US2018340020A1PendingUtilityA1
Peptide-mediated delivery of immunoglobulins across the blood-brain barrier
Assignee: MAYO FOUND MEDICAL EDUCATION & RESPriority: Aug 24, 2015Filed: Aug 9, 2018Published: Nov 29, 2018
Est. expiryAug 24, 2035(~9.1 yrs left)· nominal 20-yr term from priority
C07K 16/2863A61K 47/64C07K 14/775A61K 2039/505C07K 2317/24
51
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Claims
Abstract
Provided herein are materials and methods for delivering immunoglobulins (e.g. therapeutic immunoglobulins) across the blood-brain barrier.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A peptide comprising the sequence:
(SEQ ID NO: 1)
A p -L n -B m
wherein:
(a) A is an immunoglobulin affinity ligand;
(b) L is a linker; and
(c) B is a blood-brain barrier agent comprising the sequence:
(SEQ ID NO: 3)
L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9;
wherein:
X1 is selected from the group consisting of A, L, S, and V;
X2 is selected from the group consisting of L and M;
X3 is selected from the group consisting of A and S;
X4 is selected from the group consisting of N, S, and T;
X5 is selected from the group consisting of K and N;
X6 is selected from the group consisting of L, M, and V;
X7 is selected from the group consisting of R and P;
X8 is selected from the group consisting of L and M;
X9 is selected from the group consisting of A and L;
n is an integer from 0 to 50;
m is an integer from 1 to 3; and
p is an integer from 1 to 4.
2 . The peptide of claim 1 , wherein the immunoglobulin affinity ligand comprises the sequence H-X10-X11-X12-X13-X14 (SEQ ID NO:25)
wherein: X10 is selected from the group consisting of W, Y, and F; X11 is selected from the group consisting of R and F; X12 is selected from the group consisting of K, and R; X13 is selected from the group consisting of W, F, and H; and X14 is selected from the group consisting of Z, V, D, and L.
3 . The peptide of claim 2 , wherein the immunoglobulin affinity ligand is H-W-R-G-W-Z (SEQ ID NO:26).
4 . The peptide of claim 1 , wherein the immunoglobulin affinity ligand non-covalently binds a therapeutic immunoglobulin.
5 . The peptide of claim 4 , wherein the therapeutic immunoglobulin is an IgG immunoglobulin.
6 . The peptide of claim 1 , wherein p is 1.
7 . The peptide of claim 1 , wherein the linker is selected from the group consisting of one or more hydrophilic amino acids, one or more neutral amino acids, and one or more amino acid analogs.
8 . The peptide of claim 7 , wherein the linker is one or more hydrophilic amino acids.
9 . The peptide of claim 8 , wherein the linker is a lysine.
10 . The peptide of claim 9 , wherein n is 4.
11 . The peptide of claim 1 , wherein the blood-brain barrier agent comprises a sequence having at least 80% sequence identity to:
(SEQ ID NO: 4)
L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.
12 . The peptide of claim 11 , wherein the blood-brain barrier agent is
(SEQ ID NO: 4)
L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.
13 . A method of transporting a therapeutic immunoglobulin across the blood-brain barrier of a patient, the method comprising:
(a) administering to the patient an effective amount of a peptide comprising the sequence:
(SEQ ID NO: 1)
A p -L n -B m
wherein:
i. A is an immunoglobulin affinity ligand;
ii. L is a linker; and
iii. B is a blood-brain barrier agent comprising the sequence:
(SEQ ID NO: 3)
L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9;
wherein:
X1 is selected from the group consisting of A, L, S, and V;
X2 is selected from the group consisting of L and M;
X3 is selected from the group consisting of A and S;
X4 is selected from the group consisting of N, S, and T;
X5 is selected from the group consisting of K and N;
X6 is selected from the group consisting of L, M, and V;
X7 is selected from the group consisting of R and P;
X8 is selected from the group consisting of L and M;
X9 is selected from the group consisting of A and L;
n is an integer from 0 to 50;
m is an integer from 1 to 3; and
p is an integer from 1 to 4; and
(b) administering to the patient an effective amount of the therapeutic immunoglobulin.
