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  Methods and compositions for treating prostate cancer using dna vaccinesUSPTO Application #: 20070123487Title: Methods and compositions for treating prostate cancer using dna vaccines Abstract: A DNA vaccine for the treatment of prostate cancer, comprising a plasmid vector comprising a nucleotide sequence encoding prostatic acid phosphatase (PAP) operably linked to a transcription regulatory element, wherein upon administration to a mammal a cytotoxic immune reaction against cells expressing PAP is induced. In preferred embodiment, the PAP encoded is a xenoantigen highly homologous to the autoantigen PAP of the mammal. Also disclosed are methods for inducing prostatitis, or inducing immune reaction to PAP, or treating prostate cancer in a mammal, using the DNA vaccine and pharmaceutical compositions comprising the vaccine. Preferably, xenoantigen vaccination is followed by boosting with autoantigen PAP from the same animal species as the mammal being treated. (end of abstract)
Agent: Quarles & Brady LLP - Milwaukee, WI, US Inventor: Douglas McNeel USPTO Applicaton #: 20070123487 - Class: 514044000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20070123487. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation application of U.S. application Ser. No. 10/669,474 filed on Sep. 25, 2003, which claims the benefit of U.S. provisional application Ser. No. 60/413,777, filed Sep. 27, 2002. FIELD OF THE INVENTION [0002] This invention relates to pharmaceutical compositions and methods using plasmid DNA vaccines for the treatment of prostate cancer. Specifically, this invention relates to the use of plasmids comprising a gene or polynucleotide sequence encoding prostatic acid phosphatase (PAP) for cancer the treatment of prostate. BACKGROUND OF THE INVENTION [0003] Prostate cancer continues to be a major health problem worldwide, with over 220,000 estimated new cases this year in the United States alone (Jemal et al., Cancer Statistics, 2003. (2003) CA A Canc. Jour. Clin., 53:5-26). It is the most common tumor diagnosed among men and the second leading cause of male cancer-related death in the United States (Jemal et al., Cancer Statistics, 2003. (2003) CA A Canc. Jour. Clin., 53:5-26). Despite advances in screening and early detection, approximately 30% of patients undergoing definitive prostatectomy or ablative radiation therapy will have recurrent disease at 10 years (Oefelein et al., Long-term results of radical retropubic prostatectomy in men with high grade carcinoma of the prostate (1997) J Urol, 158:1460-1465). At present, there is no accepted adjuvant treatment for patients undergoing radical prostatectomy or ablative radiation therapy that has been shown to prevent the progression to metastatic disease. In addition to new treatments for metastatic disease, new strategies are needed to eradicate microscopic disease to prevent the progression to clinically apparent metastasis. [0004] In patients who have undergone definitive ablative therapy for prostate cancer, the presence of detectable serum levels of prostate-specific antigen (PSA) has provided a valuable indicator of microscopic metastatic disease. In a retrospective review of 1,997 men treated with radical prostatectomy, 15% were found to have evidence of a PSA-only recurrence over a median 5-year follow up, so-called stage D0 disease (Pound et al., Natural history of progression after PSA elevation following radical prostatectomy. (1999) JAMA 281:1591-7). Of these, 34% developed radiographically apparent metastatic disease, with a median time to development of metastatic disease of 8 years. In all patients with metastatic disease, the median time to death was 5 years Pound et al., Natural history of progression after PSA elevation following radical prostatectomy. (1999) JAMA 281:1591-7. These findings suggest that patients with stage D0 disease are at high risk for progressive disease, however with a long window of time to test adjuvant therapies. Similarly, many patients are found to have microscopic pelvic lymph node metastases at the time of radical prostatectomy, so-called stage D1 disease. At present, the best treatment for these patients is controversial, with some obtaining radical prostatectomy, other referred for radiation therapy with or without androgen deprivation therapy, and yet others are expectantly observed without specific treatment. In retrospective studies, 10-year disease-specific recurrence and mortality is on the order of 50 to 66% for patients with stage D1 disease (Sgrignoli et al., Prognostic factors in men with stage D1 prostate cancer: identification of patients less likely to have prolonged survival after radical prostatectomy. (1994) J Urol, 152:1077-81; Cadeddu et al., Stage D1 (T1-3, N1-3, M0) prostate cancer: a case-controlled comparison of conservative treatment versus radical prostatectomy. (1997) Urology, 50:251-5). This high-risk stage of minimal residual disease also provides an opportunity to test novel adjuvant therapies. [0005] Immunological therapies, and vaccines in particular, are appealing as possible treatment options for prostate cancer for several reasons. Once a patient is diagnosed with presumably organ-confined prostate cancer, the prostate is usually removed by prostatectomy or destroyed in vivo with radiation. Hence, an