WO2015024664A1 - Composition and vaccine for treating prostate cancer - Google Patents
Composition and vaccine for treating prostate cancer Download PDFInfo
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- WO2015024664A1 WO2015024664A1 PCT/EP2014/002297 EP2014002297W WO2015024664A1 WO 2015024664 A1 WO2015024664 A1 WO 2015024664A1 EP 2014002297 W EP2014002297 W EP 2014002297W WO 2015024664 A1 WO2015024664 A1 WO 2015024664A1
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- mrna
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/884—Vaccine for a specifically defined cancer prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y116/00—Oxidoreductases oxidizing metal ions (1.16)
- C12Y116/01—Oxidoreductases oxidizing metal ions (1.16) with NAD+ or NADP+ as acceptor (1.16.1)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
- C12Y301/03002—Acid phosphatase (3.1.3.2)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/17—Metallocarboxypeptidases (3.4.17)
- C12Y304/17021—Glutamate carboxypeptidase II (3.4.17.21)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21077—Semenogelase (3.4.21.77), i.e. prostate specific antigen or PSA or kallikrein 3
Definitions
- the present invention relates to a composition
- a composition comprising at least one mRNA encoding a combination of antigens capable of eliciting an (adaptive) immune response in a mammal, wherein the antigens are selected from the group consisting of PSA (Prostate-Specific Antigen), PSMA (Prostate-Specific Membrane Antigen), PSCA (Prostate Stem Cell Antigen), STEAP (Six Transmembrane Epithelial Antigen of the Prostate), MUC1 (Mucin 1 ) and PAP (Prostatic acid phosphatase).
- PSA Prostate-Specific Antigen
- PSMA Prostate-Specific Membrane Antigen
- PSCA Prostate Stem Cell Antigen
- STEAP Small Transmembrane Epithelial Antigen of the Prostate
- MUC1 Moc 1
- PAP Prostatic acid phosphatase
- the invention furthermore relates to a vaccine comprising at least one mRNA encoding such a combination of antigens and to the use of said composition (for the preparation of a vaccine) and/or of the vaccine for eliciting an (adaptive) immune response for the treatment of prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- PCa prostate cancer
- the invention relates to kits, particularly to kits of parts, containing the composition and/or the vaccine.
- prostate cancer is the second most commonly diagnosed cancer and the fourth leading cause of cancer- related death in men in the developed countries worldwide. Effective curative treatment modalities are debilitating, and are only currently available for localised disease.
- hormone-refractory (castration-resistant; castration-refractory) prostate cancer no agent has been shown to prolong survival beyond approximately 1 year (see e.g. Pavlenko, M., A. K. Roos, et al. (2004). "A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer.” Br J Cancer 91 (4): 688-94.).
- prostate cancer is at present even the most commonly diagnosed malignancy and the third leading cause of cancer related death among men in the United States (see e.g. Jemal, A., R. Siegel, et al. (2006). "Cancer statistics, 2006.” CA Cancer J Clin 56(2): 106-30.) and in Europe, respectively (see e.g. Thomas-Kaskel, A. K., C. F. Waller, et al. (2007). "Immunotherapy with dendritic cells for prostate cancer.” Int J Cancer 121 (3): 467-73). Most of the diagnosed tumors are adeno-carci nomas which initially proliferate in a hormone-dependent manner.
- Prostate cancer is a disease in which cancer develops in the prostate, a gland in the male reproductive system. It occurs when cells of the prostate mutate and begin to multiply out of control.
- Typical antigens which have been shown to be overexpressed by prostate cancer cells as compared to normal counterparts are inter alia antigens like PSA, PSMA, PAP, PSCA, HER-2 and Ep-CAM.
- PSA prostate cancer
- PSMA prostate cancer monogen
- PAP protein
- PSCA protein HER-2
- Ep-CAM Ep-CAM
- These prostate cancer cells may spread (metastasize) from the prostate to other parts of the body, especially the bones and lymph nodes.
- Prostate cancer may cause pain, difficulty in urinating, erectile dysfunction and other symptoms.
- prostate cancer develops most frequently in men over fifty, which represent the most common group of patients. However, prostate cancer remains most often undiscovered, even if determination would be possible.
- Determination of prostate cancer typically occurs by physical examination or by screening blood tests, such as the PSA (prostate specific antigen) test.
- PSA proteosylase inhibitor
- the cancer is typically confirmed by removing a piece of the prostate (biopsy) and examining it under a microscope. Further tests, such as X-rays and bone scans, may be performed to determine whether prostate cancer has spread.
- prostate cancer Treatment of prostate cancer still remains an unsolved challenge.
- Conventional therapy methods may be applied for treatment of prostate cancer such as surgery, radiation therapy, hormonal therapy, occasionally chemotherapy, proton therapy, or some combination of these.
- the age and underlying health of the man as well as the extent of spread, appearance under the microscope, and response of the cancer to initial treatment are important in determining the outcome of the disease.
- prostate cancer Since prostate cancer is a disease, typically diagnosed in older men, many will die of other causes before a slowly advancing prostate cancer can spread or cause symptoms. This makes treatment selection difficult.
- the decision whether or not to treat localized prostate cancer (a tumor that is contained within the prostate) with curative intent is a trade-off between the expected beneficial and harmful effects in terms of patient survival and quality of life.
- Radiation therapy is commonly used in prostate cancer treatment. It may be used instead of surgery for early cancers, and it may also be used in advanced stages of prostate cancer to treat painful bone metastases. Radiation treatments also can be combined with hormonal therapy for intermediate risk disease, when radiation therapy alone is less likely to cure the cancer. However, radiation therapy also bears high risks and often leads to a complete loss of immune defence due to destruction of the patient's immune system. Furthermore, radiation therapy is typically applied locally at the site of cancer growth and thus may not avoid the above problem of spread of prostate cancer throughout the organism. If applied systemically, radiation therapy may lead to severe damages to cells and immune system.
- Chemotherapy was considered as a less effective sort of treatment for prostate cancers since only very few patients even respond to this sort of therapy. However, some patients (responders), having a metastasizing prostate carcinoma, may benefit from chemotherapy. The response rate is at about 20% and chemotherapy will thus play a role during treatment of the tumor relapse and failing of hormonal therapy. However, chemotherapy will typically be only palliative and does not lead to a total elimination of the prostate cancer in the patient.
- Typical chemotherapeutic agents include cyclophosphamid, doxorubicin, 5- fluoruracil, adriamycin, suramin and other agents, however, none of these resulted in a significant longer survival of the patients.
- DHT dihydrotestosterone
- hormonal therapy rarely cures prostate cancer because cancers which initially respond to hormonal therapy typically become resistant after one to two years.
- palliative androgen deprivation therapy can induce remissions in up to 80% of the patients, but after 1 5-20 months, tumor cells become hormone-insensitive and androgen- independent prostate cancer develops.
- treatment options are rare, as chemotherapy has been of limited efficacy (see above).
- Hormonal therapy is therefore usually used when cancer has spread from the prostate. It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of their cancer.
- the above discussed standard therapies used for organ-confined prostate cancer including radical prostatectomy or radiation therapy such as external (beam) irradiation and brachytherapy may under some circumstances incorporate also neoadjuvant or adjuvant hormonal therapy (see e.g. Totterman, T. H., A. Loskog, et al. (2005). "The immunotherapy of prostate and bladder cancer.” BJU Int 96(5): 728-35.). While these therapies are relatively effective in the short term, a significant proportion (30-40%) of patients having initially localized disease will ultimately relapse.
- the main therapy is androgen ablation. While this usually provides cytoreduction and palliation, progression to hormone-refractory disease typically occurs within 14-20 months.
- Many clinical studies have been reported in the field of chemotherapy for advanced androgen-independent prostate cancer. Only recently two trials have revealed that chemotherapy marginally improves the overall survival of patients with hormone- refractory (castration-resistant) disease.
- PCa prostate cancer
- the immune system plays an important role in the treatment and prevention of numerous diseases.
- various mechanisms are provided by mammalians to protect the organism by identifying and killing, e.g., tumor cells.
- these tumor cells have to be detected and distinguished from the organism's normal (healthy) cells and tissues.
- the immune systems of vertebrates such as humans consist of many types of proteins, cells, organs, and tissues, which interact in an elaborate and dynamic network. As part of this complex immune response, the vertebrate system adapts over time to recognize particular pathogens or tumor cells more efficiently. The adaptation process generates immunological memory and allows even more effective protection during future encounters. This process of adaptive or acquired immunity forms the basis for vaccination strategies.
- the adaptive immune system is antigen-specific and requires the recognition of specific "self” or “non-self” antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen- infected cells or tumor cells. The ability to mount these tailored responses is maintained in the body by so called “memory cells”. When a pathogen infects the body more than once, these specific memory cells are used to quickly eliminate it.
- the adaptive immune system thus allows for a stronger immune response as well as for an immunological memory, where each pathogen or tumor cell is "remembered” by one or more signature antigens.
