US2018251534A1PendingUtilityA1
Polypeptides comprising a modified bacteriophage g3p amino acid sequence with reduced immunogenicity
Est. expiryMay 28, 2033(~6.9 yrs left)· nominal 20-yr term from priority
A61P 25/16A61P 25/14A61P 25/28A61P 21/04A61P 25/00C12N 7/00C07K 2317/76C07K 14/70514C07K 2319/30C07K 2317/24A61K 38/00C07K 16/18C07K 14/4711C12N 2795/14122A61K 9/0085C12N 2795/14133C07K 2317/21C07K 14/005A61K 9/0019C07K 14/01
50
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Claims
Abstract
The invention relates to polypeptides that comprise a portion of filamentous bacteriophage gene 3 protein (g3p) sufficient to bind to and/or disaggregate amyloid, e.g., the N1-N2 portion of g3p and mutants and fragments thereof, wherein that g3p amino acid sequence has been modified through amino acid substitution to be substantially less immunogenic than the corresponding wild-type g3p amino acid sequence when used in vivo. The polypeptides of the invention retain their ability bind to and/or disaggregate amyloid. The invention relates furthermore to the use of these variant g3p-polypeptides in the treatment and/or prevention of diseases associated with misfolding or aggregation of amyloid.
Claims
exact text as granted — not AI-modified1 - 28 . (canceled)
29 . A method of reducing amyloid or tau protein aggregates in a patient in need thereof, comprising administering to the patient an effective amount of a polypeptide or a pharmaceutical composition the polypeptide,
wherein the polypeptide comprises a variant of a starting amino acid sequence, wherein the starting amino acid sequence is selected from the group consisting of amino acids 1-217 of SEQ ID NO:1, amino acids 1-217 of SEQ ID NO:3, and amino acids 1-217 of SEQ ID NO:7,
wherein:
(a) the variant has from 1 to 9 amino acid substitutions as compared to the starting amino acid sequence, wherein each amino acid substitution is selected from the group of amino acid substitutions set forth below:
Amino Acid present in the
Amino
Starting Amino Acid
Acid #
Sequence
Amino Acid Substitutions
48
G
H, K, R, S, T, D, P
50
E
G, H, K, P, R
51
T
G, H, K, R, P, Q, N, W
53
C
F, H, K, N, Q, R, W, Y
54
Y
G, H, K, R, P
56
T
G, H, K, R, P
135
M
A, D, G, K, N, T, H, R, C, E, P,
Q, S
137
Q
D, E
138
N
D, E, G, H, P, Q, S, T
140
R
D, E, H, Q, A, G, M, N, P, S, Y
141
F
D, E, G, N, P, Q, Y
143
N
A, G
173
S
G, P, K, D, H, R, T
174
K
R
175
A
G, H, K, P, R
176
M
G, H, K, N, R, P, Q, W
178
D
G, N, Q, S, T, F, H, K, R, W, Y
179
A
H, K, P, R
181
W
G, H, K, R, P
wherein, when the starting amino acid sequence is amino acids 1-217 of SEQ ID NO:1, any of the 1 to 9 amino acid substitutions is additionally selected from the group consisting of V215S, V215T, V215C, V215D, V215E, V215F, V215H, V215K, V215N, V215P, V215Q, and V215R; and
(b) the variant optionally further comprises one or more of the following modifications as compared to the starting amino acid sequence:
(i) substitution of WV at amino acids 43-45 with AAA;
(ii) substitution C53W
(iii) deletion of amino acids 96-103;
(iv) substitution of QPP at amino acids 212-214 with AGA;
(v) substitutions W181A, F190A and F194A;
(vi) deletion of amino acid 1; and
(vii) deletion of amino acids 1 and 2;
and wherein the polypeptide binds to and/or disaggregates amyloid and has reduced immunogenicity as compared to a corresponding polypeptide comprising the starting amino acid sequence.
30 . The method of claim 29 , wherein the patient is exhibiting symptoms of a disease that is associated with the presence of amyloid or tau protein aggregates.
31 . The method of claim 29 , wherein the patient is positive for the biomarker florbetapir when that biomarker is used as an imaging agent in positron emission tomography.