14 . A method of treating a neurological disorder in a patient, the method comprising:
(a) administering to the patient an effective amount of a peptide comprising the sequence:
(SEQ ID NO: 1)
A p -L n -B m
wherein
i. A is an immunoglobulin affinity ligand;
ii. L is a linker; and
iii. B is a blood-brain barrier agent comprising the sequence:
(SEQ ID NO: 3)
L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9;
wherein:
X1 is selected from the group consisting of A, L, S, and V;
X2 is selected from the group consisting of L and M;
X3 is selected from the group consisting of A and S;
X4 is selected from the group consisting of N, S, and T;
X5 is selected from the group consisting of K and N;
X6 is selected from the group consisting of L, M, and V;
X7 is selected from the group consisting of R and P;
X8 is selected from the group consisting of L and M;
X9 is selected from the group consisting of A and L;
n is an integer from 0 to 50;
m is an integer from 1 to 3; and
p is an integer from 1 to 4; and
(b) administering to the patient an effective amount of a therapeutic immunoglobulin.
15 . The method of claim 13 or 14 , wherein the immunoglobulin affinity ligand comprises the sequence H-X10-X11-X12-X13-X14 (SEQ ID NO:25);
wherein:
X10 is selected from the group consisting of W, Y, and F;
X11 is selected from the group consisting of R and F;
X12 is selected from the group consisting of K, and R;
X13 is selected from the group consisting of W, F, and H; and
X14 is selected from the group consisting of Z, V, D, and L.
16 . The method of claim 15 , wherein the immunoglobulin affinity ligand is H-W-R-G-W-Z (SEQ ID NO:26).
17 . The method of claim 13 or 14 , wherein the immunoglobulin affinity ligand non-covalently binds the therapeutic immunoglobulin.
18 . The method of claim 17 , wherein the therapeutic immunoglobulin is an IgG immunoglobulin.
19 . The method of claim 13 or 14 , wherein p is 1.
20 . The method of claim 13 or 14 , wherein the linker is selected from the group consisting of one or more hydrophilic amino acids, one or more neutral amino acids, and one or more amino acid analogs.
21 . The method of claim 20 , wherein the linker is one or more hydrophilic amino acids.
22 . The method of claim 21 , wherein the linker is a lysine.
23 . The method of claim 22 , wherein n is 4.
24 . The method of claim 13 or 14 , wherein the blood-brain barrier agent comprises a sequence having at least 80% sequence identity to:
(SEQ ID NO: 4)
L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.
25 . The method of claim 24 , wherein the blood-brain barrier agent is
(SEQ ID NO: 4)
L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.
26 . The method of claim 13 or 14 , wherein the therapeutic immunoglobulin is selected from the group consisting of cetuximab, bococizumab, dinutuximab, racotumomab, ralpancizumab, and avastin.
27 . The method of claim 26 , wherein the therapeutic immunoglobulin is cetuximab.
28 . The method of claim 13 or 14 , wherein the peptide and the therapeutic immunoglobulin are admixed prior to administering to the patient.
29 . The method of claim 14 , wherein the neurological disorder is chosen from: meningitis, epilepsy, multiple sclerosis, neuromyelitis optica, late-stage neurological trypanosomiasis, Parkinson's, progressive multifocal leukoencephalopathy, De Vivo disease, Alzheimer's disease, HIV Encephalitis, addiction, and cancer.
30 . The method of claim 13 or 14 , wherein the method further comprises administering to the patient an additional active agent.
31 . The method of claim 30 , wherein the additional active agent is administered about 5 minutes to about 2 hours after the peptide.
32 . The method of claim 30 , wherein the additional active agent is an imaging agent.
33 . The method of claim 32 , wherein the imaging agent comprises one or more of a: radionuclide, a paramagnetic metal, a fluorochrome, a dye, and an enzyme substrate.
34 . The method of claim 30 , wherein the additional active agent is a therapeutic agent.
35 . The method of claim 34 , wherein the therapeutic agent is selected from the group consisting of a polypeptide, an oligonucleotide, an antibiotic, an antiviral agent, a cancer drug, an anti-addiction drug, and an anesthetic.
