Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2000-04-28
2002-06-04
Park, Hankyel T. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C424S185100, C424S204100, C424S278100, C530S300000
Reexamination Certificate
active
06399067
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to compositions and methods useful for inhibiting the multiplication of human immunodeficiency virus-1 (HIV-1) in infected patients, symptomatic or asymptomatic, and for attenuating HIV-1 multiplication following primary infection in previously uninfected subjects, thus minimizing progression to AIDS.
BACKGROUND OF THE INVENTION
A variety of approaches to the treatment of human immunodeficiency virus type 1 (HIV-1) have focused on the transactivating (t&agr;t) gene of HIV-1, which produces a protein (Tat) essential for transcription of the virus. The t&agr;t gene and its protein have been sequenced and examined for involvement in proposed treatments of HIV [see, e.g., U.S. Pat. Nos. 5,158,877; 5,238,882; and 5,110,802; International Patent Application Nos. WO92/07871, WO91/10453, WO91/09958, and WO87/02989, published May 14, 1992, Jul. 25, 1991, Jul. 11, 1991 and May 21, 1987, respectively]. Tat protein is released extracellularly, making it available to be taken up by other infected cells to enhance transcription of HIV-1 in the cells and by noninfected cells, to alter host cell gene activations. Tat renders the cells susceptible to infection by the virus. Uptake of Tat by cells is very strong, and has been reported as mediated by a short basic sequence of the protein [S. Fawell et al.,
Proc. Natl. Acad. Sci., USA
, 91:664-668 (1994)].
Immunization with HIV-1 Tat protein as a potential AIDS vaccine is under active investigation. The HXB/LAV HIV-1 Tat sequence has been used as the immunogen in reported studies, either as a recombinant protein [A. Cafaro et al,
Nat. Med
. 5:643-650 (1999)], a DNA vaccine [S. Calarota et al,
Lancet
, 351:1320-5 (1998)], inactivated protein (Tat toxoid) [S. S. Cohen et al,
Proc. Natl. Acad. Sci. USA
, 96(19):10842-10847 (1999); A. Gringeri et al,
J. Hum. Virol
., 1:293-8 (1998)] or a DNA vaccine expressing inactive Tat [E. Caselli et al,
J. Immunol
., 162:5631-5638 (1999)]. Immunizations with the full Tat sequence induced both cellular and humoral immunity. See, also, M. C. Rhe et al,
J. Acquir. Immmune Defic. Syndr. Hum. Virol
. 10:408-416 (1995), C. J. Li et al,
Proc. Natl. Acad, Sci. USA
, 94:8116-8120 (1997); and others].
International Patent Application No. WO92/14755, published Sep. 3, 1992, relates to the Tat protein and to the integrin cell surface receptor capable of binding to the Tat protein. Two Tat sequences that bind integrin are identified: -Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg- [SEQ ID NO: 1], as well as -Gly-Arg-Gly-Asp-Ser-Pro- [SEQ ID NO: 2]. These sequences are the basic region or domain which is the dominant binding site for the integrin. This specification demonstrates that a number of peptides corresponding to these Tat sequences and the corresponding integrins block in vitro cell binding to Tat coated plates, as do antibodies to the appropriate integrins. However, the specification also shows that these reagents do not block uptake of functional Tat by cells (see Example 9 in WO92/14755), thus nullifying the proposed mechanism of action for therapeutic benefit in HIV infection. The Tat sequences described in this international application are distinct from the peptide immunogens of the present invention.
Both monoclonal and polyclonal antibodies to Tat protein have been readily produced in animals and shown to block uptake of Tat protein in vitro [see, e.g., D. Brake et al,
J. Virol
., 64:962 (1990); D. Mann et al,
EMBO J
., 10: 1733 (1991); J. Abraham et al, cited above; P. Auron et al, cited above; M. Jaye et al, cited above; G. Zauli et al, cited above]. More recent reports showed that monoclonal or polyclonal antibodies to Tat protein added to tissue culture medium attenuated HIV-1 infection in vitro [L. Steinaa et al,
Arch. Virol
., 139:263 (1994); M. Re et al, cited above; and G. Zauli et al,
J. Acq. Imm. Def. Syndr. Hum. Retrovirol
., 10:306 (1995)].
