Source: http://www.google.com/patents/US7052699?dq=patent:7132291
Timestamp: 2016-05-05 15:15:28
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Matched Legal Cases: ['Application No. 10', 'Application No. 10', 'Application No. 10', 'Application No. 60', 'Application No. 60', 'Application No. 60']

Patent US7052699 - Immunogenic composition - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe present invention relates, in general, to human immunodeficiency virus (HIV) and, in particular, to an HLA-based HIV vaccine....http://www.google.com/patents/US7052699?utm_source=gb-gplus-sharePatent US7052699 - Immunogenic compositionAdvanced Patent SearchPublication numberUS7052699 B2Publication typeGrantApplication numberUS 10/753,339Publication dateMay 30, 2006Filing dateJan 9, 2004Priority dateFeb 4, 2000Fee statusLapsedAlso published asCA2398816A1, CN1635876A, EP1307130A1, EP1307130A4, US6982086, US7078039, US20010036461, US20040197344, US20050112136, US20060008467, WO2001056355A2Publication number10753339, 753339, US 7052699 B2, US 7052699B2, US-B2-7052699, US7052699 B2, US7052699B2InventorsBarton F. Haynes, Hua-Xin Liao, Norman LetvinOriginal AssigneeDuke University, Beth Israel Deaconess Medical CenterExport CitationBiBTeX, EndNote, RefManPatent Citations (61), Non-Patent Citations (82), Classifications (21), Legal Events (4) External Links: USPTO, USPTO Assignment, EspacenetImmunogenic composition
US 7052699 B2Abstract
1. An immunogenic composition comprising the peptide of SEQ ID NO:25.
3. The immunogenic composition according to claim 1, wherein said immunogenic composition further comprises at least one peptide selected from the group consisting of the peptides of SEQ ID NOs:14-24 and 26-42.
5. A method of inducing an immune response in a patient comprising administering to said patient an amount of the immunogenic composition according to claim 3 sufficient to effect said induciton.
This application is a division of U.S. application Ser. No. 09/775,805, filed Feb. 5, 2001, which is a continuation-in-part of U.S. application Ser. No. 09/497,497, filed Feb. 4, 2000, now abandoned, the entire contents of which are hereby incorporated herein by reference.
In a further embodiment, the vaccine of the present invention includes MHC Class I restricted cytotoxic T lymphocytes (CTL) epitopes from HIV p17 and p24 gag regions. Known HIV CTL epitopes and their MHC restricting elements are listed in “HIV Molecular Immunology Database, 1999”(Korber, BTM, Brander, C., Haynes, B. F. et al Editors, Published by the Theoretical Biology and Biophysics Group T-10, Mail Stop K710 Los Alamos National Laboratory, Los Alamos, N. Mex. 87545). The CTL regions designated CTL-J, CTL-K, CTL-L and CTL-M are selected for Vaccine 11 in Table 3. The full peptide has been designed to have at the N-terminus of the epitope the optimal Th determinant, ThA E9V from HIV gp120 C4 region. The restricting elements predicted to respond to these peptides are listed to the right in Table 3. Thus, a practical HIV gag CTL immunogen is set forth in Table 6, with A-Th/A-CTL and B-Th/B-CTL peptides mixed with the peptides in Vaccine 11. The 25 HLA Class I molecules predicted to recognize the peptides in the mixture of peptides in Table 6 are listed at the bottom of the table.
Complex immunogens made up of CTL sequences, for example, from the Los Alamos Database (Korber, BTM, Brander, C., Haynes, B. F. et al Editors, Published by the Theoretical Biology and Biophysics Group T-10, Mail Stop K710 Los Alamos National Laboratory, Los Alamos, N. Mex. 87545) can be prepared by adding to the sequences in Table 6, new sequences from CTL epitopes in envelop, rev, nef, tat, pol and other regions of the HIV genome. These sequences can be formulated with T helper sequences as above in Table 6 (generic Th-X1, Th-X2 . . . Th-Xn), or can be delivered in shorter sequences of X1,X2 . . . Xn, with T cell help being delivered by an appropriate adjuvant. In these generic designs, Th represents a helper T cell epitope, and X represents a HLA Class I restricted CTL epitope.
