U.S. patent application number 11/042514 was filed with the patent office on 2006-02-02 for prostatic cancer vaccine.
Invention is credited to Anthony E. III Maida, Lynn E. Spitler.
Application Number | 20060024316 11/042514 |
Document ID | / |
Family ID | 22305885 |
Filed Date | 2006-02-02 |
United States Patent
Application |
20060024316 |
Kind Code |
A1 |
Spitler; Lynn E. ; et
al. |
February 2, 2006 |
Prostatic cancer vaccine
Abstract
Vaccines capable of eliciting an immune antitumor response for
prostate tumors are disclosed. The active ingredient in such
vaccines is selected from the group consisting of at least one
antigen over-represented in the prostate gland or an
immunologically effective portion thereof; an expression system
capable of generating in situ said antigen or portion; a naked DNA
encoding such antigen and portion; and an anti-idiotypic antibody
or fragment thereof which mimics said antigen or portion.
Inventors: |
Spitler; Lynn E.; (Tiburon,
CA) ; Maida; Anthony E. III; (Danville, CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
12531 HIGH BLUFF DRIVE
SUITE 100
SAN DIEGO
CA
92130-2040
US
|
Family ID: |
22305885 |
Appl. No.: |
11/042514 |
Filed: |
January 24, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09300978 |
Apr 28, 1999 |
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11042514 |
Jan 24, 2005 |
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08288057 |
Aug 10, 1994 |
5925362 |
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09300978 |
Apr 28, 1999 |
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08105444 |
Aug 11, 1993 |
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08288057 |
Aug 10, 1994 |
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Current U.S.
Class: |
424/178.1 ;
424/277.1 |
Current CPC
Class: |
Y10S 424/812 20130101;
A61K 39/00 20130101; A61P 13/08 20180101; A61K 39/0011 20130101;
C07K 16/4241 20130101; A61P 37/04 20180101; A61P 35/00
20180101 |
Class at
Publication: |
424/178.1 ;
424/277.1 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 39/00 20060101 A61K039/00 |
Claims
1. A method to induce an antitumor cellular immune response in a
potential or actual prostate tumor-bearing subject which method
comprises administering to said subject a composition comprising an
ingredient which is active to induce said immune response and is
selected from the group consisting of at least one antigen
overrepresented in the prostate gland or an immunologically
effective portion thereof; or an expression system capable of
generating in situ said antigen or an immunologically effective
portion thereof; whereby administration of said composition induces
said cellular immune response to at least one antigen
overrepresented in the prostate gland.
2. The method of claim 1, where in said antigen is a protein or
peptide.
3. The method of claim 2, wherein said protein or peptide is
selected from the group consisting of prostate specific antigen
(PSA), prostate specific membrane antigen (PSMA), prostatic acid
phosphatase (PAP), and an immunologically effective portion
thereof.
4. The method of claim 1, wherein said subject is afflicted with
metastatic prostate cancer.
5. The method of claim 1, wherein said subject has been surgically
treated to excise said tumor but is at risk for recurrence.
6. The method of claim 1, wherein said composition is administered
to said subject prior to surgical excision of said prostate
tumor.
7. The method of claim 1, wherein said subject is a potential
prostate tumor-bearing subject at risk for said tumor.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 09/300,978, filed Apr. 28, 1999, which is a continuation of
U.S. application Ser. No. 08/288,057, filed Aug. 10, 1994, now U.S.
Pat. No. 5,925,362, which is a continuation-in-part of U.S.
application Ser. No. 08/105,444, filed Aug. 11, 1993. The
disclosures of the above-described applications are incorporated
herein by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention is related to the field of the
prevention and treatment of prostate cancer. More specifically, the
invention concerns the use of (1) prostate associated antigen(s),
(2) expression systems for prostate associated antigen(s) which are
peptides or proteins or (3) anti idiotypic antibodies bearing the
internal image of the antigen(s) formulated as vaccines to produce
an immune response to prevent or treat prostate cancer.
BACKGROUND ART
[0003] Cancer is the second leading cause of death in the United
States accounting for almost 500,000 deaths each year. More than
1,000,000 new cases of cancer are diagnosed in the United States
annually. The incidence of cancer is increasing largely as a
byproduct of the greater lifespan of the aging population. Cancer
is a leading cause of death in all industrialized nations, where
life expectancy continues to increase. It is expected that cancer
morbidity and mortality will continue to increase in all
industrialized areas of the world.