- lymphocytes as cellular components of the adaptive immune system include B cells and T cells which are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral response, whereas T cells are involved in cell mediated immune response. Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogenic target structure, only after antigens (e.g. small fragments of a pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule.
- MHC major histocompatibility complex
- the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes pathogens as such when antibodies on its surface bind to a specific foreign antigen.
- This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides.
- the B cell displays these antigenic peptides on its surface MHC class II molecules.
- This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring secretes millions of copies of the antibody that recognizes this antigen.
- cytotoxic T cells may also form a CTL-response. Cytotoxic T cells (CD8+) can recognize peptides from endogenous pathogens and self-antigens bound by MHC type I molecules. CD8+-T cel ls carry out their ki lling function by releasing cytotoxic proteins.
- Mechanisms of the immune system may thus form targets for curative treatments of various diseases.
- Appropriate methods are typically based on the administration of adjuvants to elicit an innate immune response or on the administration of antigens or immunogens in order to evoke an adaptive immune response.
- antigens are typically based on specific components of pathogens (e.g. surface proteins) or fragments thereof, administration of nucleic acids to the patient which is followed by the expression of desired polypeptides, proteins or antigens is envisaged as well.
- Castration-resistant prostate cancer is the only cancer indication so far in which an active immune therapy designed to induce specific immune responses has been approved based on a significant prolongation in overal l survival.
- Sipuleucel-T Provenge®
- an active immunotherapy consisting of autologous antigen presenting cells pulsed with a fusion protein consisting of the prostate cancer associated antigen PAP and the adjuvant GM-CSF
- has been shown to prolong survival in a phase III trial enrol ling 51 2 patients by a median of 4.1 months compared to placebo (25.8 vs 21 .7 mo; p 0.03) i n patients with asymptomatic or minimally symptomatic castration-resistant prostate cancer.
- sipuleucel-T has been approved by the FDA for the treatment of this group of patients in 201 0 (Kantoff, P., Higano, C, Shore, N., Berger, E.R., Small, E.J., et al. (201 0). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363 :41 1 -422).
- Some other recent approaches utilize cell based vaccination strategies, e.g. the use of different antigens in vaccination strategies or the use of dendritic cells loaded with different antigens or fragments thereof.
- vaccination of prostate cancer patients has been tested in clinical trials with autologous dendritic cel ls pulsed with recombinant human PSA (see e.g. Barrou, B., G. Benoit, et al. (2004). "Vaccination of prostatectomized prostate cancer patients in biochemical relapse, with autologous dendritic cells pulsed with recombinant human PSA.” Cancer Immunol Immunother 53(5): 453-60).
- Murphy et al. (1 996) carried out vaccination of prostate cancer patients in a corresponding phase I trial with two HLA-A*0201 PSMA epitopes to compare vaccination based on the peptide alone with vaccination based on pulsed DCs. The results showed that more patients responded to the vaccination, if the patients were vacci nated with pulsed DCs. This study showed that vaccination based on DCs loaded with peptides or proteins leads at least for a number of instances to detectable immune responses as well as a temporary PSC decline or stabi lization (see e.g. Murphy, G., B. Tjoa, et al. (1 996). "Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cel ls pulsed with HLA-A0201 -specific peptides from prostate-specific membrane antigen.” Prostate 29(6): 371 -80).
- Vaccination of prostate cancer patients may also be carried out with combinations of peptides loaded on dendritic cel ls, e.g. with peptide cocktail-loaded dendritic cells (see e.g. Fuessel, S., A. Meye, et al. (2006). "Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase I clinical trial.” Prostate 66(8): 81 1 -21 ).
- the cocktail contained peptides from PSA, PSMA, Survivin, Prostein and Trp-p8 (transient receptor potential p8).
- nucleic acids in order to incorporate the required genetic information into the cell.
- various methods have been developed for introducing nucleic acids into cells, such as calcium phosphate transfection, polyprene transfection, protoplast fusion, electroporation, microinjection and lipofection, with lipofection having been in particular proven to be a suitable method.
- Vaccination treatment of prostate cancer may, e.g., be based on the transfection of total mRNA derived from the autologous tumor into DCs (see Heiser et al. (2002) (see e.g. Heiser, A., D. Coleman, et al. (2002). "Autologous dendritic cells transfected with prostate- specific antigen RNA stimulate CTL responses against metastatic prostate tumors.” J Clin Invest 109(3): 409-1 7.).
- This strategy has the advantage of targeting multiple HLA class I and class II patient specific tumor associated antigens (TAAs) without prior HLA typing.
- TAAs patient specific tumor associated antigens
- stromal antigens were targeted by this strategy, since mRNA was obtained from surgical samples and not from tumor cell lines.
- DNA may also be utilized as a nucleic acid in vaccination strategies in order to incorporate the required genetic information into the cell.
- DNA viruses may be used as a DNA vehicle. Because of their infectious properties, such viruses achieve a very high transfection rate. The viruses used are genetically modified in such a manner that no functional infectious particles are formed in the transfected cell. E.g., phase I trials were carried out in a study of Eder et al. (2000) using recombinant vaccinia viruses expressing PSA. The authors demonstrated T cell immune responses to PSA and also serum PSA stabilizations in selected patients, (see e.g. Eder, J. P., P. W. Kantoff, et al. (2000).
- DNA While using DNA as a carrier of genetic information, it is, however, not possible to rule out the risk of uncontrolled propagation of the introduced gene or of viral genes, for example due to potential recombination events. This also entails the risk of the DNA being inserted into an intact gene of the host cell's genome by e.g. recombination, with the consequence that this gene may be mutated and thus completely or partially inactivated or the gene may give rise to misinformation. In other words, synthesis of a gene product which is vital to the cell may be completely suppressed or alternatively a modified or incorrect gene product is expressed.
- the DNA may e.g. be integrated into a gene which is involved in the regulation of cell growth.
- the host cell may become degenerate and lead to cancer or tumor formation.
- the DNA introduced into the cell is to be expressed, it is necessary for the corresponding DNA vehicle to contain a strong promoter, such as the viral CMV promoter.
- the integration of such promoters into the genome of the treated cell may result in undesired alterations of the regulation of gene expression in the cell.
- Another risk of using DNA as an agent to induce an immune response is the induction of pathogenic anti-DNA antibodies in the treated patient thereby eliciting a (possibly fatal) immune response.
- RNA based antigen compositions have been developed.
- WO 2009/046975 provides a composition comprising at least one RNA encoding at least two, three or four (preferably different) antigens selected from the group consisting of PSA (Prostate-Specific Antigen; also known as KLK3 or Kallikrein-3), PSMA (Prostate-Specific Membrane Antigen), PSCA (Prostate Stem Cell Antigen) and STEAP (Six Transmembrane Epithelial Antigen of the Prostate).
- PSA Prostate-Specific Antigen
- PSMA Prostate-Specific Membrane Antigen
- PSCA Prostate Stem Cell Antigen
- STEAP ix Transmembrane Epithelial Antigen of the Prostate
- PCa prostate cancer
- composition comprising at least one mRNA, wherein the at least one mRNA encodes the following antigens:
- PSCA Prostate Stem Cell Antigen
- the specific combination of the antigens, antigenic proteins or antigenic peptides of the afore mentioned group encoded by at least one mRNA as contained in a composition according to the present invention is capable to effectively stimulate the (adaptive) immune system to allow treatment of prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- PCa prostate cancer
- the advantageous effects on the treatment of the diseases mentioned above are achieved irrespective of whether the combination of antigens according to the invention is applied as one single composition or by separate administration of the individual antigens.
- any combination of antigens described herein may fulfil the very same purposes and achieves the desired effect.
- the number of responders to such a vaccination strategy is expected to be significantly increased as compared to other approaches.
- the terms antigens, antigenic proteins or antigenic peptides may be used synomously.
- an inventive composition shall be further understood as a composition, which is able to elicit an immune response, preferably an adaptive immune response as defined herein, due to at least one of the component(s) contained in the composition or, rather, due to at least one of the antigens encoded by the at least one component of the composition, i.e.
- the combination of antigens is capable of eliciting the desired immune response.
- Separate administration may mean that the distinct mRNAs are either essentially simultaneously, e.g. within 10 minutes or time-staggered over an extended period of time, e.g. more than 30 minutes.
- the combination of antigens according to the invention will be illustrated by the description of a composition comprising at least one mRNA encoding the combination of antigens. It is understood that the at least one mRNA according to the invention is characterized by the features as described herein, irrespective of whether it is administered as one single composition or in the form of separate formulations, e.g. formulated as six separate mRNAs, each of which encode one antigen and which are administered separately (e.g. concurrently).
- RNA is typically a single-stranded RNA, which is composed of (at least) several structural elements, e.g.
- the composition comprises at least on mRNA, which endodes at least the six antigens defined above.
- one mRNA may encode one or more antigens as long as the composition as such provides the at least six antigens as defined above.
- the at least one mRNA of the composition may thus comprise more than one ORF/coding region/coding sequence, wherein the composition as a whole comprises at least one coding region for each of the at least six antigens as defined above.
