRKASAQASLASKDKTPKSKSKKRG;
and
a sequence substantially identical to any of the above sequences.
4 . The compound of any one of claims 1 to 3 , wherein the antibody or fragment thereof comprises a sequence selected from the group consisting of:
an antibody or fragment thereof comprising a complementarity determining region (CDR) 1 sequence of GFKITHYTMG (SEQ ID NO:1), a CDR2 sequence of RITWGGDNTFYSNSVKG (SEQ ID NO:2), a CDR3 sequence of GSTSTATPLRVDY (SEQ ID NO:3);
an antibody or fragment thereof comprising CDR1 sequence of EYPSNFYA (SEQ ID NO:4), a CDR2 sequence of VSRDGLTT (SEQ ID NO:5), a CDR3 sequence of AIVITGVWNKVDVNSRSYHY (SEQ ID NO:6);
an antibody or fragment thereof comprising CDR1 sequence of GGTVSPTA (SEQ ID NO:7), a CDR2 sequence of ITWSRGTT (SEQ ID NO:8), a CDR3 sequence of AASTFLRILPEESAYTY (SEQ ID NO:9); and
an antibody or fragment thereof comprising CDR1 sequence of GRTIDNYA (SEQ ID NO:10), a CDR2 sequence of IDWGDGGX; where X is A or T (SEQ ID NO:11), a CDR3 sequence of AMARQSRVNLDVARYDY (SEQ ID NO:12).
5 . The compound of claim 4 , wherein the antibody or fragment thereof is humanized.
6 . The compound of any one of claims 1 to 5 , wherein the antibody or fragment thereof comprises a sequence selected from the group consisting of:
(SEQ ID NO: 13)
X 1 VQLVX 2 SGGGLVQPGGSLRLSCAASGFKITHYTMGWX 3 RQAPGKX 4 X 5
EX 6 VSRITWGGDNTFYSNSVKGRFTISRDNSKNTX 7 YLQMNSLRAEDTAV
YYCAAGSTSTATPLRVDYWGQGTLVTVSS,
where X 1 = D or E, X 2 = A or E, X 3 = F or V, X 4 =
E or G, X 5 = R or L, X 6 = F or W, X 7 = L or V;
(SEQ ID NO: 18)
X 1 VX 2 LX 3 ESGGGLVQX 4 GGSLRLSCX 5 ASEYPSNFYAMSWX 6 RQAPGKX 7
X 8 EX 9 VX 10 GVSRDGLTTLYADSVKGRFTX 11 SRDNX 12 KNTX 13 X 14 LQM
NSX 15 X 16 AEDTAVYYCAIVI TGVWNKVDVNSRSYHYWGQGTX 17 VTVSS,
where X 1 is E or Q; X 2 is K or Q; X 3 is V or E;
X 4 is A or P; X 5 is V or A; X 6 is F or V; X 7 is
E or G; X 8 is R or L; X 9 is F or W; X 10 is A or S;
X 11 is M or I; X 12 is A or S; X 13 is V or L; X 14 is
D or Y; X 15 is V or L; X 16 is K or R; and X 17 is
Q or L;
(SEQ ID NO: 21)
X 1 VX 2 LX 3 ESGGGLVQX 4 GGSLRLSCX 5 X 6 SGGTVSPTAMGWX 7 RQAPGKX 8
X 9 EX 10 VX 11 HITWSRGTTRX 12 ASSVKX 13 RFTISRDX 14 X 15 KNTX 16 Y
LQMNSLX 17 X 18 EDTAVYYC AASTFLRILPEESAYTYWGQGT X 19 VTVSS,
where X 1 is E or Q; X 2 is K or Q; X 3 is V or E; X 4
is A or P; X 5 is A or E; X 6 is V or A; X 7 is V or F;
X 8 is G or E; X 9 is L or R; X 10 is F or W; X 11 is G
or S; X 12 is V or Y; X 13 is D or G; X 14 is N or S;
X 15 is A or S; X 16 is L or V; X 17 is K or R; X 18 is
A or S; and X 19 is L or Q;
and
(SEQ ID NO: 24)
X 1 VX 2 LX 3 ESGGGLVQX 4 GGSLRLSCAASGRTIDNYAMAWX 5 RQAPGKX 6
X 7 EX 8 VX 9 TIDWGDGGX 10 RYANSVKGRFTISRDNX 11 KX 12 TX 13 YLQMN
X 14 LX 15 X 16 EDTAVYX 17 CAMARQSRVNLDVARYDYWGQGTX 18 VTVSS,
where X 1 is E or Q; X 2 is K or Q; X 3 is V or E; X 4
is A or P; X 5 is V or S; X 6 is D or G; X 7 is L or
R; X 8 is F or W; X 9 is A or S; X 10 is A or T; X 11 is
A or S; X 12 is G or N; X 13 is M or L; X 14 is N or R;
X 15 is E or R; X 16 is P or A; X 17 is S or Y; and X 18
is Q or L.