Immunogenicity and Safety of the C4-V3 Th-CTL Polyvalent Immunogen in HIV Seropositive Patients with CD4+ T Cell Counts>500/mm3 (DATRI010). The DATRI010 human trial of the C4-V3 PV immunogen has been completed (Bartlett et al, AIDS Res. Hum. Retro. 12:1291-1300 (1998)). The immunogen was 4 Th-CTL peptides with the Th epitope the same in each peptide and the CTL peptide was four variants of a B7-restricted env CTL epitope (Haynes, Res. Human Retro. 11:211-221-(1995), Beddows et al, J. Gen. Virol. 79:77-82 (1998), Table 5). Ten HIV-infected, HLA B7-positive patients with CD4+ T cells>500/mm3 were enrolled. Eight patients received 2 mg of C4-V3 polyvalent immunogen (ie, 500 μg of each peptide) emulsified in incomplete Freund's -adjuvant (Seppic ISA51) IM X5 over 24 weeks, and 2 controls received ISA51 IM alone. Vaccine recipients had excellent boosts of Th proliferative levels and neutralizing antibody levels to TCLA HIV (Bartlett et al, AIDS Res. Hum. Retro. 12:1291-1300 (1998)). However, in the setting of HIV infection, PBMC suspensions of immunized B7+ subjects had minimal direct CTL activity to the B7-restricted env CTL epitope in the immunogen to peptide coated targets or to vaccinia infected targets (i.e. the B7 gp120 CTL epitope was non-dominant in the setting of HIV infection) (Bartlett et al, AIDS Res. Hum. Retro. 12:1291-1300 (1998)).
Studies were made of 13 subjects (9, B7- and 4 B7+) after two immunizations 250 μg of each peptide variant. Of 9 HLA B7-subjects, 0/9 had PB CTL activity to any of the peptide variants of the B7-restricted gp120 env CTL epitope in the immunogen (FIGS. 1B and 1D). In contrast, 2/4 HLA B7+ subjects had high levels of CTL activity to the B7 epitope that was mediated by CD8+ T cells and was MHC restricted after only two immunizations (FIGS. 1A and 1C). These data provided direct evidence that Th-CTL immunogens, when formulated in potent adjuvants, could induce MHC Class I-restricted CATL in humans. Whereas one subject responded to one of the 4 B7 epitope variants, the other subject (FIG. 1A) responded to 3 of the 4 CTL variants. These data demonstrated that a human host could respond to more than one CTL epitope variant in an immunogen, and indicated that epitope-based immunizations could be used to induce MHC Class I-restricted CD8+ CTL responses to CTL epitopes and to their variants.
Frequencies of HLA Class I Alleies That an Known to Serve
as HIV CTL Restriction Elements in Four Populations
*Frequencies for HLA-A and HLA-B alleies are taken from HLA 1991 [21], HLA-C for African Americans and USA Caucasians are taken from Histo-compatibility Testing 1984 [19], HLA-C for North American Indians from Williams and McAuley, 1992 [22], and HLA-C for Thais from the Proceedings of the Second Asia and Oceania Histocompatibility Workshop Conference [23]. TABLE 2
Proportion of each of the four populations that would be predicted to present
peptides to the immune system
(S) FNCGGEFF
302-312*
126-138*
584-591*
120-144*
(Proportions of African Americans, USA Caucasians, North American Indians, and Thais expected to present
these 9 epitopes are 95.4%, 97.5%, 99.4%, and 97.2%, respectively)
*The criteria upon which choices among peptides should be made are not yet known. It may be important
to choose peptides that have been reported to be immunogenic in non-progressors to AIDS or that have been
reported to induce immunodominant anti-HIV T-cell responses.
The epitopes listed above correspond to the following sequence identifiers, respectively: SEQ ID NOs:1-5, SEQ ID NO:1, SEQ ID NO:3, SEQ ID NOs:6-8, SEQ ID NO:1, SEQ ID NOs: 9-12, SEQ ID NO:9, SEQ ID NO:13, SEQ ID NOs:1-8, SEQ ID NO:11, SEQ ID NO:9, and SEQ ID NO:13.
Mouse HIV-1
HAGPLAPGQMREPRG-KQIIDMWQEVGKAMYA
H-2nd B-Th/B-CTL
H-2 Kd C-Th/C-CTL
H-2name (D4)
ECMHEDIISLWDQSL-RIHIGPGRAFYTTKN
H-2 Da 3.
