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
2000-06-12
2004-06-15
Stucker, Jeffrey (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...
C424S208100, C424S434000, C424S435000, C424S436000, C530S324000, C530S826000
Reexamination Certificate
active
06749856
ABSTRACT:
TECHNICAL FIELD
The present invention relates to methods and compositions for stimulating immune responses in mammals. More particularly, the invention relates to methods and compositions for stimulating mucosal immunity.
BACKGROUND OF THE INVENTION
Many infectious pathogens, e.g., HIV-1, enter their mammalian hosts via a mucosal tissue prior to establishing a systemic infection. Veazey, et al.,
Science
280:427-431, 1998. Accordingly, vaccines capable of protecting against HIV should be capable of inducing long-term mucosal immune responses. A number of recent studies have shown that such immune responses require direct stimulation of mucosal tissues, and may be achieved with live attenuated virus, Cranage, et al.,
Virology
229:143-154, 1997, subunit SIV envelope Lehner, et al.,
Nature Medicine
2:767-775, 1996, HIV-recombinant viruses, including recombinant MVA 89.6 env (Belyakov et al., unpublished), or HIV peptide constructs Belyakov, et al.,
Proc. Nat. Acad. Sci
. 95:1709-1714, 1998 (see also, Gallichan, et al.,
J. Exp. Med
. 184:1879-1890, 1996; Cranage, et al.,
Virology
229:143-154, 1997; and Rosenthal, et al.,
Semin. Immunol
. 9:303-314, 1997).
Numerous questions remain, however, concerning which vaccine candidates may afford the most effective protection against mucosal challenge with virus, and what mechanisms may be involved in mediating protective immunity. While a number of studies have shown a role for CTL in protection against infections such as influenza that have a mucosal component (Taylor and Askonas,
Immunology
58:417-420, 1986; Epstein et al.,
J. Immunol
. 160:322-327, 1998; Kulkarni et al.,
J. Virol
. 69:1261-1264, 1995), these reports have not established whether the CTL need to be in a local mucosal site to protect. Conversely, while other studies have shown the induction of CTL in the mucosa, they have not established that these cells have a role in protection (Gallichan and Rosenthal,
J. Exp. Med
. 184:1879-1890, 1996; Bennink et al., Immunology 35:503-509, 1978; Lohman et al.,
J. Immunol
. 155:5855-5860, 1995); and Klavinskis, et al.,
J. Immunol
. 157:2521-2527, 1996
J. Immunol
. 155:5855-5860, 1995. Yet other studies have shown the induction by vaccines of protective immunity in the mucosa, but in the face of multiple immune responses, have not been able to sort out which responses are involved in protection (Lehner et al.,
Nature Medicine
2:767-775, 1996; Putkonen et al.,
J. Virol
. 71:4981-4984, 1997; Miller et al.,
J. Virol
. 71:1911-1921, 1997; Quesada-Rolander et al.,
AIDS Res Hwn Retroviruses
12:993-999, 1996; Bender et al.,
J. Virol
. 70:6418-6424, 1996; Wang et al.,
Vaccine
5:821-825, 1997).
Thus, although the role of CTL in protection against mucosal infections has been of interest for decades, especially in the case of influenza virus, prior investigations have failed to identify fundamental mechanisms linking immune responses to protection. In this regard, because mucosal infection by virus induces a local IgA response, it has been too readily assumed that this response, and not a concomitant CTL response, was responsible for protection against viral infection through the mucosal route. However, the role of secretary IgA in neutralizing and protecting against mucosal HIV challenge is also not clear.
CTL are crucial mediators of immunity to intracellular microorganisms such as viruses as well as certain bacteria and protozoan parasites. CTL specifically recognize “non-self” antigenic peptides bound to major histocompatibility complex (MHC) class I molecules on the surface of “target cells” and then kill the target cells expressing the non-self antigenic peptides. Non-self polypeptides from which the non-self peptides are derived can be a) proteins encoded by intracellular microbes, b) host-encoded proteins whose expression is induced by a microbe, or c) mutant host encoded proteins expressed by, for example, tumor cells.
Thus, generation of CTL responses in the inductive and the effector mucosal immune system may be important to establishing effective protective immunity to intracellular microbial pathogens that establish infection via the mucosal barriers. In some cases, administration of antigens via parenteral routes (subcutaneous, intramuscular, intravenous or intraperitoneal, for example) either fails to induce mucosal immunity or does so extremely inefficiently.