- a coding region for each of the at least six antigens may be located on separate mRNAs of the composition. More preferred embodiments for the at least one mRNA are provided below:
- PSA is "Prostate-specific antigen” and may be synomously named KLK3 (Kallikrein-3) in the literature.
- Prostate-specific antigen (PSA) is a 33 kDa protein and an androgen-regulated kallikrein-like, serine protease that is produced exclusively by the epithelial cells of all types of prostatic tissue, benign and malignant.
- PSA is highly expressed by normal prostatic epithelial cells and represents one of the best characterized tumor associated antigens in prostate cancer.
- PSA is present in the seminal fluid at high concentration and functions to cleave the high molecular weight protein responsible for the seminal coagulum into smaller polypeptides. This action results in liquefaction of the coagulum.
- PSA is also present in the serum and can be measured reliably by either a monoclonal immunoradiometric assay or a polyclonal radioimmunoassay.
- PSA is the most widely used tumor marker for screening, diagnosing, and monitoring prostate cancer today.
- several immunoassays for the detection of serum PSA are in widespread clinical use.
- RT-PCR reverse transcriptase-polymerase chain reaction
- the preferred sequence of the at least one mRNA encoding PSA may contain a sequence coding for the amino acid sequence of PSA as deposited under accession number NP_001 639.1 (Fig. 31 ; SEQ ID NO: 76) or a sequence as deposited under accession number NM_001 648.
- the at least one mRNA contains a coding sequence as shown in any of Figures 2, 3 or 27 (SEQ ID NOs: 2, 3 or 82). More preferably, the at least on mRNA contains or consists of a sequence as shown in Fig. 1 or 1 9 (SEQ ID NO: 1 or 19).
- the at least one mRNA of the composition may alternatively encode a PSA antigen sequence selected from a fragment, a variant or an epitope of a PSA sequence as deposited under accession number NP_001 639.1 or as shown in Figure 31 (SEQ ID NO: 76) or may contain a fragment or variant of the sequence as deposited under accession number NM_001 648 or as shown in any of Figures 1 , 2, 3, 19 or 27 (SEQ ID NOs: 1 , 2, 3, 19 or 82).
- a PSA antigen sequence selected from a fragment, a variant or an epitope of a PSA sequence as deposited under accession number NP_001 639.1 or as shown in Figure 31 (SEQ ID NO: 76) or may contain a fragment or variant of the sequence as deposited under accession number NM_001 648 or as shown in any of Figures 1 , 2, 3, 19 or 27 (SEQ ID NOs: 1 , 2, 3, 19 or 82).
- PSMA is another antigen, which is encoded by the at least one mRNA of the composition.
- PSMA is "Prostate-specific membrane antigen” and may be synomously named FOLH1 (Folate hydrolase 1 ) or "PSM”.
- FOLH1 Frelate hydrolase 1
- PSM Protein-binding protein
- PSMA is a 100 kDa type II transmembrane glycoprotein, wherein PSMA expression is largely restricted to prostate tissues, but detectable levels of PSMA mRNA have been observed in brain, salivary gland, small intestine, and renal cell carcinoma (Israeli et al., 1 993, Cancer Res 53 : 227-230).
- PSMA is highly expressed in most primary and metastatic prostate cancers, but is also expressed in most normal intraepithelial neoplasia specimens (Gao et al. (1 997), supra). Particularly, PSMA is highly expressed in prostate cancer cells and nonprostatic solid tumor neovasculature and is a target for anticancer imaging and therapeutic agents.
- PSMA acts as a glutamate carboxypeptidase (GCPII) on small molecule substrates, including folate, the anticancer drug methotrexate, and the neuropeptide N-acetyl-L-aspartyl-L-glutamate.
- GCPII glutamate carboxypeptidase
- PSMA expression has been shown to correlate with disease progression, with highest levels expressed in hormone-refractory and metastatic disease.
- the cellular localization of PSMA is cytoplasmic and/or membranous.
- PSMA is considered a biomarker for prostate cancer (PCa) and is under intense investigation for use as an
- the preferred sequence of the at least one mRNA encoding PSMA may contain a sequence coding for the amino acid sequence of PSMA as deposited under accession number NP_004467.1 (Fig. 32; SEQ ID NO: 77) or a sequence as deposited under accession number NM_004476.
- it contains a coding sequence as shown in any of Figures 5, 6 or 28 (SEQ ID NO: 5, 6 or 83).
- the at least one mRNA contains or consists of a sequence as shown in Fig. 4 or 20 (SEQ ID NO: 4 or 20).
- the at least one mRNA of the composition may alternatively encode a PSMA antigen sequence selected from a fragment, a variant or an epitope of a PSMA sequence as deposited under accession number NP_004467.1 or as shown in Figure 32 (SEQ ID NO: 77) or may contain a fragment or variant of the sequence as deposited under accession number NM_004476 or as shown in any of Figures 4, 5, 6, 20 or 28 (SEQ ID NOs: 4, 5, 6, 20 or 83).
- a PSMA antigen sequence selected from a fragment, a variant or an epitope of a PSMA sequence as deposited under accession number NP_004467.1 or as shown in Figure 32 (SEQ ID NO: 77) or may contain a fragment or variant of the sequence as deposited under accession number NM_004476 or as shown in any of Figures 4, 5, 6, 20 or 28 (SEQ ID NOs: 4, 5, 6, 20 or 83).
- PSCA is a further antigen encoded by the at least one mRNA of the composition according to the invention.
- PSCA is "prostate stem cell antigen”. PSCA is widely over-expressed across all stages of prostate cancer, including high grade prostatic intraepithelial neoplasia (PIN), androgen-dependent and androgen- independent prostate tumors.
- the PSCA gene shows 30% homology to stem cell antigen-2, a member of the Thy-l/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens, and encodes a 123 amino acid protein with an amino-terminal signal sequence, a carboxy- terminal GPI-anchoring sequence, and multiple N-glycosylation sites.
- PSCA mRNA expression is highly upregulated in both androgen dependent and androgen independent prostate cancer xenografts. In situ mRNA analysis localizes PSCA expression to the basal cell epithelium, the putative stem cell compartment of the prostate. Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage.
- PSCA Fluorescent in situ hybridization analysis localizes the PSCA gene to chromosome 8q24. 2, a region of allelic gain in more than 80% of prostate cancers.
- PSCA may be used as a prostate cancer marker to discriminate between malignant prostate cancers, normal prostate glands and non-malignant neoplasias.
- PSCA is expressed at very high levels in prostate cancer in relation to benign prostatic hyperplasia (BPH).
- the preferred sequence of the at least one mRNA encoding PSCA may contain a sequence coding for the ami no acid sequence of PSCA as deposited under accession number ⁇ 43653.1 (Fig. 33; SEQ I D NO: 78) or a sequence as deposited under accession number NM_005672.
- it contains a coding sequence as shown in any of Figures 8, 9 or 29(SEQ ID NOs: 8, 9 or 84).
- the at least one mRNA comprises or consists of a sequence as shown i n Fig. 7 or 21 (SEQ ID NO: 7 or 21 ).
- the at least one mRNA of the composition may alternatively encode a PSCA antigen sequence selected from a fragment, a variant or an epitope of a PSCA sequence as deposited under accession number ⁇ 43653.1 or as shown in Figure 33 (SEQ ID NO: 78) or may contain a fragment or variant of the sequence as deposited under accession number NM_005672 or as shown in any of Figures 7, 8, 9, 21 or 29 (SEQ ID NOs: 7, 8, 9,21 or 84).
- STEAP is encoded by the at least one mRNA of the composition according to the invention.
- "STEAP” is "six transmembrane epithelial antigen of the prostate” and may synomously be named STEAP1 .
- STEAP or STEAP-1 is a novel cell surface protein and is expressed predominantly in human prostate tissue and in other common malignancies including prostate, bladder, colon, and ovarian carcinomas, and in Ewing's sarcoma, suggesti ng that it could function as an almost universal tumor antigen.
- the preferred sequence of the at least one mRNA encoding STEAP may contain a sequence coding for the amino acid sequence of STEAP as deposited under accession number NPJ 6581 .1 (Fig. 34; SEQ ID NO: 79) or a sequence as deposited under accession number NM_012449.
- it contains a coding sequence as shown in any of Figures 1 1 , 12 or 30 (SEQ ID NO: 1 1 , 12 or 85).
- the at least one mRNA contains or consists of a sequence as shown in Fig. 10 or 22 (SEQ ID NO: 10 or 22).
- the at least one mRNA of the composition may alternatively encode a STEAP antigen sequence selected from a fragment, a variant or an epitope of a STEAP sequence as deposited under accession number NP_036581 .1 or as shown in Figure 34 (SEQ ID NO: 79) or may contain a fragment or variant of the sequence as deposited under accession number NM_012449 or as shown in any of Figures 10, 1 1 , 12, 22, or 30 (SEQ ID NOs: 10, 1 1 , 12, 22 or 85).