immune response directed against the prostate that destroys any remaining prostate tissue following ablative therapy might be clinically beneficial to eradicate microscopic metastatic disease. The target of such immune-based therapy following ablative initial therapy would not need to be specific to malignant prostate tissue, but to any prostate tissue. In addition, such therapies may be relatively safe and inexpensive treatments compared with chemotherapies for a disease for which no standard adjuvant treatments exist (Kent et al., Immunity of prostate specific antigens in the clinical expression of prostatic carcinoma. (1976) In: Crispen R G, ed. Neoplasm immunity: mechanisms. Chicago, ITR, pp. 85-95; Guinan et al., Immunotherapy of prostate cancer: a review. (1984) Prostate, 5:221-230; McNeel et al., Tumor vaccines for the management of prostate cancer. (2000) Arch. Immunol. Ther. Exp., 48:85-93). Moreover, prostate cancer is a slow-growing disease, with typically over five years from the time of diagnosis of organ-confined disease to the development of clinically apparent metastatic disease. Such a slow-growing disease might be more amenable to vaccine-based treatments than a rapidly growing tumor, assuming that microscopic amounts of disease would be easier to treat than bulky or rapidly growing disease by vaccines. In fact, vaccines have already entered clinical trials for prostate cancer targeting a variety of prostate-specific proteins, with at least two dendritic cell-based vaccines suggesting clinical benefit in patients with low-volume metastatic disease (Murphy et al., Phase II prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment. (1999) Prostate, 39:54-59; Small et al., Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. (2000) J. Clin. Oncol., 18:3894-3903). [0006] PAP was first identified in the serum of patients with metastatic prostate cancer in 1938 (Gutman et al., An acid phosphatase in the serum of patients with metastasizing carcinoma of the prostate gland. (1938) J. Clin. Invest., 17:473-479). It was subsequently found to be expressed almost exclusively in normal and malignant prostate tissue, and used as a serum marker to follow the progression of the disease before more general use of the PSA serum protein marker (Siddall et al., An evaluation of the immunochemical measurement of prostatic acid phosphatase and prostatic specific antigen in carcinoma of the prostate. (1986) Eur. Urol., 12:123-130). The ubiquitous expression of PAP in prostate tissue makes it an appealing antigen as a potential universal target for immune-directed therapies of prostate cancer, unlike specific oncogenes that may or may not be expressed by a particular tumor. In addition, the discovery of the rodent homologue, rPAP, has provided an animal model for preclinical evaluation, as described below. Moreover, in human preclinical work, the present inventor has previously demonstrated that T cell responses of a Th1 phenotype specific for PAP can be detected in some patients with prostate cancer, suggesting that immune tolerance to this protein can be circumvented in vivo in at least a subset of patients, and consequently might be elicited and/or augmented by means of vaccines (McNeel et al., Naturally occurring prostate cancer antigen-specific T cell responses of a Th1 phenotype can be detected in patients with prostate cancer. (2001) Prostate, 47:222-229). Finally, vaccine trials targeting PAP have entered clinical testing and results of early phase studies suggest that immunity to this protein can be elicited or augmented in patients with prostate cancer by means of dendritic cell (DC)-based vaccines, in some cases with evidence of clinical benefit (Small et al., Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. (2000) J. Clin. Oncol., 18:3894-3903; Burch et al., Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. (2000) Clin. Cancer Res., 6:2175-2182; Fong et al., Dendritic Cell-Based Xenoantigen Vaccination for Prostate Cancer Immunotherapy. (2001) J Immunol, 167:7150-7156). A multi-site randomized, placebo-controlled phase III trial sponsored by Dendreon Corporation targeting PAP by means of a dendritic cell vaccine in patients with androgen-independent prostate cancer is currently underway based on these findings. [0007] The use of plasmid DNA alone as a means of in vivo gene delivery by direct injection into muscle tissue was first described by Wolff et al. (Wolff et al., Direct gene transfer into mouse muscle in vivo. (1990) Science, 247:1465-1468). It was subsequently found that intramuscular or intradermal administration of plasmids expressing foreign genes elicited immune responses (Tang, et al., Genetic immunization is a simple method for eliciting an immune response. (1992) Nature, 356:152-154; Wang et al., Gene inoculation generates immune responses against human immunodeficiency virus type 1. (1993) Proc Natl. Acad. Sci. USA, 90:4156-4160; Raz et al., Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses. (1994) Proc Natl. Acad. Sci. USA, 91:9519-9523). This has quickly led to numerous investigations into the use of plasmid DNA as a means of vaccine antigen delivery, both in animal and human models. DNA vaccines, like peptide-based vaccines, are advantageous in being relatively easy and inexpensive to manufacture, and are not individualized for patients