[0004] Prostate cancer is the most common malignancy among males in
the U.S. accounting for 28% of all malignancies in men. It is
estimated there will be 165,000 new cases of prostate cancer in the
United States in 1993 and 35,000 deaths (Boring, C C, et al CA
Cancer J Clin (1993) 43:7-26).
[0005] Prostate cancer continues to be refractory to treatment
despite many years of efforts to improve therapy. Surgery and
radiation remain the mainstays of therapy; improved therapeutic
modalities are needed. Vaccine development has been slow and no
vaccine approved by the FDA for marketing currently exists for any
form of cancer. There is therefore a continuing need for the
development of new therapeutic and prophylactic compounds effective
in the prevention and treatment of prostate cancer
[0006] The use of vaccines as cancer therapy is known (reviewed in
Hoover, Jr. H C and Hanna, Jr. M G, Biological Therapy of Cancer
(1991) Devita, Jr., D T, et al., eds. J. B. Lippincott Co., pp
670-701. There are many reports in the open literature of vaccines
consisting of whole autologous or allogeneic tumor cells or their
extracts formulated with bacterial adjuvants such as
Bacillus-Calmette-Guerrin (BCG), Corynebacterium parvum or vaccinia
virus. There has been no report of the use of an antigen unique to
the prostate such as a prostate associated protein or an anti
idiotypic antibody bearing the internal image of the prostate
antigen as a vaccine for prostate cancer.
[0007] U.S. Pat. No. 3,960,827 describes a cancer-associated
polypeptide antigen which is described as having a molecular weight
of 20-27 kd and as associated with a number of types of cancers.
The use of this antigen in antitumor vaccines is suggested. U.S.
Pat. No. 4,372,945 discloses the use of tumor cells as secondary
antigens in immunotherapeutic treatment of cancer. U.S. Pat. No.
4,446,122 discloses the use of prostate specific antigen (PSA)
isolated from human tissue to prepare antibodies for tumor
diagnosis. U.S. Pat. No. 4,468,457 describes the isolation of a
colon specific antigen which is digested with trypsin to obtain a
peptide used to produce monospecific antibodies against the
antigen. U.S. Pat. No. 4,689,222 describes a method for alleviation
of symptomatic pain associated with neoplasia by administering a
low dose of human chorionic gonadotropin insufficient to provoke a
humoral response. U.S. Pat. No. 4,877,611 describes vaccines
containing tumor-associated antigens. The vaccines contain the
tumor-associated antigen in the presence of specific adjuvants. PCT
application WO91/11465 describes anticancer vaccines using
antiidiotype antibodies that mimic an antigen produced by or
associated with the malignant cell.
[0008] U.S. Pat. No. 5,053,224 issued Oct. 1, 1991 describes the
preparation of both polyclonal and monoclonal anti idiotypic
antibodies that recognize the paratope of an antitumor antibody.
The issued patent further describes the use of these anti idiotypic
antibodies generally to stimulate the production of anti anti
idiotypic antibodies in tumor patients. Copending patent
application Ser. No. 07/938,079 filed Aug. 31, 1992, now abandoned
in favor of File Wrapper, Continuation Ser. No. 08/185,313 filed
Jan. 21, 1994 the disclosure of which is incorporated herein by
reference discloses the use of anti idiotypic antibodies generally
to stimulate an antitumor T cell response for prevention and/or
therapy of cancer. Copending patent application Ser. No. 07/800,474
filed Nov. 26, 1991, now abandoned in favor of File Wrapper
Continuation Ser. No. 08/151,568 filed Nov. 12, 1993 the disclosure
of which is incorporated herein by reference describes generally
the use of pure tumor antigen encapsulated in or conjugated to
liposomes for the treatment and prevention of cancer.
[0009] The present invention concerns the use of prostate antigens
or their representatives in vaccines to produce an immune response
to prevent or treat prostate cancer.