7 . The compound of any one of claims 1 to 6 , wherein the antibody or fragment thereof comprises a sequence selected from any one of:
(SEQ ID NO: 14)
DVQLQASGGGLVQAGGSLRLSCAASGFKITHYTMGWFRQAPGKEREFVSR
ITWGGDNTFYSNSVKGRFTISRDNAKNTVYLQMNSLKPEDTADYYCAAGS
TSTATPLRVDYWGKGTQVTVSS;
(SEQ ID NO: 15)
EVQLVESGGGLVQPGGSLRLSCAASGFKITHYTMGWVRQAPGKGLEWVSR
ITWGGDNTFYSNSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGS
TSTATPLRVDYWGQGTLVTVSS
(SEQ ID NO: 16)
EVQLVESGGGLVQPGGSLRLSCAASGFKITHYTMGWVRQAPGKGLEWVSR
ITWGGDNTFYSNSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAAGS
TSTATPLRVDYWGQGTLVTVSS;
(SEQ ID NO: 17)
EVQLVESGGGLVQPGGSLRLSCAASGFKITHYTMGWFRQAPGKGLEFVSR
ITWGGDNTFYSNSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAAGS
TSTATPLRVDYWGQGTLVTVSS;
(SEQ ID NO: 19)
QVKLEESGGGLVQAGGSLRLSCVASEYPSNFYAMSWFRQAPGKEREFVAG
VSRDGLTTLYADSVKGRFTMSRDNAKNTVDLQMNSVKAEDTAVYYCAIVI
TGVWNKVDVNSRSYHYWGQGTQVTVSS;
(SEQ ID NO: 20)
EVQLVESGGGLVQPGGSLRLSCAASEYPSNFYAMSWFRQAPGKEREFVSG
VSRDGLTTLYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIVI
TGVWNKVDVNSRSYHYWGQGTLVTVSS;
(SEQ ID NO: 22)
QVKLEESGGGLVQAGGSLRLSCEVSGGTVSPTAMGWFRQAPGKEREFVGH
ITWSRGTTRVASSVKDRFTISRDSAKNTVYLQMNSLKSEDTAVYYCAAST
FLRILPEESAYTYWGQGTQVTVSS;
(SEQ ID NO 23)
QVQLVESGGGLVQPGGSLRLSCAVSGGTVSPTAMGWFRQAPGKGLEFVGH
ITWSRGTTRYASSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAAST
FLRILPEESAYTYWGQGTLVTVSS
(SEQ ID NO: 25)
QVKLEESGGGLVQAGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVAT
IDWGDGGARYANSVKGRFTISRDNAKGTMYLQMNNLEPEDTAVYSCAMAR
QSRVNLDVARYDYWGQGTQVTVSS;
(SEQ ID NO: 26)
QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVAT
IDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMAR
QSRVNLDVARYDYWGQGTLVTVSS;
and
a sequence substantially identical to any of the above sequences.
8 . The compound of any one of claims 1 and 7 , wherein the antibody or fragment thereof is a single-domain antibody (sdAb).
9 . The compound of any one of claims 1 to 8 , wherein the Fc fragment is mouse Fc2a or human Fc1.
10 . The compound of claim 9 , wherein the Fc fragment comprises SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41.
11 . The compound of any one of claim 1 to claim 10 , wherein the fusion protein forms a dimer.
12 . The compound of claim any one of claims 10 to 11 , wherein the fusion protein comprises an antibody or fragment thereof, an Fc fragment, and the polypeptide that binds β-amyloid.
13 . The compound of claim 12 , wherein the fusion protein comprises the antibody or fragment thereof linked to the N-terminus of the Fc fragment, and the polypeptide that binds β-amyloid is linked to the C-terminus of the Fc fragment.
14 . The compound of claim 12 , wherein the antibody or fragment thereof is linked to the C-terminus of the Fc fragment and the polypeptide that binds β-amyloid linked to the N-terminus of the Fc fragment.
15 . The compound of claim 13 or 14 , wherein the fusion protein further comprises a linker.
16 . The compound of claim 15 , wherein the linker is an independently selected linker sequence linking the antibody or fragment thereof and/or linking the polypeptide that binds β-amyloid to the Fc.
17 . The compound of claim 16 wherein the linker sequence is GGGSGGGGS, or any suitable linker and in SEQ ID NO: 53.
18 . The compound of claim 13 , wherein the fusion protein comprises an antibody or fragment thereof selected from the group consisting of SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO: 25, SEQ ID NO:26; a polypeptide that binds b-amyloid selected from the group consisting of SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38; and an Fc fragment selected from the group consisting of SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41.