As noted above, previous reports of mucosal immune responses elicited by mucosal challenge with viruses have disclosed that the latter induces antiviral antibody responses, and in some cases CTL responses, in the intraepithelial lymphoid populations. Chen et al.,
J. Virol
. 71:3431-3436, 1997; Sydora, et al.,
Cell Inununol
. 167:161-169, 1996. However, it is not clear if either of such responses is relevant to protection against viral infection in general, or HIV infection in particular. Additional studies have suggested a role for CTL in protection against infections that involve the mucosa, such as influenza or respiratory syncytial virus, Taylor et al.,
Immunology
58:417-420, 1986; Epstein et al.,
J. Immunol
. 160:322-327, 1998; Kulkarni et al.,
J. Virol
. 69:1261-1264, 1995. However, these studies have not addressed the question of whether CTL must be present at the mucosal site of infection, or if their principal activity occurs systemically.
Accordingly, a need exists in the art to better define the roles and mechanisms of CTL in mediating immunity and to develop new tools for mediating immune protection against HIV and other pathogens, particularly by conferring immune protection at mucosal sites where such pathogens initially proliferate.
SUMMARY OF THE INVENTION
The present invention is directed to methods and compositions for inducing a protective mucosal CTL response in a subject. The methods of the invention involve administering either a soluble antigen itself, or a polynucleotide encoding the soluble antigen, to a mucosal surface. The soluble antigens can be full length, naturally occurring polypeptides or fragments (i.e., peptides) derived from them. Peptides to be administered can be any length less than that of the naturally occurring polypeptide. They can be, for example, five to one hundred amino acid residues long, preferably twenty to seventy five amino acid residues long, more preferably twenty five to sixty amino acid residues long and most preferably thirty to fifty amino acid residues long.
The soluble antigen is administered with an adjuvant at the mucosal site or without an adjuvant. Adjuvants can be, for example, cholera toxin (CT), mutant CT (MCT),
E. coli
heat labile enterotoxin (LT) or mutant LT D1 (MLT). IL-12 and/or IFN&ggr; can be administered with the soluble antigen either in the presence or absence of an adjuvant. Alternatively, the two cytokines (IL-12 and/or IFN&ggr;) can be administered systemically and separately from the soluble antigen which is administered mucosally, optionally with adjuvant. Mucosal routes of administration include IR, intranasal (IN), intragastric (IG), intravaginal (IVG) or intratracheal (IT).
Soluble antigens can be derived from pathogenic viruses (e.g., HIV-1, influenza virus or hepatitis A virus), bacteria (e.g,
Listeria monocytogenes
), protozoans (e.g.,
Giardia lamblia
). Alternatively, the soluble antigen can be a tumor-associated antigen, e.g., prostate specific antigen produced by prostate tumor cells or tyrosinase produced by melanoma cells. Peptide antigens can be cluster peptide vaccine constructs (CL WvAC). For example, an HIV-1 CLUVAC can include one or more of the following sequences: EQMHEDIISLWDQSLKPCVKRIQRGPGRAFVTIGK (SEQ ID NO:1), KQIINMWQEVGKAMYAPPISGQIRRIQRGPGRAFVTIGK (SEQ ID NO:2), RDNWRSELYKYKVVKIEPLGVAPTRIQRGPGRAFVTIGK (SEQ ID NO:3), AVAEGTDRVIEVWQGAYRAIRHIPRRIRQGLERRIQRGPGRAFVTIGK (SEQ ID NO:4), DRVIEVVQGAYRAIRHIPRRIRQGLERRIQRGPGRAFVTIGK (SEQ ID NO:5), DRVIEVVQGAYRAIRRIQRGPGRAFVTIGK (SEQ ID NO:6), AQGAYRAIRHIPRRIRRIQRGPGPRAFVTIGK (SEQ ID NO:7), EQMHEDIISLWDQSLKPCVKRIHIGPGRAFYTTKN (SEQ ID NO:8), KQIINMWQEVGKAMYAPPISGQIRRIHIGPGRAFYTTKN (SEQ ID NO:9), RDNW
Belyakov Igor M.
Berzofsky Jay A.
Derby Michael A.
Kelsall Brian L.
Strober Warren
Stucker Jeffrey
The United States of America as represented by the Department o
Towsend and Towsend and Crew LLP
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