DISCLOSURE OF THE INVENTION
[0010] While the prior art suggests the use of antigens uniquely
associated with tumor tissue as components of antitumor vaccines,
there appears to be no suggestion to use antigens which are
uniquely represented on host tissue for the tumor. Since the
prostate is not an essential organ, elimination of the prostate
gland, which may be a concomitant effect of the vaccines of the
invention, does not adversely impact the general health of the
subject. Thus, prostate cancer offers a unique opportunity for
treatment with vaccines which characterize the host organ itself,
rather than the malignant or metastatic nature of the cells per
se.
[0011] Accordingly, in one aspect, the invention is directed to a
method to induce an antitumor immune response in a potential or
actual prostate tumor-bearing subject which method comprises
administering to said subject a composition comprising an active
ingredient selected from the group consisting of at least one
antigen over-represented in the prostate gland or an
immunologically effective portion thereof; an expression system
capable of generating in situ said antigen; and an anti idiotypic
antibody or fragment thereof which mimics said antigen.
[0012] In another aspect, the invention is directed to a
pharmaceutical or veterinary vaccine for eliciting an antitumor
immune response to prostate tumors which comprises, as active
ingredient, at least one antigen over-represented on the prostate
gland with respect to other tissues or an immunologically effective
portion thereof; or an expression system capable of generating in
situ said antigen; or an anti idiotypic antibody or fragment
thereof which mimics said antigen.
MODES OF CARRYING OUT THE INVENTION
[0013] The invention utilizes compositions which contain, as active
ingredient, at least one antigen which is over-represented on
prostate tissue or an immunologically effective portion thereof or
a representative thereof. By "over-represented" is meant that the
concentration of this antigen in prostate is sufficiently higher
than its concentration in any other tissue such that the prostate
can effectively be targeted by the immune response raised against
this antigen with relative sparing of other organs or tissues.
Sparing can be measured by overall clinical toxicity to the
subject. Toxicity to the subject is generally grade 3 or less,
preferably grade 2 or less most preferably grade 1 or grade 0. The
approach does not lose value with regard to metastatic prostate
cancer, since the antigens over-represented in the prostate gland
are also carried by the metastatic cells.
[0014] By an "immunologically effective portion thereof" is meant
that portion of an antigen, taken alone, which is capable of
eliciting an immune response. Typically, such portions represent an
individual epitope or a specific subset of the epitopes that
comprise the complete antigen.
[0015] The antigen can be any substance which is, in the sense used
above, unique to or over-represented in prostate tissue. Thus, the
antigen may be a protein or a peptide, or peptide fragment of the
protein, or may be a carbohydrate, glycoprotein, lipoprotein or
lipid. Most commonly, the antigen will be a protein or a peptide
fragment thereof; or a protein which includes the amino acid
sequence of the antigen or epitope. Proteins may be modified by
glycosylation or other derivatization. It is clear that in the case
of protein antigen, peptides representing epitopes of the antigen
may also be used, The relevant amino acid sequence can be supplied
in the context of a larger fusion protein that contains amino acid
sequence heterologous to the antigen or its epitope.
[0016] It is also understood that in the case of peptide or protein
antigens, the antigens may be generated in situ by providing
suitable expression systems containing the DNA encoding the desired
peptide or protein (including fusion proteins containing the
relevant sequence); the expression systems can then be used as the
active ingredient in the vaccines. By "expression system" is meant
any DNA construct which is effective in producing the encoded
protein in the desired environment. Conventional expression systems
contain the encoding DNA operably linked to control sequences such
as promoters, terminating signals and the like. However, it has
recently been shown that the coding sequences per se can behave as
effective expression systems in situ when injected into animals.
The work of Ulmer, J. B., et al., Science (1993) 259:1745-1749, and
summarized in a "Research News" presentation by Cohen, J., in the
same issue on pages 1691-1692 demonstrates this concept. Injection
of "naked" DNA encoding the nucleoprotein of influenza A was shown
to be protective against a challenge of the virus. Although it is
not understood why such naked DNA is apparently capable of
expression to provide the protein in situ, this apparently is the
case. Accordingly, such "naked" DNA is included in the definition
of expression systems herein.
[0017] Furthermore, any antigen may be mimicked by an anti
idiotypic antibody; it has long been recognized that anti idiotypic
antibodies can be prepared that bear an internal image of tumor
associated antigens, (Herlyn, D., et al. Science (1986)
232:100-102.