- a STEAP antigen sequence selected from a fragment, a variant or an epitope of a STEAP sequence as deposited under accession number NP_036581 .1 or as shown in Figure 34 (SEQ ID NO: 79) or may contain a fragment or variant of the sequence as deposited under accession number NM_012449 or as shown in any of Figures 10, 1 1 , 12, 22, or 30 (SEQ ID NOs: 10, 1 1 , 12, 22 or 85).
- the at least one mRNA of the composition according to the invention encodes PAP.
- PAP is "prostatic acid phosphatase” and may be synonymously referred to as, for instance, PSAP (prostate specific acid phosphatase) or ACPP (acid phosphatase, prostate).
- PAP is an enzyme, which is secreted by epithelial cells of the prostate gland and catalyzes the conversion of orthophosphoric monoester to alcohol and orthophosphate. > 95% of normal adult prostate tissue samples, including normal tissue adjacent to tumor, as well as >95% of primary adenocarcinomas, strongly express PAP.
- PAP expression can be detected in some normal human tissues besides the prostate (e.g.
- PAP has generally been considered a tissue-specific prostate antigen, highly expressed in both normal and malignant prostate cells. Furthermore it has been demonstrated that PAP is strongly expressed in prostate cancer bone metastases and may play a causal role in the osteoblastic phase of the disease. PAP has been shown to induce long term CD4+ and CD8+ T-cell responses, including CTL responses, in patients. Treatment of prostate cancer patients with autologous antigen presenting cells stimulated with PAP has resulted in improved survival and a favorable safety profile.
- the preferred sequence of the at least one mRNA encoding PAP may contain a sequence coding for the amino acid sequence of PAP as deposited under accession number NP_001090.2 (Fig. 35; SEQ ID NO: 80) or a sequence as deposited under accession number NM_001099.4.
- it contains a coding sequence as shown in any of Figures 14 or 1 5 (SEQ ID NO: 14 or 1 5).
- the at least one mRNA comprises or consists of a sequence as shown in Figure 13 or 23 (SEQ ID NO: 1 3 or 23).
- the at least one mRNA of the composition may alternatively encode a PAP antigen sequence selected from a fragment, a variant or an epitope of a PAP sequence as deposited under accession number NP_001090.2 or as shown in Figure 35 (SEQ ID NO: 80) or may contain a fragment or variant of the sequence as deposited under accession number NM_001099.4 or as shown in Figure 13, 14, 15 or 23 (SEQ ID NO: 13, 14, 1 5 or 23).
- MUC1 is encoded by the at least one mRNA of the composition according to the invention.
- “MUC1” is “Mucin 1 " and may be synonymously referred to as, for instance, CD227 or DF3.
- MUC1 is a large mucinous glycoprotein that is normally expressed on the luminar surface of glandular epithelia. Its function in normal epithelia is to lubricate and to protect epithelial cells. The expression of MUC1 is often increased, no longer restricted to a luminal surface and characterized by aberrant glycosylation in many human malignancies, including prostate cancer. MUC1 is expressed in about 60% of primary prostate cancers and 90% of lymph node metastases.
- MUC1 -positive primary prostate tumors were Gleason grade >7, supporting an association with more aggressive disease.
- Gene expression profiling of human prostate cancers has also shown that MUC1 is highly expressed in subgroups with aggressive clinicopathologic features and an elevated risk of recurrence. Both over- and underexpression of MUC-1 have been found to increase the risk of prostate cancer progression.
- MUC1 has been shown to be immunogenic and has been described to induce specific immune responses comprising CD8+ CTLs and IgM antibodies in patients. Vaccination against MUC1 using different vaccination approaches was associated with trends for clinical benefit in phase II trials in patients with advanced non- small cell lung cancer and appeared well tolerated.
- Vaccination against MUC1 in prostate cancer using the same vaccines was associated with a prolongation in PSA doubling time in some patients.
- MVA- MUC1 -IL2 vaccine immunotherapy (TG4010) improves PSA doubling time in patients with prostate cancer with biochemical failure.
- L-BLP25 a MUC1 -targeted peptide vaccine therapy in prostate cancer. Expert Opin Biol Ther. 7:1 723-1 730).
- the preferred sequence of the at least one mRNA, preferably of the mRNA, encoding MUC1 may contain a sequence coding for the amino acid sequence of MUC1 as deposited under accession number AAA60019.1 (Fig. 36; SEQ ID NO: 81 ), or a truncated amino acid sequence as shown in Fig. 37 (SEQ ID NO: 86; MUC1 5xVNTR) or the at least one mRNA may contain a sequence as deposited under accession number J05582.1 .
- it contains a coding sequence as shown in any of Figures 1 7, 18 or 38 (SEQ ID NO: 1 7, 18 or 87).
- the at least one mRNA contains or consists of a sequence as shown in Fig. 1 6 or 24 (SEQ ID NO: 1 6 or 24).
- the at least one mRNA of the composition may alternatively or additionally encode a MUC1 antigen sequence selected from a fragment, a variant or an epitope of a MUC1 sequence as deposited under accession number AAA6001 9.1 or as shown in Figure 36 or 37 (SEQ ID NO: 81 or 86) or may contain a fragment or variant of the sequence as deposited under accession number J05582.1 or as shown in Figure 1 6, 1 7, 18, 24 or 38 (SEQ ID NO: 1 6, 1 7, 18, 24 or 87).
- antigens or fragments or variants thereof it is understood that the reference concerns the antigen or peptide encoded by one or more of the mRNA sequences provided in the present invention.
- antigens, antigenic proteins or antigenic peptides as defined above which are encoded by the at least one mRNA of the composition according to the present invention, may comprise fragments or variants of those sequences.
- Such fragments or variants may typically comprise a sequence having a sequence homology with one of the above mentioned antigens, antigenic proteins or antigenic peptides or sequences or their encoding nucleic acid sequences of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, preferably at least 70%, more preferably at least 80%, equally more preferably at least 85%, even more preferably at least 90% and most preferably at least 95% or even 97%, to the entire wild-type sequence, either on nucleic acid level or on amino acid level.
- “Fragments” of antigens, antigenic proteins or antigenic peptides in the context of the present invention may comprise a sequence of an antigen, antigenic protein or antigenic peptide as defined above, which is, with regard to its amino acid sequence (or its encoded nucleic acid sequence), N-terminally, C-terminally and/or intrasequentially truncated compared to the amino acid sequence of the original (native) protein (or its encoded nucleic acid sequence). Such truncation may thus occur either on the amino acid level or correspondingly on the nucleic acid level.
- a sequence homology with respect to such a fragment as defined above may therefore preferably refer to the entire antigen, antigenic protein or antigenic peptide as defined above or to the entire (coding) nucleic acid sequence of such an antigen, antigenic protein or antigenic peptide.
- Fragments of antigens, antigenic proteins or antigenic peptides in the context of the present invention may furthermore comprise a sequence of an antigen, antigenic protein or antigenic peptide as defined above, which has a length of about 6 to about 20 or even more amino acids, e.g. fragments as processed and presented by MHC class I molecules, preferably having a length of about 8 to about 10 amino acids, e.g. 8, 9, or 1 0, (or even 6, 7, 1 1 , or 12 amino acids), or fragments as processed and presented by MHC class II molecules, preferably having a length of about 13 or more amino acids, e.g. 1 3, 14, 1 5, 1 6, 1 7, 18, 19, 20 or even more amino acids, wherein these fragments may be selected from any part of the amino acid sequence.
- These fragments are typically recognized by T-cells in form of a complex consisting of the peptide fragment and an MHC molecule, i.e. the fragments are typically not recognized in their native form.
- Fragments of antigens, antigenic proteins or antigenic peptides as defined herein may also comprise epitopes of those antigens, antigenic proteins or antigenic peptides.
- Epitopes also called "antigen determinants" in the context of the present invention are typically fragments located on the outer surface of (native) antigens, antigenic proteins or antigenic peptides as defined herein, preferably having 5 to 1 5 amino acids, more preferably having 5 to 12 amino acids, even more preferably having 6 to 9 amino acids, which may be recognized by antibodies or B-cell receptors, i.e. in their native form.
- Such epitopes of antigens, antigenic proteins or antigenic peptides may furthermore be selected from any of the herein mentioned variants of such antigens, antigenic proteins or antigenic peptides.
- antigenic determinants can be conformational or discontinous epitopes which are composed of segments of the antigens, antigenic proteins or antigenic peptides as defined herein that are discontinuous in the amino acid sequence of the antigens, antigenic proteins or antigenic peptides as defined herein but are brought together in the three-dimensional structure or continuous or linear epitopes which are composed of a single polypeptide chain. Therefore in this context it is particularly preferred that the fragment of the antigen, the antigenic protein or antigenic peptide comprises at least one epitope of the antigen.
- “Variants” of antigens, antigenic proteins or antigenic peptides as defined above may be encoded by the at least one mRNA of the composition according to the present invention, wherein nucleic acids of the at least one mRNA, encodi ng the antigen, antigenic protein or antigenic peptide as defined above, are exchanged.
- an antigen, antigenic protein or antigenic peptide may be generated, having an amino acid sequence which differs from the original sequence in one or more mutation(s), such as one or more substituted, inserted and/or deleted amino acid(s).
