US2019119326A1PendingUtilityA1
Cyclin a1-targeted t-cell immunotherapy for cancer
Assignee: HUTCHINSON FRED CANCER RESPriority: Nov 11, 2011Filed: Dec 20, 2018Published: Apr 25, 2019
Est. expiryNov 11, 2031(~5.3 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 37/04A61P 35/02A61K 38/08C07K 14/4738A61K 38/00C07K 7/06C12N 2502/99C07K 7/08C12N 2510/00C12N 15/8509A61K 38/10C12N 9/12C12N 2502/1121A61P 37/00C12N 2015/8518A61K 2039/5154A61K 2039/5158A61K 39/0011A61K 40/4239A61K 40/11A61K 2239/48C12N 5/0639C12N 5/0636A61K 39/001149
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Claims
Abstract
Compositions and methods are provided for eliciting antigen-specific T-cell responses against human cyclin A1 (CCNA1), which is herein identified as a leukemia-associated antigen based on its overexpression in acute myeloid leukemia (AML) including leukemia stem cells (LSC) and in immunologically privileged testis cells, but not in other normal cell types. CCNA1-derived peptide epitopes that are immunogenic for T-cells including CTL are disclosed, as are immunotherapeutic approaches using such peptides for vaccines and generation of adoptive transfer therapeutic cells.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A polypeptide capable of eliciting an antigen-specific T-cell response to human cyclin A1 (CCNA1), said polypeptide being selected from:
(1) a polypeptide of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8 or 7 amino acids comprising a sequence of at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous amino acids from the CCNA1 amino acid sequence set forth in SEQ ID NO:9, (2) a polypeptide of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 or 9 amino acids wherein the polypeptide comprises a sequence of at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous amino acids from the CCNA1 amino acid sequence set forth in SEQ ID NO:9 that includes one of SEQ ID NOS:1-8, (3) a polypeptide of general formula I:
N—X—C, [I]
wherein:
(a) N—X—C is a polypeptide of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 or 9 amino acids in which X comprises an amino acid sequence that is selected from:
CCNA1(120-131)
[SEQ ID NO: 1]
VDTGTLKSDLHF,
CCNA1(218-226)
[SEQ ID NO: 2]
AETLYLAVN,
CCNA1(227-235)
[SEQ ID NO: 3]
FLDRFLSCM,
CCNA1(253-261)
[SEQ ID NO: 4]
ASKYEEIYP,
CCNA1(118-127)
[SEQ ID NO: 5]
YEVDTGTLKS,
CCNA1(167-175)
[SEQ ID NO: 6]
YAEEIYQYL,
CCNA1(330-339)
[SEQ ID NO: 7]
LEADPFLKYL,
and
CCNA1(341-351)
[SEQ IN NO: 8]
SLIAAAAFCLA,
(b) N is an amino terminus of the peptide and consists of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 amino acids that are independently selected from natural amino acids and non-natural amino acids, and
(c) C is a carboxy terminus of the peptide and consists of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 amino acids that are independently selected from natural amino acids and non-natural amino acids, and
(4) the polypeptide of (3) in which either:
(i) the polypeptide of general formula I comprises at least 75% and no more than 99% sequence identity to a fragment of no more than 20 contiguous amino acids of SEQ ID NO:9, or
(ii) either or both of N and C in general formula I has an amino acid sequence that is not present in SEQ ID NO:9.
2 . The polypeptide of claim 1 wherein the antigen-specific T-cell response comprises at least one of:
(a) an antigen-specific T-cell response comprising major histocompatibility complex (MHC)-restricted T-cell recognition of the polypeptide,
(b) an antigen-specific CD8 + T-cell response to human cyclin A1 (CCNA1) in a class I human leukocyte antigen (HLA)-restricted manner,
(c) an antigen-specific CD8 + T-cell response to human cyclin A1 (CCNA1) in a class I HLA-A*201-restricted manner,
(d) an antigen-specific CD4 + T-cell response to human cyclin A1 (CCNA1) in a class II human leukocyte antigen (HLA)-restricted manner,
(e) an antigen-specific T-cell response that comprises an interferon-gamma (IFN-γ) response,
(f) an antigen-specific T-cell response that comprises at least one of a CD4 + helper T lymphocyte (Th) response and a CD8 + cytotoxic T lymphocyte (CTL) response,
(g) an antigen-specific T-cell response comprising a CTL response that is directed against a CCNA1-overexpressing cell, and
(h) an antigen-specific T-cell response comprising a CTL response that is directed against a CCNA1-overexpressing cell that is an acute myeloid leukemia (AML) cell or a leukemic stem cell (LSC).
3 . An isolated polynucleotide that encodes the polypeptide of claim 1 , wherein the polynucleotide does not encode more than 20 contiguous amino acids of SEQ ID NO:9.
4 . A recombinant expression vector comprising one or more polynucleotides according to claim 3 , wherein each of said one or more polynucleotides is operably linked to an expression control sequence.
5 . An immunogenic composition comprising one or more isolated polypeptides according to claim 1 .
6 . An immunogenic composition that is capable of eliciting an antigen-specific T-cell response to human cyclin A1 (CCNA1) and that is selected from:
(a) a composition comprising one or more isolated polynucleotides according to claim 3 , and (b) a composition comprising one or more recombinant expression vectors, each of said recombinant expression vectors comprising one or more polynucleotides according to claim 3 , wherein each of said one or more polynucleotides is operably linked to an expression control sequence.