Illustrative Antigens
[0018] The first widely studied antigen which is over-represented
in the prostate gland is prostatic acid phosphatase (PAP). Elevated
levels of PAP in the bloodstream are considered indicative of
prostate cancer, and this enzyme has been widely studied (Yam, Amer
J Med (1974) 56:604. Improved methods of cancer detection using
this enzyme were described by Chu et al. in PCT application
WO79/00475. The structure of the enzyme has also been studied by
Sharief, F. S., et al., Biochem Biophys Res Commun (1992)
184:1468-1476 and by Van Etten, R. L., et al., J Biol Chem (1991)
266:9993-9999. The nucleotide sequence encoding human PAP has been
determined from a full length cDNA clone (Sharief, F. S., et al.,
Biochem Biophys Res Commun (1989) 180:79-86; Tailor, P. G., et al.,
Nucleic Acids Res (1990) 18:4928.
[0019] In addition to PAP, other suitable candidates for antigens
over-represented on prostate tissue are known. Most prominent among
these is "prostate specific antigen" or "PSA".
[0020] U.S. Pat. No. 4,446,122 discloses methods for the
purification of human prostate specific antigen (PSA) from either
normal or cancerous human prostate tissue, prostatic fluid,
cultured human prostatic malignant cells, or their media. Also
disclosed are polyclonal and monoclonal antibodies to the prostate
specific antigen and their use in a method for diagnosing carcinoma
of the prostate. PSA is a member of the glandular kallikrein family
and is a protease with a restricted chymotrypsin-like specificity;
it is present in the epithelial cells comprising the prostatic
ductal elements. It has been demonstrated in all primary and
metastatic prostatic tumors tested and in normal benign prostate
but not in nonprostatic cancer tissues or in normal tissues other
than prostate.
[0021] The complete amino acid sequence of PSA from human seminal
plasma has been determined (Watt KW et al., Proc Natl Acad Sci USA
(1986) 83:3166-3170). PSA consists of a single polypeptide chain
with 240 amino acid residues and has a calculated molecular weight
of 26,496. Carbohydrate side chains are possibly attached. The cDNA
encoding PSA has been produced and characterized (Lundwall A,
Lilja, H, FEBS Lett (1987) 214:317-322; Schultz P, et al., Nucleic
Acids Res (1988) 16:6226; and Henttu P and Bihko P, Biochem and
Biophys Res Commun (1989) 160:903-910). The gene for the PSA has
also been characterized (Lundwall A, Biochem and Biophys Res Commun
(1989) 162:1151-1159, Riegman, P H J, et al., Biochem and Biophys
Res Commun (1989) 159:103-111 and Klobeck G, et al., Nucleic Acids
Res 1989 17:3981.)
[0022] cDNA encoding a different prostate specific membrane antigen
(PSMA) has also described (Israeli R S et al., Cancer Res (1993)
53:227-230). The cDNA consists of 2.65 kilobase and a portion of
the coding region from nucleotide 1250 to 1700 has 54% homology to
the human transferrin receptor mRNA. In contrast to PSA and
prostatic acid phosphatase which are secreted proteins, the
prostate specific membrane antigen is an integral membrane
protein.
[0023] The PSMA (molecular weight 100,000) similarly has
representation on both benign and neoplastic prostate cells with
more intense staining seen with malignant cells. Metastases of
prostate cancer also have representation of the antigen. This
antigen, therefore, is an appealing as a vaccine candidate for the
same reasons as those described for PSA. Moreover, PSMA is an
integral membrane protein rather a secreted protein as is PSA ,and,
therefore, may be an even more appropriate vaccine component.
[0024] The foregoing list of known antigens which are
over-represented on prostate: prostatic acid phosphatase (PAP);
prostate specific antigen (PSA); and prostate specific membrane
antigen (PSMA) is offered for the purpose of illustration. These
well known antigens (or the epitope bearing fragments thereof) are
proteins (or peptides) and are useful in the vaccines of the
invention. However, the invention includes any other antigens
substantially uniquely present on the prostate gland so that
prostate derived tissue can be distinguished from other tissue by
virtue of the presence of these antigens.