- these fragments and/or variants have the same biological function or specific activity compared to the full-length native antigen or antigenic potein, e.g. its specific antigenic property.
- the at least one mRNA of the composition according to the present invention may also encode an antigen or an antigenic protein as defined above, wherein the encoded amino acid sequence comprises conservative amino acid substitution(s) compared to its physiological sequence.
- Substitutions in which amino acids which originate from the same class are exchanged for one another are called conservative substitutions.
- these are amino acids having aliphatic side chains, positively or negatively charged side chains, aromatic groups in the side chains or amino acids, the side chains of which can enter into hydrogen bridges, e.g. side chains which have a hydroxy! function. This means that e.g.
- an amino acid having a polar side chain is replaced by another amino acid having a li kewise polar side chain, or, for example, an amino acid characterized by a hydrophobic side chain is substituted by another amino acid having a likewise hydrophobic side chain (e.g. serine (threonine) by threonine (serine) or leucine (isoleucine) by isoleucine (leucine)).
- Insertions and substitutions are possible, in particular, at those sequence positions which cause no modification to the three-dimensional structure or do not affect the binding region. Modifications to a three-dimensional structure by i nsertion(s) or deletion(s) can easily be determined e.g.
- CD spectra circular dichroism spectra
- variants of antigens, antigenic proteins or antigenic peptides as defined above, which may be encoded by the at least one mRNA of the composition according to the present invention may also comprise those sequences, wherein nucleic acids of the at least one mRNA are exchanged according to the degeneration of the genetic code, without leading to an alteration of respective amino acid sequence of the antigen, antigenic protein or antigenic peptide, i.e. the amino acid sequence or at least part thereof may not differ from the original sequence in one or more mutation(s) within the above meaning.
- variants of antigens, antigenic proteins or antigenic peptides as defined above, which may be encoded by the at least one mRNA of the composition according to the present invention may also comprise those DNA sequences, which correspond to an RNA sequence as defined herewithin and comprise further RNA sequences, which correspond to DNA sequences as defined herewithin.
- RNA sequences which correspond to an RNA sequence as defined herewithin
- Those skilled in the art are familiar with the translation of an RNA sequence into a DNA sequence (or vice versa) or with the creation of the complementary strand sequence (i.e. by substitution of U residues with T residues and/or by constructing the complementary strand with respect to a given sequence).
- nucleic acid sequences e.g. RNA or mRNA sequences as defined herein, or amino acid sequences, preferably their encoded amino acid sequences, e.g. the amino acid sequences of the antigens, antigenic proteins or antigenic peptides as defined above
- the sequences can be aligned in order to be subsequently compared to one another. Therefore, e.g. gaps can be inserted into the sequence of the first sequence and the component at the corresponding position of the second sequence can be compared. If a position in the first sequence is occupied by the same component as is the case at a position in the second sequence, the two sequences are identical at this position.
- the percentage to which two sequences are identical is a function of the number of identical positions divided by the total number of positions.
- the percentage to which two sequences are identical can be determined using a mathematical algorithm.
- a preferred, but not limiting, example of a mathematical algorithm which can be used is the algorithm of Karlin et al. (1 993), PNAS USA, 90:5873-5877 or Altschul et al. (1997), Nucleic Acids Res., 25:3389-3402. Such an algorithm is integrated in the BLAST program. Sequences which are identical to the sequences of the present invention to a certain extent can be identified by this program.
- composition refers to at least one mRNA and, optionally, further excipients.
- composition thus comprises any mixture of mRNAs (mRNA species) encoding the antigens as defined above, irrespective of whether the mRNAs are mono-, bi- or multicistronic.
- composition also refers to an embodiment consisting of a multicistronic RNA, which encodes all six antigens as defined above.
- the composition contains at least six distinct mRNA species, whereby each mRNA species encodes one of the above antigens.
- composition preferably relates to the at least one mRNA together with at least one other suitable substance.
- the composition may be a pharmaceutical composition, which is designed for use in the medical field. Accordingly, the composition typically comprises at least one further excipient, which is pharmaceutically acceptable and which may be selected, for example, from carriers, vehicles and the like.
- the “composition” may be a liquid or a dry composition. If the composition is liquid, it will be preferably an aqueous solution or dispersion of the at least one RNA. If the “composition” is a dry composition, it will typically be a lyophilized composition of at least one mRNA.
- composition as used herewithin, further refers to the at least one mRNA of the invention in combination with a further active ingredient.
- the composition is an immunostimulatory composition, i.e.
- composition comprising at least one component, which is able to induce an immune response or from which a component, which is able to induce an immune response, is derivable.
- the immune response may be the result of the adaptive and/or of the innate immune system.
- composition according to the present invention comprises at least one mRNA encoding at least six antigens as defined above, as it was found out that the specific combination of said antigens is capable of effectively stimulating the (adaptive) immune system, thus allowing treatment of prostate cancer (PCa).
- the object of the present invention is solved by the provision of a composition comprising at least one mRNA coding for a novel combination of antigens as defined herein.
- the composition comprises six antigens (PSA, PSMA, PSCA, STEAP, PAP and MUC1 ) which are encoded by six monocistronic mRNAs, each of these mRNAs encoding a different antigen selected from the defined group of antigens.
- the composition may comprise a combination of monocistronic, bi- and/or multicistronic mRNAs, wherein more than one of the six antigens is encoded by a bi- or multicistronic mRNA.
- any combination of mono-, bi- or multicistronic mRNA is envisaged that encode all six antigens as defined herein, e.g.
- the composition comprises at least one mRNA, which comprises at least one coding sequence selected from mRNA sequences being identical or at least 80% identical to the RNA sequence of SEQ ID NOs: 2, 5, 8, 1 1 , 14 or 1 7 (or 87). Even more preferably, the composition comprises six mRNAs, wherein the coding sequence in each mRNA is identical or at least 80% identical to one of the RNA sequences according to SEQ ID NOs: 2, 5, 8, 1 1 , 14 and 1 7 (or 87).
- each of the at least six antigens of the composition of the present invention may be encoded by one (monocistronic) mRNA.
- the composition of the present invention may contain six (monocistronic) mRNAs, wherein each of these six (monocistronic) mRNAs, may encode just one antigen as defined above.
- the composition comprises six mRNAs, wherein one mRNA encodes PSA, one mRNA encodes PSMA, one mRNA encodes PSCA, one mRNA encodes STEAP, one mRNA encodes PAP and one mRNA encodes MUC1 or fragments or variants thereof, respectively.
- the composition comprises six mRNAs, wherein one mRNA encodes PSA and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 2, one mRNA encodes PSMA and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 5, one mRNA encodes PSCA and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 8, one mRNA encodes STEAP and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 1 1 , one mRNA encodes PAP and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 14 and one mRNA encodes MUC1 and comprises a coding sequence identical or at least 80% identical to SEQ ID NO:1 7 (or 87) (or fragments or variants of each of these sequences) and optionally further excipients.
- the composition comprises six mRNAs, wherein one mRNA encodes PSA and comprises the coding sequence according to SEQ ID NO: 2, one mRNA encodes PSMA and comprises the coding sequence according to SEQ ID NO: 5, one mRNA encodes PSCA and comprises the coding sequence according to SEQ ID NO: 8, one mRNA encodes STEAP and comprises the coding sequence according to SEQ ID NO: 1 1 , one mRNA encodes PAP and comprises the coding sequence according to SEQ ID NO: 14 and one mRNA encodes MUC1 and comprises the coding sequence according to SEQ ID NO:1 7 (or 87) or fragments thereof, respectively.
- the at least one mRNA of the composition may preferably comprise a histone stem-loop in the 3' UTR region.
- the composition comprises six mRNAs, wherein each mRNA comprises a histone stem-loop as defined herein.
- the composition of the present invention may comprise (at least) one bi- or even multicistronic mRNA, i.e. (at least) one mRNA which carries the coding sequences of two or more of the six antigens according to the invention.
- Such coding sequences of two or more antigens of the (at least) one bi- or even multicistronic mRNA may be separated by at least one IRES (internal ribosomal entry site) sequence, as defined below.
- IRES internal ribosomal entry site
- the term "encoding two or more antigens” may mean, without being limited thereto, that the (at least) one (bi- or even multicistronic) mRNA may encode e.g.
- the (at least) one (bi- or even multicistronic) mRNA may encode e.g. at least two, three, four, five or six (preferably different) antigens of the above mentioned antigens or their fragments or variants within the above definitions.
- IRES internal ribosomal entry site
- IRES sequences which can be used according to the invention are those from picornaviruses (e.g.
- FMDV pestiviruses
- CFFV pestiviruses
- PV polioviruses
- ECMV encephalomyocarditis viruses
- FMDV foot and mouth disease viruses
- HCV hepatitis C viruses
- CSFV classical swine fever viruses
- MLV mouse leukoma virus
- SIV simian immunodeficiency viruses
- CrPV cricket paralysis viruses
- the composition of the present invention may comprise a mixture of at least one monocistronic mRNA as defined above, and at least one bi- or even multicistronic mRNA as defined above.