Macaque SIV/
Mama-A*01
Th3/CTL/HIV-1
Th1/CTL/SIV Gug
ELYKYKVVKTEPLGVAPTKA-CTPYDINQM
Th2/CTL/SIV Gug
Th3/CTL/SIV Gug
Th4/CTL/SIV Gug
Th5/CTL/SIV Gug
HLA B57,B58
YKRWIILGLNKVRMYS-NPPIPVGEIYKRWI-
HLA B35,B8,B27,A33,Bw62,B52
HLA,A1,B7,B8,B35,A11,A2,A3,A31
HLA B7,B57,A1,B8,B18,B35
ASLNNWFNITNWLWY-GGKKKYKL
Humane HIV-1 Th-CTL
A2,A202,A5,B7,B14,
A2,A25,A26,B7,B12,
A2,A202,A5,A24,
A1,A2,A3,A3.1,A03,
A11,A23,A24,A0201,
A*-Th = C4E9V The amino acid sequences listed above correspond to the following sequence identifiers, respectively: SEQ ID NOs:14-20, SEQ ID NO:18, and SEQ ID NOs:21-42.
HAGPIAPGQMREPRG--KQIINMWQEVGKAMYA----KEKVYLAWVPAHGIG----MYAPPIGGQI-
--QLLFIHFRIGCRHSR---DRVIEVVQGAYRAIR----EQMHEDIISLWDQSL---RIHIGPGRAFYTTKN
ELYKYKVVKIEPLGVAPTKA-------CTPYDINQM--------VSTVQCTHGIRPVVSTQLLL-----STPPLVRL-
--STSIRGKVQKEYAFFYKLDI--------YAPPISGQI
ELYKYKVVKIEPLGVAPTKA----CTPYDINQML-------VSTVQCTHGIRPVVSTQLLL----CTPYDYNQML-
-STSIRGKVQKEYAFFYKLDI---CTPYDANQML-------EYAFFYKLDIIPIDNDTTSY------CTPYDDNQML-
-REQFGNNKTIIFKQSSGGDPE----CTPYDKNQML
KQIINMWQEVGKAMYA----KAFSPEVIPMF----YKRWIILGLNKIVRMYS----NPPIPVGEIYKRWIILGLNKIVRMYSPTSI-
--DRVIEVVQGAYRAIR---VGFPVRPQVPLRPMTYK---ASLWNWFNITNWLWY----WVYHTQGFFPDWQNYTP
Restricting elements for CTL eiptopes:
A-CTL epitope = HLA B57/B58: B-CTL epitope = HLA B35/B8/B27/A33/Bw62/B52:
C-CTL epitope = HLA A1/B7/B8/B35/A11/A2/A3/A31): D-CTL epitope = HLA B7/B57/A1/B8/B18/B35.
KQIINMWQEVGKAMYA-----SLYNTVATL-----YKRWIILGLNKIVRMYS----KIRLRPGGK------DRVIEVVQGAYRAIR-
--KRWIILGLNK-----ASLWNWFNITNWLWY-----GGKKKYKL------MREPRGSKIAGTTST----ERYLKDQQL-
YKRWIILGLNKIVRMYS----SLYNTVATL------DRVIEVVQGAYRAIR----SLFNTVATL-------KQIINMWQEVGKAMYA-
--SLYNAVATL----ASLWNWFNITNWLWY-------SLYNTVAVL--------MREPRGSKIAGTTST-----SLFNLLAVL
HIV Polyvalent C4-V3 Peptides Studied
in Guinea Pigs, Primates Or In Humans
gp120 C4 Region gp120 V3 Region
KQIINMWQEVGKAMYATRPNYNKRKRIHIGPGRAFYTTK
C4-V3RF
KQIINMWQEVGKAMYATRPNNNTRKSITKGPGRVIYATG
C4-V3EV91
KQIINMWQEVGKAMYATRPGNNTRKSIPIGPGRAFIATS
C4-V3CanOA
KQIINMWQEVGKAMYATRPHNNTRKSIHMGPGKAFYTTG
C4E9G-V3RF
KQIINMWQGVGKAMYATRPNNNTRKSITKGPGRVIYATG
C4E9V-V3RF
KQIINMWQVVGKAMYATRPNNNTRKSITKGPGRVIYATG
C4K12E-V3RF
KQIINMWQEVGEAMYATRPNNNTRKSITKGPGRVIYATG
Sequences from the Los Alamos Database. The peptides presented above correspond to the following sequence identifiers, respectively: SEQ ID NOs:95-101.
- CTL
YKRWIILGLNKIVRMYS-NPPIPVGEIYKRWIILGLNKIVRMYSPTSI
KQIINWQVVGKAMYA-ATPQDLNTMLNTVGGHQAAQMLKETINEAAEW
A2,A202,A5,A24,A2402,A25,
KQIINWQVVGKAMAYA-
Bw62,Cw3,Cw8,Cw0401A2,A3,
The amino acid sequences above correspond to the following sequence identifiers, respectively: SEQ ID NOs: 102-107.
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