Preparation of the Antigens
[0025] Antigens useful in the vaccines may be prepared by any
suitable methods. The antigens may be isolated and purified from
prostatic tissue using conventional methods. The purification of
the representative antigens set forth above is already known, and
art-known techniques for their purification may be employed. In
addition, affinity columns employing antibodies or fragments
thereof for specific adsorption of the desired antigen can be used
to advantage. The nature of the purification method will, of
course, depend on the nature of the antigen obtained.
[0026] For antigens that are proteins or peptides, a number of
options is available in addition to isolation and purification. In
addition to genetic engineering techniques, peptides, and even
proteins, can be prepared using standard chemical synthesis
methods, preferably the commercially available solid-phase-based
techniques. These techniques are well known and automated systems
to conduct them can be purchased and employed according to the
manufacturer's instructions.
[0027] In addition, protein or peptide antigens may be prepared
using genetic engineering. Procedures for the production of pure
antigens from the DNA encoding the desired antigen are well known
to those skilled in the art. Briefly, the preferred DNA is
expressed in a suitable recombinant expression vector such as those
adapted for E. coli; yeast, such as Saccharomyces cerevisiae or
Pichia pastoris; or filamentous fungi such as Aspergillus nidulans.
The yeast, fungi or bacteria, can be grown in continuous culture
producing recombinant protein which may be then be isolated and
purified. Alternately, higher organisms may be used for recombinant
protein production. For example, the encoding DNA may be expressed
in an insect virus expression vector such as recombinant
baculovirus and the resulting recombinant baculovirus then used to
infect susceptible cultured SF9 cells (Spodotera frugiperda insect
cells) to produce the protein product of the DNA. Other expression
systems commonly used include those appropriate for production of
proteins in mammalian cells, such as CHO cells or even plant cells.
The choice of host will determine the nature of the
posttranslational processing, and is a consideration in devising
purification techniques.
[0028] The preparation of recombinant forms of protein antigens in
a variety of host cells results in a variety of posttranslational
modifications which affect the immunogenicity and other
pharmaceutical properties, such as pharmacokinetics, of the
product. Accordingly, although human prostate-specific antigen
(PSA) isolated from human tissues has been used to induce the
production of antibodies for diagnostic use, the immunogen prepared
in this way differs from the immunogen as prepared in nonhuman
cells, such as insect cells. The posttranslational modifications
peculiar to the recombinant host result in alternations in
glycosylation pattern, folding, and the like.
[0029] The technique of recombinant expression may also be used to
produce portions of the desired antigen rather than the entire
antigen. For example, it maybe desirable to express the
extracellular domain without the intracellular and/or transmembrane
domains to facilitate purification of membrane associated antigen.
Similarly, it may be desirable to express just the epitopes of
choice eliminating unrelated or competing epitopes. All of these
may be accomplished through techniques well known to those skilled
in the art. Techniques for identifying peptides representing
important epitopes of the antigen are well known, and are
summarized in Berzofsky, J A and Berkower I J, Fundamental
Immunology 2nd edition, Raven Press, (1989) W. E. Paul (ed.) pp.
169-208. The peptides identified may then be synthesized using
conventional solid phase peptide synthesis (Merrifield R B, J Am
Chem Soc (1983) 85:2149-2154) which has now been automated
(Merrifield R B, Science (1965) 150:178-185) as described above. An
alternate method designed to make large numbers of peptides for
screening is the "tea-bag" technique (Houghten R A, Proc Natl Acad
Sci USA (1985) 82:5131-5135.
[0030] Whether the antigen or a suitable epitope is prepared
synthetically or recombinantly, it may be prepared initially as a
fusion protein containing amino acid sequence heterologous to the
amino acid sequence of interest. Construction of such fusion
proteins is common in recombinant production in order to stabilize
the product produced in the cell. It may be unnecessary to
stabilize the desired peptide or protein in this way, especially if
it is to be secreted from the recombinant cell. However, the fusion
protein itself may be useful as an ingredient in the vaccine,
especially if the additional heterologous amino acid sequence
supplies an immunogenicity enhancing property on the relevant
epitope. Thus, the fusion proteins which contain the relevant amino
acid sequences may be used simply as precursors of the immunogen or
may provide the end-product for use in the vaccine. If the fusion
protein is intended as an intermediate, it is useful to provide a
cleavage site between the heterologous portion and the desired
epitope. Such cleavage sites include, for example, the target
sequences for various proteolytic enzymes, or, if the epitope does
not contain methionine, may constitute simply a methionine residue
which is cleaved by cyanogen bromide. Methods to provide suitable
cleavage sites are well known in the art.