- the at least one monocistronic mRNA and/or the at least one bi- or even multicistronic mRNA preferably encode different antigens or their fragments or variants within the above definitions.
- the at least one monocistronic mRNA and the at least one bi- or even multicistronic mRNA may preferably also encode (in part) identical antigens selected from the above mentioned antigens, provided that the composition of the present invention as a whole provides the six antigens as defined above.
- the relative protein amounts of said one or more antigens can be increased, i.e. the ratio between the amounts of each of the six antigens can be modulated.
- Such an embodiment may further be advantageous e.g. for a staggered, e.g. time dependent, administration of the composition of the present invention to a patient in need thereof.
- the components of such a composition of the present invention as defined herein, particularly the different mRNAs encoding the specific combination of the at least six antigens according to the invention may be e.g. contained in (different parts of) a kit of parts or may be e.g. administered separately as components of different compositions according to the present invention.
- each of the at least six antigens is encoded by a distinct mRNA and is comprised in different parts of a kit.
- Each mRNA encoding one of the at least six antigens is preferably administered separately as components of different compositions as defined herein. All embodiments disclosed for the inventive composition are applicable for such a combination of compositions comprising mRNAs encoding different antigens.
- the at least one mRNA of the composition, encoding at least one of the six antigens typically comprises a length of about 50 to about 20000, or 100 to about 20000 nucleotides, preferably of about 250 to about 20000 nucleotides, more preferably of about 500 to about 10000, even more preferably of about 500 to about 5000.
- the at least one mRNA of the composition may be in the form of a modified RNA, wherein any modification, as defined herein, may be introduced into the at least one mRNA of the composition. Modifications as defined herein preferably lead to a stabilized at least one mRNA of the composition of the present invention.
- the at least one mRNA of the composition of the present invention may thus be provided as a "stabilized mRNA", that is to say as an mRNA that is essentially resistant to in vivo degradation (e.g. by an exo- or endo-nuclease).
- Such stabilization can be effected, for example, by a modified phosphate backbone of the at least one mRNA of the composition of the present invention.
- a backbone modification in connection with the present invention is a modification in which phosphates of the backbone of the nucleotides contained in the mRNA are chemically modified.
- Nucleotides that may be preferably used in this connection contain e.g. a phosphorothioate-modified phosphate backbone, preferably at least one of the phosphate oxygens contained in the phosphate backbone being replaced by a sulfur atom.
- Stabilized mRNAs may further include, for example: non-ionic phosphate analogues, such as, for example, alkyl and aryl phosphonates, in which the charged phosphonate oxygen is replaced by an alkyl or aryl group, or phosphodiesters and alkylphosphotriesters, in which the charged oxygen residue is present in alkylated form.
- non-ionic phosphate analogues such as, for example, alkyl and aryl phosphonates, in which the charged phosphonate oxygen is replaced by an alkyl or aryl group
- phosphodiesters and alkylphosphotriesters in which the charged oxygen residue is present in alkylated form.
- backbone modifications typically include, without implying any limitation, modifications from the group consisting of methylphosphonates, phosphoramidates and phosphorothioates (e.g. cytidine-5'-0-(1 -thiophosphate)).
- the at least one mRNA of the composition of the present invention may additionally or alternatively also contain sugar modifications.
- a sugar modification in connection with the present invention is a chemical modification of the sugar of the nucleotides of the at least one mRNA and typically includes, without implying any limitation, sugar modifications selected from the group consisting of 2'-deoxy-2 '-fluoro-oligoribonucleotide (2'-fluoro-2'- deoxycytidine-5 '-triphosphate, 2 '-fluoro-2'-deoxyuridine-5 '-triphosphate), 2'-deoxy-2 '- deamine oligoribonucleotide (2'-amino-2'-deoxycytidine-5 '-triphosphate, 2'-amino-2'- deoxyuridine-5'-triphosphate), 2'-0-alkyl oligoribonucleotide, 2'-deoxy-2'-C-alkyl oligoribonucleotide (2'-0-methylcyt
- Significant in this case means an increase in the expression of the protein compared with the expression of the native mRNA sequence by at least 20%, preferably at least 30%, 40%, 50% or 60%, more preferably by at least 70%, 80%, 90% or even 1 00% and most preferably by at least 150%, 200% or even 300% or more.
- a nucleotide having such a base modification is preferably selected from the group of the base-modified nucleotides consisting of 2-amino-6-chloropurineriboside- 5 '-triphosphate, 2-aminoadenosine-5'-triphosphate, 2-thiocytidine-5'-triphosphate, 2- thiouridine-5 '-triphosphate, 4-thiouridine-5 '-triphosphate, 5-aminoallylcytidine-5'- triphosphate, 5-aminoallyluridine-5'-triphosphate, 5-bromocytidine-5'-triphosphate, 5- bromouridine-5 '-triphosphate, 5-iodocytidine-5 '-triphosphate, 5-iodouridine-5'- triphosphate, 5-methylcytidine-5'-triphosphate, 5-methyluridine-5'-triphosphate, 6- azacytidine-5 '-triphosphate, 6-azauridine-5 '-triphosphate, 6-azaur
- nucleotides for base modifications selected from the group of base- modified nucleotides consisting of 5-methylcytidine-5'-triphosphate, 7-deazaguanosine-5'- triphosphate, 5-bromocytidine-5'-triphosphate, and pseudouridine-5'-triphosphate.
- the at least one mRNA of the composition of the present invention can likewise be modified (and preferably stabilized) by introducing further modified nucleotides containing modifications of their ribose or base moieties.
- nucleotide analogues are defined as non-natively occurring variants of naturally occurring nucleotides.
- analogues are chemically derivatized nucleotides with non-natively occurring functional groups, which are preferably added to or deleted from the naturally occurring nucleotide or which substitute the naturally occurring functional groups of a nucleotide. Accordingly, each component of the naturally occurring nucleotide may be modified, namely the base component, the sugar (ribose) component and/or the phosphate component forming the backbone (see above) of the mRNA sequence.
- Analogues of guanosine, uracil, adenosine, and cytosine include, without implying any limitation, any naturally occurring or non- naturally occurring guanosine, uracil, adenosine, thymidine or cytosine that has been altered chemically, for example by acetylation, methylation, hydroxylation, etc., including 1 -methyl-adenosine, 1 -methyl-guanosine, 1 -methyl-inosine, 2,2-dimethyl-guanosine, 2,6- diaminopurine, 2'-Amino-2 '-deoxyadenosine, 2 '-Amino-2 '-deoxycytidine, 2 '-Amino-2'- deoxyguanosine, 2'-Amino-2 '-deoxyuridine, 2-Amino-6-chloropurineriboside, 2- Aminopurine-riboside, 2'-Araadeno
- the at least one mRNA of the composition of the present invention can contain a lipid modification.
- a lipid-modified mRNA typically comprises an mRNA as defined herein, encoding at least one of the six antigens as defined above.
- Such a lipid-modified mRNA typically further comprises at least one linker covalently linked with that mRNA, and at least one lipid covalently linked with the respective linker.
- the lipid-modified mRNA comprises an (at least one) mRNA as defined herein and at least one (bifunctional) lipid covalently linked (without a linker) with that mRNA.
- the lipid-modified mRNA comprises an mRNA as defined herein, at least one linker covalently linked with that mRNA, and at least one lipid covalently linked with the respective linker, and also at least one (bifunctional) lipid covalently linked (without a linker) with that mRNA.
- the lipid contained in the at least one mRNA of the inventive composition is typically a lipid or a lipophilic residue that preferably is itself biologically active.
- lipids preferably include natural substances or compounds such as, for example, vitamins, e.g. alpha-tocopherol (vitamin E), including RRR-alpha-tocopherol (formerly D-alpha-tocopherol), L-alpha-tocopherol, the racemate D,L-alpha-tocopherol, vitamin E succinate (VES), or vitamin A and its derivatives, e.g. retinoic acid, retinol, vitamin D and its derivatives, e.g.
- vitamins e.g. alpha-tocopherol (vitamin E), including RRR-alpha-tocopherol (formerly D-alpha-tocopherol), L-alpha-tocopherol, the racemate D,L-alpha-tocopherol, vitamin E succinate (VES), or vitamin A and its derivatives, e
- bile acids for example cholic acid, deoxycholic acid, dehydrocholic acid, cortisone, digoxygenin, testosterone, cholesterol or thiocholesterol.
- Further lipids or lipophilic residues within the scope of the present invention include, without implying any limitation, polyalkylene glycols (Oberhauser et al., Nucl.