36 . The method of claim 34 , wherein the therapeutic agent is a cancer drug selected from the group consisting of ZD6474 and INCB3619.
37 . A peptide having at least 80% sequence identity to the sequence H-W-R-G-W-Z-L-L-L-L-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A (SEQ ID NO:42).
38 . A complex comprising:
(a) a peptide comprising the sequence:
(SEQ ID NO: 1)
A p -L n -B m
wherein
i. A is an immunoglobulin affinity ligand;
ii. L is a linker; and
iii. B is a blood-brain barrier agent comprising the sequence:
(SEQ ID NO: 3)
L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9;
wherein:
X1 is selected from the group consisting of A, L, S, and V;
X2 is selected from the group consisting of L and M;
X3 is selected from the group consisting of A and S;
X4 is selected from the group consisting of N, S, and T;
X5 is selected from the group consisting of K and N;
X6 is selected from the group consisting of L, M, and V;
X7 is selected from the group consisting of R and P;
X8 is selected from the group consisting of L and M;
X9 is selected from the group consisting of A and L;
n is an integer from 0 to 50;
m is an integer from 1 to 3; and
p is an integer from 1 to 4; and
(b) a therapeutic immunoglobulin.
39 . The complex of claim 38 , wherein the immunoglobulin affinity ligand comprises the sequence H-X10-X11-X12-X13-X14 (SEQ ID NO:25);
wherein: X10 is selected from the group consisting of W, Y, and F; X11 is selected from the group consisting of R and F; X12 is selected from the group consisting of K, and R; X13 is selected from the group consisting of W, F, and H; and X14 is selected from the group consisting of Z, V, D, and L.
40 . The complex of claim 38 , wherein the immunoglobulin affinity ligand is H-W-R-G-W-Z (SEQ ID NO:26).
41 . The complex of claim 38 , wherein the immunoglobulin affinity ligand is non-covalently bound to the therapeutic immunoglobulin.
42 . The complex of claim 38 , wherein the therapeutic immunoglobulin is an IgG immunoglobulin.
43 . The complex of claim 38 , wherein p is 1.
44 . The complex of claim 38 , wherein the linker is selected from the group consisting of one or more hydrophilic amino acids, one or more neutral amino acids, and one or more amino acid analogs.
45 . The complex of claim 44 , wherein the linker is one or more hydrophilic amino acids.
46 . The complex of claim 45 , wherein the linker is a lysine.
47 . The complex of claim 46 , wherein n is 4.
48 . The complex of claim 38 , wherein the blood-brain barrier agent comprises a sequence having at least 80% sequence identity to:
(SEQ ID NO: 4)
L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.
49 . The complex of claim 48 , wherein the blood-brain barrier agent is
(SEQ ID NO: 4)
L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.
50 . The complex of claim 38 , wherein the therapeutic immunoglobulin is selected from the group consisting of cetuximab, bococizumab, dinutuximab, racotumomab, ralpancizumab, and avastin.
51 . The complex of claim 50 , wherein the therapeutic immunoglobulin is cetuximab.
52 . A complex comprising:
(a) a peptide comprising the sequence:
(SEQ ID NO: 41)
H-X10-X11-X12-X13-X14-L-L-L-L-L-R-X1-R-X2-X3-X4-H-
L-R-X5-X6-X7-K-R-L-X8-R-D-X9;
wherein
X1 is selected from the group consisting of A, L, S, and V;
X2 is selected from the group consisting of L and M;
X3 is selected from the group consisting of A and S;
X4 is selected from the group consisting of N, S, and T;
X5 is selected from the group consisting of K and N;
X6 is selected from the group consisting of L, M, and V;
X7 is selected from the group consisting of R and P;
X8 is selected from the group consisting of L and M;
X9 is selected from the group consisting of A and L;
X10 is selected from the group consisting of W, Y, and F;
X11 is selected from the group consisting of R and F;
X12 is selected from the group consisting of K, and R;
X13 is selected from the group consisting of W, F, and H; and
X14 is selected from the group consisting of Z, V, D, and L
and
(b) a therapeutic immunoglobulin, wherein the therapeutic immunoglobulin is cetuximab.