Preparation of Antiidiotypic Antibodies
[0031] An alternative approach in formulating the vaccines of the
invention is to prepare a "representative" of the antigen in the
form of an anti idiotypic antibody which bears an internal image of
the antigen. Anti idiotypic antibodies can be prepared with respect
to antigens of any chemical nature, including, in addition to
peptides and proteins, carbohydrates, lipids, and small
molecules.
[0032] Ways to prepare both monoclonal and polyclonal anti
idiotypic antibodies which bear the internal image of the tumor
associated antigens is described in detail in U.S. Pat. No.
5,053,224 the disclosure of which is incorporated herein by
reference. Briefly, polyclonal anti idiotypic antibodies may be
produced by immunizing animals with monoclonal idiotypic antibodies
raised against the antigen and screened for reactivity with the
antigen and screening for antisera which react with idiotypic
antibodies to the prostate antigens. Monoclonal antibodies may also
be prepared from such animals using standard techniques of
immortalizing the antibody secreting cells of the animal and
screening the cultures with idiotypic antibodies in competition
with the prostate antigen. Human or murine monoclonals are
preferred; polyclonal preparations made in a variety of mammalian
systems may also be used.
Vaccine Compositions
[0033] While the prostate antigens of the invention may by
themselves constitute the vaccine, it is a further feature of the
invention these prostate antigens are administered in a formulation
designed to enhance the antitumor response. Formulations include
but are not limited to incorporation of the prostate antigen into a
liposome with or without out additional adjuvants, use of adjuvants
and/or cloning DNA encoding of peptide or protein antigens into a
viral or bacterial vector.
[0034] Of course, the formulations may not contain only a single
active ingredient; any combination of the immunogenic substances of
the invention can be used.
[0035] However, generally, such "cocktails" comprise active
ingredients of the same type--i.e., generally the active ingredient
mixture will include either two or several antigens, two or several
expression systems for protein or peptide antigens, or two or
several anti idiotypic antibodies representing different antigens.
However, there is no theoretical reason that, for example, a single
vaccine could not include both anti idiotypic antibody and an
expression system.
[0036] If the protein form of the antigen is to be used, it may be
desirable to couple the protein or peptide to a carrier in order to
enhance immunogenicity. Such coupling can be effected using
standard and conventional coupling techniques, optionally utilizing
spacer moieties in order to provide correct juxtaposition of the
carrier and epitope. A large number of suitable carriers for such
purposes is known, including keyhole limpet hemocyanin, rotavirus
VP6 inner capsid protein, pilin protein and the like. In addition,
enhanced immunogenicity may be obtained by supplying the epitope or
antigen in the form of a fusion protein wherein the epitope bearing
portion is fused to heterologous amino acid sequences to enhance
the effect of the epitope administered.
[0037] Whether administered alone, coupled to carrier, or as part
of a fusion protein, the epitope bearing proteins of the invention,
the DNA constructs and the anti idiotypic antibodies are
administered in the presence of suitable excipients. Conventional
excipients may be used, but the following are of particular
interest.
[0038] Compositions employing liposomes encapsulating or
conjugating to the active ingredient of the vaccine may be used and
are especially preferred. Liposomes localize in the
reticuloendothelial system, one of the sites of generation of the
immune response in a mammalian host including humans and enhance
the immune response to antigens incorporated in the liposome The
liposomal formulations incorporating the prostate antigens may also
include immune system adjuvants, including one or more of
lipopolysaccharide (LPS), lipid A, or muramyl dipeptide (MDP) as
described in Liposomes, Ostro M J, Editor, Marcel Dekker, Inc.
(1983) page 249). Other immune system adjuvants such as glucan or
certain cytokines, including interleukins, interferons, and colony
stimulating factors, such as IL1, IL2, gamma interferon, and GM-CSF
may also be incorporated with antigen into the liposome.