- Acids Res., 1 992, 20, 533) aliphatic groups such as, for example, C1 -C20-alkanes, C1 -C20-alkenes or C1 -C20-alkanol compounds, etc., such as, for example, dodecanediol, hexadecanol or undecyl residues (Saison-Behmoaras et al., EMBO J, 1 991 , 10, 1 1 1 1 ; Kabanov et al., FEBS Lett., 1990, 259, 327; Svinarchuk et al., Biochimie, 1 993, 75, 49), phospholipids such as, for example, phosphatidylglycerol, diacylphosphatidylglycerol, phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylserine, phosphatidy
- polyamines or polyalkylene glycols such as, for example, polyethylene glycol (PEG) (Manoharan et al., Nucleosides & Nucleotides, 1 995, 14, 969), hexaethylene glycol (HEG), palmitin or palmityl residues (Mishra et al., Biochim. Biophys. Acta, 1 995, 1264, 229), octadecylamines or hexylamino-carbonyl-oxycholesterol residues (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923), and also waxes, terpenes, alicyclic hydrocarbons, saturated and mono- or poly-unsaturated fatty acid residues, etc..
- PEG polyethylene glycol
- HEG hexaethylene glycol
- HOG hexaethylene glycol
- palmitin or palmityl residues Mishr
- the at least one mRNA of the composition of the present invention may likewise be stabilized in order to prevent degradation of the mRNA in vivo by various approaches. It is known in the art that instability and (fast) degradation of mRNA or of RNA in vivo in general may represent a serious problem in the application of RNA based compositions. This instability of RNA is typically due to RNA-degrading enzymes, "RNases" (ribonucleases), wherein contamination with such ribonucleases may sometimes completely degrade RNA in solution.
- RNases ribonucleases
- the natural degradation of mRNA in the cytoplasm of cells is very finely regulated and RNase contaminations may be generally removed by special treatment prior to use of said sompositions, in particular with diethyl pyrocarbonate (DEPC).
- DEPC diethyl pyrocarbonate
- a number of mechanisms of natural degradation are known in this connection in the prior art, which may be utilized as well.
- the terminal structure is typically of critical importance for an mRNA in vivo.
- cap structure a modified guanosine nucleotide
- the so-called poly-A tail is typically a sequence of up to 200 adenosine nucleotides
- the at least one mRNA of the composition of the present invention can therefore be stabilized against degradation by RNases by the addition of a so-called "5' cap” structure.
- a so-called "5' cap” structure Particular preference is given in this connection to an m7G(5')ppp (5'(A,G(5')ppp(5 ')A or G(5')ppp(5')G as the 5' cap" structure.
- a modification is introduced only if a modification, for example a lipid modification, has not already been introduced at the 5' end of the mRNA of the inventive composition or if the modification does not interfere with the immunogenic properties of the (unmodified or chemically modified) mRNA.
- the at least one mRNA of the composition of the present invention may contain a poly-A tail on the 3 ' terminus of typically about 10 to 200 adenosine nucleotides, preferably about 10 to 100 adenosine nucleotides, more preferably about 40 to 80 adenosine nucleotides or even more preferably about 50 to 70 adenosine nucleotides.
- the at least one mRNA of the composition of the present invention may contain a poly-C tail on the 3 ' terminus of typically about 10 to 200 cytosine nucleotides, preferably about 10 to 100 cytosine nucleotides, more preferably about 20 to 70 cytosine nucleotides or even more preferably about 20 to 60 or even 10 to 40 cytosine nucleotides.
- the at least one mRNA according to the invention preferably comprises or codes for at least one histone stem-loop.
- a histone stem-loop in general (irrespective of whether it is a histone stem loop or not), is typically derived from histone genes and comprises an intramolecular base pairing of two neighboring entirely or partially reverse complementary sequences, thereby forming a stem-loop.
- a stem-loop can occur in single-stranded DNA or, more commonly, in RNA.
- a histone stem-loop sequence may be described by its DNA or by its corresponding RNA sequence.
- any reference - throughout the present application - to histone stem-loop sequences which are represented herein by DNA sequences (e.g. SEQ ID NO: 37 to 66 and 70), also comprises the corresponding RNA sequence.
- the structure is also known as a hairpin or hairpin loop and usually consists of a stem and a (terminal) loop within a consecutive sequence, wherein the stem is formed by two neighbored entirely or partially reverse complementary sequences separated by a short sequence as sort of spacer, which builds the loop of the stem-loop structure.
- the two neighbored entirely or partially reverse complementary sequences may be defined as e.g. stem loop elements stemi and stem2.
- the stem loop is formed when these two neighbored entirely or partially reverse complementary sequences, e.g.
- stem loop elements stemi and stem2 form base-pairs with each other, leading to a double stranded nucleic acid sequence stretch comprising an unpaired loop at its terminal ending formed by the short sequence located between stem loop elements steml and stem2 on the consecutive sequence.
- the unpaired loop thereby typically represents a region of the nucleic acid which is not capable of base pairing with either of these stem loop elements.
- the resulting lollipop-shaped structure is a key building block of many RNA secondary structures. The formation of a stem-loop structure is thus dependent on the stability of the resulting stem and loop regions, wherein the first prerequisite is typically the presence of a sequence that can fold back on itself to form a paired double strand.
- the stability of paired stem loop elements is determined by the length, the number of mismatches or bulges it contains (a small number of mismatches is typically tolerable, especially in a long double stranded stretch), and the base composition of the paired region.
- a loop length of 3 to 1 5 bases is conceivable, while a more preferred loop length is 3-1 0 bases, more preferably 3 to 8, 3 to 7, 3 to 6 or even more preferably 4 to 5 bases, and most preferably 4 bases.
- the sequence forming the stem region in the histone stem-loop typically has a length of between 5 to 10 bases, more preferably, between 5 to 8 bases, wherein preferably at least one of the bases represents a mismatch, i.e. does not base pair.
- a histone stem-loop is typically derived from histone genes (e.g. genes from the histone families H1 , H2A, H2B, H3, H4) and comprises an intramolecular base pairing of two neighbored entirely or partially reverse complementary sequences, thereby forming a stem-loop.
- histone 3' UTR stem-loop is an RNA element involved in nucleocytoplasmic transport of the histone mRNAs, and in the regulation of stability and of translation efficiency in the cytoplasm.
- the mRNAs of metazoan histone genes lack polyadenylation and a poly-A tail, instead 3' end processing occurs at a site between this highly conserved stem-loop and a purine rich region around 20 nucleotides downstream (the histone downstream element, or HDE).
- the histone stem-loop is bound by a 31 kDa stem-loop binding protein (SLBP - also termed the histone hairpin binding protein, or HBP).
- SLBP stem-loop binding protein
- HBP histone hairpin binding protein
- one embodiment of the invention comprises the combination of a histone stem-loop structure with a poly(A) sequence or a sequence representing a polyadenylation signal (3'-terminal of a coding region), which does not occur in metazoan histone genes.
- a combination of a histone stem-loop structure with a coding region coding for at least one of the antigens according to the invention as defined above, which does, preferably not occur in metazoan histone genes, is provided herewith (coding region and histone stem loop sequence are heterologous).
- a histone stem loop is, therefore, a stem-loop structure as described herein, which, if preferably functionally defined, exhibits/retains the property of binding to its natural binding partner, the stem-loop binding protein (SLBP - also termed the histone hairpin binding protein, or HBP).
- SLBP stem-loop binding protein
- HBP histone hairpin binding protein
- the histone stem loop sequence is not derived from a mouse histone protein. More specifically, the histone stem loop sequence may not be derived from mouse histone gene H2A614. Also, the at least one mRNA according to the invention may neither contain a mouse histone stem loop sequence nor contain mouse histone gene H2A614. Further, the at least one mRNA according to the invention may not contain a stem-loop processing signal, more specifically, a mouse histone processing signal and, most specifically, may not contain mouse stem loop processing signal H2kA614, even if the at least one mRNA contains at least one mammalian histone gene. However, the at least one mammalian histone gene may not be Seq. ID No. 7 of WO 01/12824.
- the at least one mRNA as define above preferably comprises a coding region encoding the antigens as defined above or a fragment, variant or derivative thereof; and a 3' UTR containing at least one histone stem-loop.
- a further peptide or protein is encoded by the at least one mRNA, then the encoded peptide or protein is preferably no histone protein, no reporter protein and/or no marker or selection protein, as defined above.
- the 3' UTR of the at least one mRNA preferably comprises also a poly(A) and/or a poly(C) sequence as defined herewithin.
- the single elements of the 3' UTR may occur therein in any order from 5' to 3' along the sequence of the at least one mRNA.
- further elements as described herein may also be contained, such as a stabilizing sequence as defined herewithin (e.g. derived from the UTR of a globin gene), IRES sequences, etc.
- a stabilizing sequence as defined herewithin (e.g. derived from the UTR of a globin gene), IRES sequences, etc.
- Each of the elements may also be repeated in the at least one mRNA according to the invention at least once (particularly in di- or multicistronic constructs), preferably twice or more.
- the single elements may be present in the at least one mRNA in the following order:
- a further peptide or protein is encoded by the at least one mRNA - the encoded peptide or protein is preferably no histone protein, no reporter protein (e.g. Luciferase, GFP, EGFP, ⁇ - Galactosidase, particularly EGFP) and/or no marker or selection protein (e.g. alpha-Globin, Galactokinase and Xanthine:Guanine phosphoribosyl transferase (GPT)).