53 . The complex of claim 52 , where the peptide comprises the sequence:
(SEQ ID NO: 42)
H-W-R-G-W-Z-L-L-L-L-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-
L-L-R-D-A.
54 . A method of transporting a therapeutic immunoglobulin across the blood-brain barrier of a patient, the method comprising:
(a) administering to the patient: an effective amount of a peptide comprising the sequence:
(SEQ ID NO: 1)
A p -L n -B m
wherein:
i. A is an immunoglobulin affinity ligand;
ii. L is a linker; and
iii. B is a blood-brain barrier agent comprising the sequence:
(SEQ ID NO: 3)
L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9;
wherein:
X1 is selected from the group consisting of A, L, S, and V;
X2 is selected from the group consisting of L and M;
X3 is selected from the group consisting of A and S;
X4 is selected from the group consisting of N, S, and T;
X5 is selected from the group consisting of K and N;
X6 is selected from the group consisting of L, M, and V;
X7 is selected from the group consisting of R and P;
X8 is selected from the group consisting of L and M;
X9 is selected from the group consisting of A and L;
n is an integer from 0 to 50;
m is an integer from 1 to 3; and
p is an integer from 1 to 4; and
an effective amount of the therapeutic immunoglobulin; and
(b) subsequently administering to the patient an additional active agent.
55 . The method of claim 54 , wherein the immunoglobulin affinity ligand comprises the sequence H-X10-X11-X12-X13-X14 (SEQ ID NO:25),
wherein: X10 is selected from the group consisting of W, Y, and F; X11 is selected from the group consisting of R and F; X12 is selected from the group consisting of K, and R; X13 is selected from the group consisting of W, F, and H; and X14 is selected from the group consisting of Z, V, D, and L.
56 . The method of claim 55 , wherein the immunoglobulin affinity ligand is H-W-R-G-W-Z (SEQ ID NO:26).
57 . The method of claim 54 , wherein the immunoglobulin affinity ligand non-covalently binds the therapeutic immunoglobulin.
58 . The method of claim 54 , wherein the therapeutic immunoglobulin is an IgG immunoglobulin.
59 . The method of claim 54 , wherein p is 2.
60 . The method of claim 54 , wherein the linker is selected from the group consisting of one or more hydrophilic amino acids, one or more neutral amino acids, and one or more amino acid analogs.
61 . The method of claim 60 , wherein the linker is one or more hydrophilic amino acids.
62 . The method of claim 61 , wherein the linker is a lysine.
63 . The method of claim 62 , wherein n is 4.
64 . The method of claim 54 , wherein the blood-brain barrier agent comprises a sequence having at least 80% sequence identity to:
(SEQ ID NO: 4)
L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.
65 . The method of claim 64 , wherein the blood-brain barrier agent is
(SEQ ID NO: 4)
L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.
66 . The method of claim 54 , wherein the therapeutic immunoglobulin is selected from the group consisting of cetuximab, bococizumab, dinutuximab, racotumomab, ralpancizumab, and avastin.
67 . The method of claim 66 , wherein the therapeutic immunoglobulin is cetuximab.
68 . The method of claim 54 , wherein the peptide and the therapeutic immunoglobulin are admixed prior to administering to the patient.
69 . The method of claim 54 , wherein the additional active agent is administered about 5 minutes to about 2 hours after the peptide.
70 . The method of claim 54 , wherein the additional active agent is an imaging agent.
71 . The method of claim 70 , wherein the imaging agent comprises one or more of a: radionuclide, a paramagnetic metal, a fluorochrome, a dye, and an enzyme substrate.
72 . The method of claim 54 , wherein the additional active agent is a therapeutic agent.
73 . The method of claim 72 , wherein the therapeutic agent is selected from the group consisting of a polypeptide, an oligonucleotide, an antibiotic, an antiviral agent, a cancer drug, an anti-addiction drug, and an anesthetic.
74 . The method of claim 73 , wherein the therapeutic agent is selected from the group consisting of cetuximab, ZD6474, and INCB3619.Join the waitlist — get patent alerts
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