32 . The method of claim 29 , wherein the patient is suffering from a disease selected from Alzheimer's disease, early onset Alzheimer's disease, late onset Alzheimer's disease, presymptomatic Alzheimer's disease, Parkinson's disease, SAA amyloidosis, cystatin C, hereditary Icelandic syndrome, senility, multiple myeloma, familial amyloidotic polyneuropathy (FAP), Finnish form of FAP (aggregation of gelsolin), familial amyloidotic cardiomyopathy (FAC), senile systemic amyloidosis (SSA), islet amyloid polypeptide (IAPP) amyloidosis, disease characterized by formation of amyloid protein by aggregation of IgG kappa light chain, prion disease, kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), scrapie, bovine spongiform encephalitis (BSE), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1, SCA3, SCA6, or SCA7), Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, hereditary cerebral amyloid angiopathy, familial amyloidosis, British/Danish dementia, familial encephalopathy, Amyotrophic lateral sclerosis/parkinsonism-dementia complex, Argyrophilic grain dementia, Corticobasal degeneration, Dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Myotonic dystrophy, Niemann-Pick disease type C, Non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, Postencephalitic parkinsonism, Prion protein cerebral amyloid angiopathy, Progressive subcortical gliosis, Progressive supranuclear palsy, Subacute sclerosing panencephalitis, Tangle only dementia, frontotemporal lobar degenerations (FTLDs), and frontotemporal lobe dementia (FTD) including a patient having one or more of the following clinical syndromes: behavioral variant FTD (bvFTD), progressive non-fluent aphasia (PNFA), frontotemporal dementia with parkinsonism linked to chromosome 17, Progressive Supranuclear Palsey (PSP), and semantic dementia (SD).
33 . A nucleic acid sequence encoding a polypeptide comprising a variant of a starting amino acid sequence, wherein the starting amino acid sequence is selected from the group consisting of amino acids 1-217 of SEQ ID NO:1, amino acids 1-217 of SEQ ID NO:3, and amino acids 1-217 of SEQ ID NO:7, wherein:
(a) the variant has from 1 to 9 amino acid substitutions as compared to the starting amino acid sequence, wherein each amino acid substitution is selected from the group of amino acid substitutions set forth below:
Amino Acid present in the
Amino
Starting Amino Acid
Acid #
Sequence
Amino Acid Substitutions
48
G
H, K, R, S, T, D, P
50
E
G, H, K, P, R
51
T
G, H, K, R, P, Q, N, W
53
C
F, H, K, N, Q, R, W, Y
54
Y
G, H, K, R, P
56
T
G, H, K, R, P
135
M
A, D, G, K, N, T, H, R, C, E, P,
Q, S
137
Q
D, E
138
N
D, E, G, H, P, Q, S, T
140
R
D, E, H, Q, A, G, M, N, P, S, Y
141
F
D, E, G, N, P, Q, Y
143
N
A, G
173
S
G, P, K, D, H, R, T
174
K
R
175
A
G, H, K, P, R
176
M
G, H, K, N, R, P, Q, W
178
D
G, N, Q, S, T, F, H, K, R, W, Y
179
A
H, K, P, R
181
W
G, H, K, R, P
wherein, when the starting amino acid sequence is amino acids 1-217 of SEQ ID NO:1, any of the 1 to 9 amino acid substitutions is additionally selected from the group consisting of V215S, V215T, V215C, V215D, V215E, V215F, V215H, V215K, V215N, V215P, V215Q, and V215R; and
(b) the variant optionally further comprises one or more of the following modifications as compared to the starting amino acid sequence:
(i) substitution of WV at amino acids 43-45 with AAA;
(ii) substitution C53W
(iii) deletion of amino acids 96-103;
(iv) substitution of QPP at amino acids 212-214 with AGA;
(v) substitutions W181A, F190A and F194A;
(vi) deletion of amino acid 1; and
(vii) deletion of amino acids 1 and 2;
and wherein the polypeptide binds to and/or disaggregates amyloid and has reduced immunogenicity as compared to a corresponding polypeptide comprising the starting amino acid sequence.
34 . The nucleic acid sequence of claim 33 , further encoding a mammalian signal sequence fused to and in frame with the polypeptide encoding sequence.
35 . A vector comprising the nucleic acid sequence of claim 33 , wherein the nucleic acid sequence is operatively linked to an expression control sequence in the vector.
36 . A host cell comprising the vector of claim 35 .
37 . A method of making the polypeptide encoded by the nucleic acid sequence of claim 33 , comprising the steps of expressing the protein encoded by the nucleic acid sequence of claim 33 ; and isolating the expressed polypeptide.
38 . A method of making the polypeptide encoded by the nucleic acid sequence of claim 33 , comprising the steps of culturing the host cell of claim 36 under conditions sufficient to allow expression of the polypeptide; and isolating the expressed polypeptide.Cited by (0)
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