as are dendritic cell-based vaccines. Unlike recombinant protein vaccines, in which the antigen is taken up by antigen presenting cells and expressed predominantly in the context of MHC class II, animal studies have demonstrated that DNA in nucleic acid vaccines is taken up and expressed by antigen-presenting cells directly, leading to antigen presentation through naturally processed MHC class I and II epitopes (Iwasaki, et al. The dominant role of bone marrow-derived cells in CTL induction following plasmid DNA immunization at different sites. (1997) J Immunol, 159:11-14). This method of immunization is consequently similar to the use of viral immunization vectors, however without the additional foreign antigens introduced with a viral vector and therefore with less risk of an overwhelming immune response to the vector itself (Irvine et al. The next wave of recombinant and synthetic anticancer vaccines. (1995) Seminars in Canc. Biol. 6:337-347). This direct expression by host cells, including MHC class I expressing bystander cells, has been demonstrated to lead to vigorous CD8+CTL responses specific for the targeted antigen (Iwasaki et al., The dominant role of bone marrow-derived cells in CTL induction following plasmid DNA immunization at different sites. (1997) J. Immunol. 159:11-14; Chen et al., Induction of CD8+T cell responses to dominant and subdominant epitopes and protective immunity to Sendai virus infection by DNA vaccination. (1998) J. Immunol., 160:2425-2432; Thomson et al., Delivery of multiple CD8 cytotoxic T cell epitopes by DNA vaccination. (1998) J. Immunol., 160:1717-1723; Cho et al., Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism. (2000) Nat. Biotechnol. 18:509-514). In addition, plasmid DNA used for immunization may potentially stay present within cells at the site of immunization, providing a constant source of antigenic stimulation, rather than protein or peptide vaccines that are rapidly cleared by the reticuloendothelial system (Wolff et al., Direct gene transfer into mouse muscle in vivo. (1990) Science, 247:1465-1468; Tighe et al., Gene vaccination: plasmid DNA is more than just a blueprint. (1998) Immunol. Today, 19:89-97). It has been suggested that persistent antigen expression may lead to long-lived immunity (Raz et al., Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses. (1994) Proc. Natl. Acad. Sci. USA, 91:9519-9523). Given that a CTL response to PAP would be predicted based on the prior animal studies to be the most effective immune response in eliciting tissue destructive prostatitis, a DNA-based immunization would be predicted to be an ideal method of immunization in an MHC-diverse human population. [0008] Recently, clinical trials have suggested that plasmid DNA vaccines are safe and immunologically effective in humans. Boyer and colleagues reported that doses of 300 .mu.g of plasmid DNA encoding HIV rev and env proteins administered intramuscularly were capable of eliciting antigen-specific, IFN.gamma.-secreting T cell responses in HIV-seronegative patients (Boyer et al., Vaccination of seronegative volunteers with a human immunodeficiency virus type 1 env/rev DNA vaccine induces antigen-specific proliferation and lymphocyte production of beta-chemokines. (2000) J. Infect. Dis. 181:476-83). In addition, results of a clinical trial targeting prostate-specific membrane antigen (PSMA) in patients with prostate cancer by means of plasmid DNA and adenovirus have been reported (Mincheff et al., Naked DNA and Adenoviral Immunizations for Immunotherapy of Prostate Cancer: A Phase VI/II Clinical Trial. (2000) Eur. Urol., 38:208-217). In this study, 26 patients were immunized either in a prime/boost strategy with an adenoviral vector expressing PSMA followed by immunization with plasmid DNA expressing PSMA, or with plasmid DNA alone. The authors report no significant toxicity with doses of 100-800 .mu.g of plasmid DNA administered intradermally, and suggest that patients receiving plasmid DNA expressing PSMA and CD86 with soluble GM-CSF as an adjuvant were all successfully immunized (Mincheff et al., Naked DNA and Adenoviral Immunizations for Immunotherapy of Prostate Cancer: A Phase I/II Clinical Trial. (2000) Eur. Urol., 38:208-217). [0009] Previous work in rodent models has shown that a cytotoxic cellular immune response (CTL) specific for PAP elicits prostate tissue inflammation, and the destruction of normal rat prostate tissue (Fong et al., 1997, J. Immunol. 159:3113-3117; McNeel and Disis, 1999, Proc. Amer. Assn Canc. Res. 40:256). In addition, McNeel et al. demonstrated that T cell responses of a Th1 phenotype specific for PAP could be detected in some patients with prostate cancer, suggesting that immune tolerance to this autoantigen can be circumvented in vivo in at least some patients, and that host immune reaction to this protein might be augmented by means of vaccines (McNeel et al., 2001, Prostate 47:222-229). [0010] Dendritic cell (DC)-based and protein-based vaccines have been tested for the treatment of prostate cancer. DC-based vaccine trials targeting PAP have entered clinical testing and results of early phase studies suggest that immunity to this protein can be elicited or augmented in patients with prostate cancer (Burch et al., 2000, P, Clin. Cancer Res. 6:2175-2182; Fong et al., 2001, J. Immunol, 167:7150-7156). Dendritic