19 . The compound of claim 18 , wherein the fusion protein comprises any one of SEQ ID NO: 42 to SEQ ID NO: 53, and a sequence substantially identical to any of these sequences, and/or dimers thereof.
20 . The compound of claim 19 , wherein the fusion protein comprises a linker sequence that may be substituted for any suitable linker sequence.
21 . The compound of any one of claims 1 to 20 , wherein the compound comprises dimers of the fusion protein.
22 . The compound of any one of claims 1 to 20 , wherein the antibody or fragment thereof transmigrates the blood-brain barrier.
23 . A nucleic acid molecule encoding a compound of any one of claims 1 to 20 .
24 . A vector comprising the nucleic acid molecule of claim 23 .
25 . A composition comprising a compound of any one of claims 1 to 22 and a pharmaceutically-acceptable carrier, diluent, or excipient.
26 . A kit comprising the pharmaceutical composition of claim 25 .
27 . A composition according to claim 25 for treating Alzheimer's disease in a patient.
28 . A method of treating Alzheimer's diseases, comprising administering a compound of any one of claims 1 to 22 or the composition of claim 25 to a subject in need thereof.
29 . A method of reducing toxic β-amyloid levels in the brain of a subject having increased levels of brain amyloid beta comprising the steps of repeated parenteral administration of a sufficient amount of a pharmaceutical composition of claim 25 to a subject.
30 . A method of claim 29 , wherein parenteral administration is subcutaneous or intravenous administration.
31 . A method of claim 29 or 30 wherein toxic β-amyloid levels are reduced, after repeated parenteral administration of the composition of claim 25 , in the brains of subjects having increased brain levels of amyloid beta.
32 . A method according to claim 31 wherein toxic β-amyloid are reduced within four weeks of repeated parenteral administration of the composition of claim 22 .
33 . A method according to claim 29 , wherein toxic β-amyloid levels in the cerebrospinal fluid (CSF) of subjects having increased CSF is reduced after parenteral administration of the composition of claim 25 .
34 . A method according to claim 30 , wherein toxic β-amyloid levels in the cerebrospinal fluid (CSF) of subjects having increased CSF is reduced within 24 hours of a single parenteral administration of the composition of claim 25 .
35 . A method of reducing toxic β-amyloid levels in the brains of subjects having increased levels of brain amyloid beta comprising the administration of a compound of any one of claims 1 to 22 .
36 . An isolated polypeptide comprising an amino acid sequence
(SEQ ID NO: 31)
X 1 TFX 2 TX 3 X 4 ASAQASLASKDKTPKSKSKKX 5 X 6 STQLX 7 SX 8 VX 9 NI
wherein X 1 = G or A, X 2 = G or V, X 3 = G or A,
X 4 = G or A, X 5 = G or V, X 6 = G or V, X 7 =
G or V, X 8 = G or A, X 9 = G or A.
37 . An isolated polypeptide according to claim 36 , wherein the polypeptide sequence is selected from the group consisting of SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, and sequence substantially equivalent thereto.
38 . An isolated polypeptide according to claim 36 or 37 , fused to an antibody or fragment capable of transmigrating the blood brain barrier.
39 . A isolated polypeptide according to claim 36 or 37 , further comprising an antibody or fragment capable of transmigrating the blood brain barrier.
40 . A isolated polypeptide according to claim 36 or 37 , further comprising an Fc fragment.
41 . A fusion protein comprising an antibody or fragment thereof selected from the group consisting of SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO: 25, SEQ ID NO:26; a polypeptide that binds b-amyloid selected from the group consisting of SEQ ID NO: 32, SEQ ID NO:33, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38; and an Fc fragment selected from the group consisting of SEQ ID NO: SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41.
42 . A fusion protein according to claim 41 , wherein the fusion protein further comprises a linker peptide (for example GGGSGGGGS); wherein the fusion protein is a single chain polypeptide.
43 . A fusion protein according to claim 42 , wherein the fusion protein forms a dimeric polypeptide.
44 . A composition comprising the fusion protein of any one of claims 41 to 43 , and a pharmacologically acceptable carrier.
45 . A fusion protein of any one of claims 41 to 43 , comprising an Fc with attenuated effector functions.
46 . A nucleic acid, or vector comprising a nucleic acid, encoding a fusion protein of any one of claims 41 to 43 and 45 .
47 . A pharmaceutical composition comprising the isolated polypeptide of any one of claims 36 to 40 , and a pharmaceutically acceptable diluent, carrier, vehicle or excipient for ameliorating the symptoms of Alzheimer's disease.
48 . A pharmaceutical composition of claim 47 for use in reducing toxic β-amyloid levels in the brains of subjects having increased levels of brain amyloid beta.
49 . A method of reducing toxic I3-amyloid levels in the brains of subjects having increased levels of brain amyloid beta comprising the step of introducing a pharmaceutical composition of claim 48 into a subject's body.Join the waitlist — get patent alerts
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