[0039] The prostate antigen may also be formulated with various
adjuvants which enhance antitumor response, in particular, cellular
immune response to the prostate antigens. Such adjuvants include,
but are not limited to, Freund's Complete Adjuvant, alum, lipid A,
monophosphoryl lipid A, Bacillus-Calmette-Guerrin (BCG) and other
bacteria, polysaccharides such as glucan, acemannan, and lentinan,
saponins, detoxified endotoxin (DETOX), muramyl tripeptide, muramyl
dipeptide and their derivatives, SAF1, lymphokines and cytokines,
including interleukins and interferons such as IL2 and gamma
interferon, as well as colony stimulating factors such as GM-CSF,
nonionic block copolymers, or immune stimulating complexes
(ISCOMS).
[0040] In an additional formulation the DNA encoding proteins such
as PAP, PSA, PSMA, or portions of these is administered in a viral
expression vector such as vaccinia or other pox virus or bacterial
vectors such as BCG. Viral vectors are described, for example, by
Hruby, D E, Vet Parasitol (1988) 29:281-282, and by Uiu, S I "AIDS
Research Reviews" Dekker, Inc. (1991) 1:403-416. The recombinant
vectors may be administered in the traditional manner via a skin
scratch or an injection or may included in a liposome injectable as
described above. As noted above, "naked" DNA can also be used as a
form of expression system in the vaccines of the invention.
Administration and Use
[0041] In the method of the invention, the prostatic cancer vaccine
is administered for both prevention and treatment of prostatic
cancer. The prostatic cancer vaccine of the invention is
administered to subjects at risk for the development for the
development of prostate cancer or showing a diagnosis thereof.
While the target cancer is specifically that associated with the
prostate gland, the effect of the vaccines of the invention will be
to enhance the potential of the immune system generally, generating
T cell responses as well as the production of antibodies. To the
extent that the enhancement of the cellular immune system is
effected, the vaccines of the invention are useful in the
prevention and therapy of other types of cancer as well as that of
the prostate. Thus, the cellular responses generated are effective
against, for example, cancers of the colon, lung, bladder, stomach,
breast, cervix, and the like as well as certain lymphomas and
leukemias.
[0042] The compositions are formulated for parenteral
administration using a formulation appropriate to the
administration route such as those described in Remington's
Pharmaceutical Sciences, latest edition, Mack Publishing Company,
Easton, Pa.
[0043] Suitable routes for parenteral administration include
intracutaneous, subcutaneous, intramuscular, and intravenous
injection or oral administration. For formulation for injection,
the vaccine is generally formulated in a suitable liquid such as
Hank's solution or Ringer's solution along with suitable excipients
providing buffering, stabilizing, and other desirable
characteristics, as well as additional components desired, as
described below. Alternative routes for parenteral administration
include oral administration in which case additional components for
stabilizing the preparation may also be included.
[0044] In addition to administration in an appropriate isotonic
vehicle for injection, liposomes are desirably used as a carrier to
direct the product to the immune system as disclosed in copending
application Ser. No. 07/800,474, the disclosure of which is
incorporated herein by reference.
[0045] In general, the dosage range for the prostate antigens of
the invention is of the order of 0.01 .mu.g-100 mg per dose,
preferably 0.1 .mu.g-10 mg per dose and more preferably 10 .mu.g-1
mg per dose. Suitable volumes for parenteral administration are
about 0.1-5 ml.
[0046] The protocols may involve administration of cocktails of
various antigens or their representatives or may involve sequential
administration of these active ingredients. The antigens and their
representatives may represent a variety of immunogens or may
represent different forms of the same immunogen. In general,
protocols involving one or more immunogenic species can be designed
according to routine optimization procedures.
[0047] The prostatic cancer vaccine of the invention is
administered generally in multiple doses, typically once per week
for one or two months and with decreasing frequency thereafter for
a period extending to about one year. Following the initial one
year course of vaccination, booster inoculations may be given every
two months to five years. Alternate protocols may be appropriate in
individual instances. For example, if vaccine formulation involves
the use of liposomes and is administered intramuscularly, the
vaccine might be administered once a month from the inception
because of the depot effect of the liposomes.
[0048] In addition, it may be advantageous to substitute for the
first administrations a recombinant form of the antigen wherein the
antigen gene or cDNA is administered in a living expression vector
such as vaccinia virus.
[0049] It is a further feature of the invention that the vaccine
may be formulated along with adjuvants which enhance the immune
responses as described above. The prostate antigens may be
formulated with these adjuvants alone or they may be incorporated
into liposomes.
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