cell-based vaccines, however, must be individualized for each patient, and as a consequence are costly and cumbersome in large-scale application. Protein based vaccines, on the other hand, are taken up by antigen presenting cells and expressed predominantly in the context of MHC class II, thus often are difficult to be delivered effectively and may not induce robust immune response to the antigen. In addition, protein or peptide vaccines are rapidly cleared by the reticuloendothelial system (Wolff et al., 1990, Science 247:1465-8; Tighe et al., 1998, Immunol. Today 19:89-97.) [0011] There is, therefore, a need for an improved method that overcome the short falls of the above existing methods. SUMMARY OF THE INVENTION [0012] The invention provides a method for inducing an immune reaction to prostatic acid phosphatase (PAP) in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a recombinant DNA construct comprising a polynucleotide sequence encoding PAP operatively linked to a transcriptional regulatory element, whereby the mammal develops an immune reaction against PAP. In a preferred embodiment, the mammal, preferably a human, is a prostate cancer patient. [0013] Preferably, the polynucleotide sequence encoding PAP is a human PAP gene. In another embodiment, the polynucleotide sequence encoding PAP is a rodent PAP gene. [0014] According to the invention, the recombinant DNA construct is administered to the mammal intramuscularly or intravascularly, including intravenously and intraarterially, [0015] The method according to the present invention induces cytotoxic immune reaction against cells expressing PAP. Preferably, both humoral and cellular immune reactions against PAP are induced. The method according to the invention preferably induces destructive prostatitis in the mammal. Most preferably, cancer cells expression PAP are selectively killed by the method of the present invention. [0016] In a preferred embodiment, the method of the present invention employs a "prime-boost" strategy, which comprises administering to the mammal an effective amount of a first recombinant DNA construct comprising a first polynucleotide sequence encoding a first PAP polypeptide operatively linked to a transcriptional regulatory element; followed by administering to the mammal an effective amount of a second recombinant DNA construct comprising a second polynucleotide sequence encoding a second PAP polypeptide operatively linked to a transcriptional regulatory element; wherein the first polynucleotide sequence and the second polynucleotide molecule originate from two different animal species, whereby an immune reaction against PAP is induced in the mammal. In one embodiment, the first polynucleotide sequence originates from an animal species other than the mammal, and the second polynucleotide sequence originates from the same animal species as the mammal. Preferably, the mammal is a human, and the first polynucleotide sequence encoding PAP originates from a rodent. In another embodiment, the second polynucleotide sequence originates from the same animal species as the mammal, and the first polynucleotide sequence encodes a PAP polypeptide that shares at least 85%, preferably at least 88%, still more preferably at least 90%, more preferably at least 95%, and most preferably at least 98% homology to the first PAP polypeptide. [0017] According to another aspect of the present invention, a DNA vaccine is contemplated which comprises a plasmid vector comprising a polynucleotide sequence encoding prostatic acid phosphatase operably linked to a transcription regulatory element, wherein upon administration to a mammal a cytotoxic immune reaction against cells expressing PAP is induced in the mammal. The vaccine of the present invention preferably is suitable for intradermal, intramuscular or intraarterial administration to a human. According to a preferred embodiment, the plasmid vector comprises a backbone of pNGVL3, a polynucleotide sequence encoding PAP operably inserted therein, and one or a plurality of an immuno-stimulatory sequence (ISS) motif. [0018] Preferably, the DNA vaccine according to the invention comprises a plasmid vector that comprises a polynucleotide sequence encoding PAP operatively linked to a CMV promoter; a CMV intron A operatively linked to the polynucleotide sequence encoding PAP for enhancing expression of the polynucleotide sequence; and at least one copy of an immuno-stimulatory fragment comprising 5'-GTCGTT-3'. In one embodiment, the plasmid construct does not express in eukaryotic cells any gene other than the polynucleotide sequence encoding PAP. The plasmid vector pTVG4 is particularly preferred. [0019] Also disclosed are pharmaceutical compositions comprising the DNA vaccine of the invention, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition of the invention comprises the DNA vaccine and further a suitable amount of immuno-stimulant such as GM-CSF, optionally with a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS Continue reading... Full patent description for Methods and compositions for treating prostate cancer using dna vaccines Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods and compositions for treating prostate cancer using dna vaccines patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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