US2023257424A1PendingUtilityA1
Blood-brain barrier transmigrating compounds and uses thereof
Est. expiryJan 30, 2037(~10.5 yrs left)· nominal 20-yr term from priority
C07K 2317/622C07K 16/2863C07K 14/4711C07K 16/28C07K 14/001C07K 16/18A61P 25/28C07K 2319/30C07K 2317/24C07K 2317/569A61K 47/68C07K 2319/10C07K 2319/70A61K 2039/505C07K 2319/33C07K 2317/94C07K 16/1282A61K 9/0019C07K 2317/565
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Claims
Abstract
A brain-penetrating composition of amyloid-ß 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-ß 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 . An isolated peptide that binds β-amyloid comprising an amino acid sequence of:
X 1 TFX 2 TX 3 X 4 ASAQASLASKDKTPKSKSKKX 5 X 6
where X 1 =K, G or A or X 1 =G or A, X 2 =K, G or V, X 3 =R, G or A, X 4 =K, G or A, X 5 =R, G or V, X 6 =N, G or V, (SEQ ID NO: 46).
2 . An isolated peptide that binds β-amyloid comprising an amino acid sequence of:
(SEQ ID NO: 31)
X 1 TFX 2 TX 3 X 4 ASAQASLASKDKTPKSKSK
KX 5 X 6 STQLX 7 SX 8 VX 9 NI
wherein X 1 =K, G or A, or X 1 =G or A, X 2 =K, G or V, X 3 =R, G or A, X 4 =K, G or A, X 5 =R, G or V, X 6 =N, G or V, X 7 =K, G or V, X 8 =R, G or A, X 9 =K, G or A, or any C-terminally cleaved β-amyloid binding product thereof.
3 . The isolated peptide of claim 1 , wherein the amino acid sequence comprises a sequence selected from the group consisting of:
(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)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKSRVK;
(SEQ ID NO: 38)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKSRV;
(SEQ ID NO: 39)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKSR;
(SEQ ID NO: 40)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKS;
(SEQ ID NO: 41)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLK;
(SEQ ID NO: 42)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQL;
(SEQ ID NO: 43)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQ;
(SEQ ID NO: 44)
KTFKTRKASAQASLASKDKTPKSKSKKGGSTVKNI;
(SEQ ID NO: 45)
KTFKTRKASAQASLASKDKTPKSKSKKRG;
(SEQ ID NO: 47)
GTFGTGGASAQASLASKDKTPKSKSKKGG;
and
a sequence that is at least 95% identical to any of the above sequences, or a C-terminally cleaved β-amyloid binding peptide thereof,
optionally wherein the C-terminally cleaved β-amyloid binding peptide comprises a sequence selected from the group consisting of:
(SEQ ID NO: 37)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKSRVK;
(SEQ ID NO: 38)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKSRV;
(SEQ ID NO: 39)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKSR;
(SEQ ID NO: 40)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLKS;
(SEQ ID NO: 41)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQLK;
(SEQ ID NO: 42)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQL;
and
(SEQ ID NO: 43)
GTFGTGGASAQASLASKDKTPKSKSKKGGSTQ.
4 . (canceled)
5 . The isolated peptide of claim 1 , fused to an antibody or antibody fragment capable of transmigrating the blood brain barrier, optionally wherein the antibody or antibody fragment is an Fc fragment.
6 . (canceled)
7 . The isolated peptide of claim 5 , wherein the isolated peptide, the antibody or fragment thereof, and the Fc fragment form a single-chain polypeptide fusion protein.
8 . The isolated peptide of claim 5 , wherein the Fc fragment comprises an Fc with attenuated effector functions.
9 . A fusion protein comprising the isolated peptide of claim 1 , and an antibody or antibody fragment that transmigrates the blood brain barrier (BBB), optionally wherein the fusion protein is a single-chain polypeptide further comprising an Fc fragment, and further optionally wherein the single-chain polypeptide forms a dimer.
10 - 12 . (canceled)
13 . The fusion protein of claim 9 , wherein the single-chain polypeptide comprises:
an antibody or fragment thereof; a peptide that binds β-amyloid selected from the group consisting of SEQ ID NO:31, 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, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, and SEQ ID NO:47; and an Fc fragment selected from the group consisting of SEQ ID NO: SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, optionally wherein the antibody comprises:
a sequence 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);
a sequence 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);
a sequence 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); or
a sequence 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).
14 . (canceled)
15 . The fusion protein of claim 13 , wherein the antibody or fragment thereof comprises
a sequence selected from any one of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 21, SEQ ID NO: 24, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 26, and a sequence that is at least 95% identical to any of the above sequences.
16 - 19 . (canceled)
20 . The fusion protein according to claim 13 , wherein the single-chain polypeptide comprising the antibody or fragment thereof is linked to the peptide that binds β-amyloid via the Fc fragment, optionally wherein the fusion protein is a single-chain polypeptide comprising a sequences selected from the group consisting of: SEQ ID NO:51 SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO: 54, SEQ ID NO:55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, and a sequence that is at least 95% identical to any of the above sequences, optionally wherein the single-chain polypeptide forms a dimer.
21 . (canceled)
22 . The fusion protein according to claim 20 , wherein the fusion protein is a single-chain polypeptide comprising any suitable peptide linker, optionally wherein the peptide linker comprises an amino acid sequence that allows for the linked components of the fusion protein to maintain their unrestricted desired biological function.
23 - 28 . (canceled)
28 . The fusion protein of claim 9 , wherein the antibody or fragment thereof is humanized, or a single-domain antibody (sdAb).
29 - 30 . (canceled)
31 . The fusion protein of claim 9 , wherein the Fc fragment is mouse Fc2a or human Fc1, optionally wherein the Fc fragment comprises SEQ ID NO: 48, SEQ ID NO: 49, or SEQ ID NO: 50.
32 . The fusion protein of claim 9 , 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 linked to the C-terminus of the Fc fragment; or the antibody or fragment thereof 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.
33 - 37 . (canceled)
38 . A pharmaceutical composition comprising the isolated peptide of claim 1 , and a pharmacologically acceptable carrier.
39 . A pharmaceutical composition comprising the fusion protein of claim 9 , and a pharmacologically acceptable carrier.
40 . A nucleic acid molecule encoding the isolated peptide of claim 1 .
41 . A vector comprising the nucleic acid molecule of claim 40 .
42 - 43 . (canceled)
44 . A method of treating Alzheimer's diseases, comprising administering the fusion protein of claim 9 to a subject in need thereof.
45 . A method of reducing β-amyloid levels in a subject having increased levels of β-amyloid comprising the steps of repeated parenteral administration of a sufficient amount of the pharmaceutical composition of claim 39 to a subject.
46 - 58 . (canceled)Join the waitlist — get patent alerts
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