7 . A method of treating a condition characterized by CCNA1 overexpression in cells of a subject, comprising administering to the subject an effective amount of a composition that comprises the polypeptide of claim 1 .
8 . A method of treating a condition characterized by CCNA1 overexpression in cells of a subject, comprising administering to the subject an effective amount of the immunogenic composition of claim 6 .
9 . The method of claim 8 wherein the condition characterized by CCNA1 overexpression is a leukemia.
10 . A method for preparing antigen-pulsed antigen-presenting cells, comprising:
contacting in vitro, under conditions and for a time sufficient for antigen processing and presentation by antigen-presenting cells to take place, (i) a population of antigen-presenting cells that are immunocompatible with a subject, and (ii) the polypeptide of claim 1 , thereby obtaining antigen-pulsed antigen-presenting cells capable of eliciting an antigen-specific T-cell response to human cyclin A1 (CCNA1).
11 . An antigen-pulsed antigen-presenting cell, comprising
(A) a cell surface on which is presented a polypeptide that is capable of eliciting an antigen-specific T-cell response to human cyclin A1 (CCNA1), wherein said polypeptide is selected from:
(1) a polypeptide of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8 or 7 amino acids comprising a sequence of at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous amino acids from the CCNA1 amino acid sequence set forth in SEQ ID NO:9,
(2) a polypeptide of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 or 9 amino acids wherein the polypeptide comprises a sequence of at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous amino acids from the CCNA1 amino acid sequence set forth in SEQ ID NO:9 that includes one of SEQ ID NOS:1-8,
(3) a polypeptide of general formula I:
N—X—C, [I]
wherein:
(a) N—X—C is a polypeptide of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 or 9 amino acids in which X comprises an amino acid sequence that is selected from:
CCNA1(120-131)
[SEQ ID NO: 1]
VDTGTLKSDLHF,
CCNA1(218-226)
[SEQ ID NO: 2]
AETLYLAVN,
CCNA1(227-235)
[SEQ ID NO: 3]
FLDRFLSCM,
CCNA1(253-261)
[SEQ ID NO: 4]
ASKYEEIYP,
CCNA1(118-127)
[SEQ ID NO: 5]
YEVDTGTLKS,
CCNA1(167-175)
[SEQ ID NO: 6]
YAEEIYQYL,
CCNA1(330-339)
[SEQ ID NO: 7]
LEADPFLKYL,
and
CCNA1(341-351)
[SEQ IN NO: 8]
SLIAAAAFCLA,
(b) N is an amino terminus of the peptide and consists of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 amino acids that are independently selected from natural amino acids and non-natural amino acids, and
(c) C is a carboxy terminus of the peptide and consists of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 amino acids that are independently selected from natural amino acids and non-natural amino acids, and
(4) the polypeptide of (3) in which either:
(i) the polypeptide of general formula I comprises at least 75% and no more than 99% sequence identity to a fragment of no more than 20 contiguous amino acids of SEQ ID NO:9, or
(ii) either or both of N and C in general formula I has an amino acid sequence that is not present in SEQ ID NO:9; and
(B) a recombinant expression vector which comprises a polynucleotide encoding the polypeptide of (A), the polynucleotide being operably linked to an expression control sequence such that the polypeptide can be expressed and presented on a surface of said antigen-presenting cell, rendering it capable of eliciting an antigen-specific T-cell response to human cyclin A1 (CCNA1).
12 . A method, comprising contacting the antigen-pulsed antigen-presenting cell of claim 11 with one or a plurality of immunocompatible T-cells, under conditions and for a time sufficient to generate CCNA1-specific T cells.
13 . The method of claim 12 , further comprising expanding the CCNA1-specific T-cells to obtain a clone of one or more of said CCNA1-specific T-cells in amounts sufficient for T-cell receptor structural characterization.
14 . The method of claim 13 , further comprising determining a T-cell receptor polypeptide-encoding nucleic acid sequence for one or more of said CCNA1-specific T-cell clones.
15 . The method of claim 14 which further comprises transfecting or transducing a T-cell population with at least one nucleic acid having said T-cell receptor polypeptide-encoding nucleic acid sequence so-determined, thereby to obtain one or a plurality of engineered CCNA1-specific T-cells.
16 . The method of claim 15 which further comprises expanding said engineered CCNA1-specific T-cells to obtain an amount of the engineered CCNA1-specific T-cells that is effective for adoptive transfer to a subject.
17 . A method comprising transfecting or transducing a T cell population in vitro with a polynucleotide having a TCR-encoding nucleic acid sequence of one of the one or more CCNA1-specific T cells produced by the method of claim 14 , thereby obtaining a population of engineered CCNA1 -specific T cells.
18 . The method of claim 17 , which further comprises adoptively transferring an effective amount of the engineered CCNA1-specific T-cells to a subject having a condition characterized by CCNA1 overexpression in cells of the subject.
19 . A method for treating a subject having a leukemia that is characterized by CCNA1 overexpression, comprising adoptively transferring to the subject an effective amount of an isolated human cyclin A1 (CCNA1)-specific T cell comprising at least one recombinant expression vector encoding a T-cell receptor polypeptide that specifically binds in a human class I HLA-restricted manner to a CCNA1 polypeptide epitope of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, or 9 amino acids comprising the amino acid sequence set forth in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, or 8.
20 . The method of claim 19 wherein the leukemia is acute myeloid leukemia.Join the waitlist — get patent alerts
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