The inventor's own publications [G. Goldstein,
Nature Med
., 2:960 (1996), and International Patent Application No. WO95/3 1999, published Nov. 30, 1995] reviewed the evidence indicating that secretion of HIV-1 Tat protein from infected cells and uptake by both infected and uninfected cells was important for the infectivity of HIV-1. Previous studies also showed that antibodies to Tat protein in vitro blocked uptake of Tat and inhibited in vitro infectivity. Active immunization of mammals was suggested to induce antibodies to HIV-1 Tat protein as a potential AIDS vaccine. See, also, G. Goldstein et al, “Minimization of chronic plasma viremia in rhesus macaques immunized with synthetic HIV-1 Tat peptides and infected with a chimeric simian/human immunodeficiency virus (SHIV
33
)”,
Vaccine
, 18:2789 (2000).
Other publications by the inventor, International Patent Application No. WO99/02185, published Jan. 21, 1999, and U.S. Pat. No. 5,891,994, issued Apr. 6, 1999 (both incorporated by reference herein), revealed a new concept in treatment and prevention of HIV-1 infection that utilized Tat sequences which were recognized as epitopes by the rabbit immune system. Unlike the prior disclosures discussed above, these publications relate to therapeutic and immunogenic combinations requiring at least two, and preferably all four, of the Tat peptides or polypeptides comprising the “Epitope I” sequences spanning Tat amino acid residues 4 (or 5) through 10, as follows: -Asp-Pro-X
7
-Leu-Glu-Pro- [SEQ ID NO: 3] or R
1
-Val-Asp-Pro-X
7
-Leu-Glu-Pro-R
2
[SEQ ID NO: 4], wherein X
7
is Arg, Lys, Ser or Asn. Such compositions induce antibodies that react with most HIV-1 Tat proteins and impair the multiplication of HIV-1. According to this publication, certain other Tat sequences, which comprise an “Epitope II” peptide or polypeptide spanning Tat amino acid residues 41-50 of the formula R3-Lys-X
42
-Leu-Gly-Ile-Ser-Tyr-Gly-Arg-Lys-R4 [SEQ ID NO:5], wherein X
42
is selected from the group consisting of Gly or Ala, may be added to this composition. Alternatively, an “Epitope III” peptide or polypeptide spanning Tat amino acid residues 56-62 of the formula R5-Arg-Arg-X
58
-Z
59
-A
60
-Y
61
-Ser-R6 [SEQ ID NO:6], wherein X
58
is selected from the group consisting of Ala, Pro Ser and Gln; wherein Y
61
is selected from the group consisting of Asp, Asn, Gly and Ser; wherein Z
59
is selected from the group consisting of Pro and His; wherein A
60
is selected from the group consisting of Gln and Pro, may be added to this composition. Still alternatively, an “Epitope IV” peptide or polypeptide spanning Tat AA residues 62-73 of the formula R7-Ser-Gln-X
64
-His-Gln-Y
67
-Ser-Leu-Ser-Lys-Gln-Pro-R8 [SEQ ID NO:7], wherein X
64
is selected from the group consisting of Asn and Thr; wherein Y
67
is selected from the group consisting of Ala and Val, may be added to this composition. The composition itself may be employed to induce antibodies to a large number of Tat sequences characteristic of the multiple variants of HIV-1. The compositions or antibodies generated are used as vaccine or prophylactic treatments against these multiple variants.
Despite the growing knowledge about HIV-1 disease progression, there remains a need in the art for the development of compositions and methods for treatment of HIV-1, both prophylactically and therapeutically, which are useful to lower the viral levels of HIV-1 for the treatment and possible prevention of the subsequent, generally fatal, AIDS disease.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a composition comprising at least two variants of a peptide or polypeptide of the Epitope I formula R1-Asp-Pro-Y
7
-Leu-X
9
-Pro-Trp-Z
12
-R2 [SEQ ID NO:8], wherein Y
7
is selected from the group consisting of Arg, Lys, Ser and Asn; wherein X
9
is selected from the group consisting of Glu and Asp; wherein Z
12
is selected from the group consisting of Lys and Asn; wherein R1 is selected
Brown Stacy S.
Howson and Howson
Thymon L.L.C.
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