- reporter protein e.g. Luciferase, GFP, EGFP, ⁇ - Galactosidase, particularly EGFP
- marker or selection protein e.g. alpha-Globin, Galactokinase and Xanthine:Guanine phosphoribosyl transferase (GPT)
- the mRNA according to the invention does not comprise a reporter gene or a marker gene.
- the mRNA according to the invention does not encode, for instance, luciferase; green fluorescent protein (GFP) and its variants (such as eGFP, RFP or BFP); a-globin; hypoxanthine-guanine phosphoribosyltransferase (HGPRT); ⁇ - galactosidase; galactokinase; alkaline phosphatase; secreted embryonic alkaline phosphatase (SEAP)) or a resistance gene (such as a resistance gene against neomycin, puromycin, hygromycin and zeocin).
- the mRNA according to the invention does not encode luciferase.
- the mRNA according to the invention does not encode GFP or a variant thereof.
- the mRNA according to the invention does not encode a protein (or a fragment of a protein) derived from a virus, preferably from a virus belonging to the family of Orthomyxoviridae.
- the mRNA does not encode a protein that is derived from an influenza virus, more preferably an influenza A virus.
- the mRNA according to the invention does not encode an influenza A protein selected from the group consisting of hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml , M2, NS1 , NS2 (NEP: nuclear export protein), PA, PB1 (polymerase basic 1 ), PB1 -F2 and PB2.
- the mRNA according to the invention does not encode ovalbumin (OVA) or a fragment thereof.
- the mRNA according to the invention does not encode an influenza A protein or ovalbumin.
- the at least one mRNA according to the invention comprises at least one histone stem-loop sequence, preferably according to at least one of the following formulae (I) or (II): formula (I) (stem-loop sequence without stem bordering elements):
- stemi stemi loop stem2 stem2 bordering element bordering element wherein: stemi or stem2 bordering elements is a consecutive sequence of 1 to 6, preferably of
- N0-2GN is reverse complementary or partially reverse complementary with element stem2, and is a consecutive sequence between of 5 to 7 nucleotides; wherein N 0 - 2 is a consecutive sequence of 0 to 2, preferably of 0 to 1 , more preferably of 1 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C or a nucleotide analogue thereof; wherein N3-5 is a consecutive sequence of 3 to 5, preferably of 4 to 5, more preferably of 4 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C or a nucleotide analogue thereof, and wherein G is gu
- stem2 [N3-5CN0-2] is reverse complementary or partially reverse complementary with element steml , and is a consecutive sequence between of 5 to 7 nucleotides; wherein N3-5 is a consecutive sequence of 3 to 5, preferably of 4 to 5, more preferably of 4 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C or a nucleotide analogue thereof; wherein N0-2 is a consecutive sequence of 0 to 2, preferably of 0 to 1 , more preferably of 1 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G or C or a nucleotide analogue thereof; and wherein C is cytidine or an analogue thereof, and may be optionally replaced by a guanosine or an analogue thereof provided that its complementary nucle
- steml and stem2 are capable of base pairing with each other forming a reverse complementary sequence, wherein base pairing may occur between steml and stem2, e.g. by Watson-Crick base pairing of nucleotides A and U/T or G and C or by non-Watson-Crick base pairing e.g. wobble base pairing, reverse Watson-Crick base pairing, Hoogsteen base pairing, reverse Hoogsteen base pairing or are capable of base pairing with each other forming a partially reverse complementary sequence, wherein an incomplete base pairing may occur between stemi and stem2, on the basis that one or more bases in one stem do not have a complementary base in the reverse complementary sequence of the other stem.
- a wobble base pairing is typically a non-Watson-Crick base pairing between two nucleotides.
- the four main wobble base pairs in the present context which may be used, are guanosine-uridine, inosine-uridine, inosine-adenosine, inosine-cytidine (G-U T, l-U/ , l-A and l-C) and adenosine-cytidine (A-C).
- a wobble base is a base, which forms a wobble base pair with a further base as described above. Therefore non-Watson-Crick base pairing, e.g. wobble base pairing, may occur in the stem of the histone stem-loop structure in the at least one mRNA according to the present invention.
- a partially reverse complementary sequence comprises maximally 2, preferably only one mismatch in the stem-structure of the stem-loop sequence formed by base pairing of stemi and stem2.
- stemi and stem2 are preferably capable of (full) base pairing with each other throughout the entire sequence of stemi and stem2 (100% of possible correct Watson-Crick or non-Watson-Crick base pairings), thereby forming a reverse complementary sequence, wherein each base has its correct Watson- Crick or non-Watson-Crick base pendant as a complementary binding partner.
- stemi and stem2 are preferably capable of partial base pairing with each other throughout the entire sequence of stemi and stem2, wherein at least about 70%, 75%, 80%, 85%, 90%, or 95% of the 100% possible correct Watson-Crick or non-Watson- Crick base pairings are occupied with the correct Watson-Crick or non-Watson-Crick base pairings and at most about 30%, 25%, 20%, 1 5%, 10%, or 5% of the remaining bases are unpaired.
- the at least one histone stem-loop sequence (with stem bordering elements) of the at least one mRNA as defined herein comprises a length of about 1 5 to about 45 nucleotides, preferably a length of about 1 5 to about 40 nucleotides, preferably a length of about 1 5 to about 35 nucleotides, preferably a length of about 1 5 to about 30 nucleotides and even more preferably a length of about 20 to about 30 and most preferably a length of about 24 to about 28 nucleotides.
- the at least one histone stem-loop sequence (without stem bordering elements) of the the at least one mRNA as defined herein comprises a length of about 10 to about 30 nucleotides, preferably a length of about 1 0 to about 20 nucleotides, preferably a length of about 12 to about 20 nucleotides, preferably a length of about 14 to about 20 nucleotides and even more preferably a length of about 1 6 to about 1 7 and most preferably a length of about 1 6 nucleotides.
- the at least one mRNA according to the present invention may comprise at least one histone stem-loop sequence according to at least one of the following specific formulae (la) or (lla): formula (la) (stem-loop sequence without stem bordering elements):
- steml loop stem2 formula (lla) (stem-loop sequence with stem bordering elements):
- N2-5 [N0-1GN3.5 ⁇ ], [N,. 3 (UAT)No-2] N2-5
- N, C, G, T and U are as defined above.
- the at least one mRNA may comprise or code for at least one histone stem-loop sequence according to at least one of the following specific formulae (lb) or (Mb): formula (lb) (stem-loop sequence without stem bordering elements):
- N, C, G, T and U are as defined above.
- the at least one mRNA according to the present invention may comprise at least one histone stem-loop sequence according to at least one of the following specific formulae (Ic) to (Ih) or (lie) to (llh), shown alternatively in its stem- loop structure and as a linear sequence representing histone stem-loop sequences:
- N, C, G, A, T and U are as defined above;
- each U may be replaced by T;
- each (highly) conserved G or C in the stem elements 1 and 2 may be replaced by its complementary nucleotide base C or G, provided that its complementary nucleotide in the corresponding stem is replaced by its complementary nucleotide in parallel; and/or G, A, T, U, C, R, Y, M, K, S, W, H, B, V, D, and N are nucleotide bases as defined in the following Table:
- the histone stem-loop sequence according to at least one of the formulae (I) or (la) to (Ih) or (II) or (1 la) to (llh) above is selected from a naturally occurring histone stem loop sequence, more particularly preferred from protozoan or metazoan histone stem-loop sequences, and even more particularly preferred from vertebrate and mostly preferred from mammalian histone stem-loop sequences especially from human histone stem-loop sequences.
- the histone stem-loop sequence according to at least one of the specific formulae (I) or (la) to (Ih) or (II) or (Ma) to (llh) is a histone stem- loop sequence comprising at each nucleotide position the most frequently occurring nucleotide, or either the most frequently or the second-most frequently occurring nucleotide of naturally occurring histone stem-loop sequences in metazoa and protozoa, protozoa, metazoa, vertebrates and humans.
- at least 80%, preferably at least 85%, or most preferably at least 90% of all nucleotides correspond to the most frequently occurring nucleotide of naturally occurring histone stem-loop sequences.
- the histone stem-loop sequence according to at least one of the specific formulae (I) or (la) to (Ih) above is selected from following histone stem-loop sequences (without stem-bordering elements):
- GGCTCTTTTMAGRGCC SEQ ID NO: 48 according to formula (lg)
- H*H*MAMGGYYCTTYTHAGRRCCVHN*N*M* (SEQ ID NO: 61 according to formula (llg)) H * H * A AMG G C YCTT YTM AG RG CC VC H * H *M * (SEQ ID NO: 62 according to formula (llg)) M*M*AAMGGCTCTTTTMAGRGCCMCY*M*M* (SEQ ID NO: 63 according to formula (llg))
- the at least one mRNA of the composition according to the present invention comprises at least one histone stem-loop sequence showing at least about 80%, preferably at least about 85%, more preferably at least about 90%, or even more preferably at least about 95%, sequence identity with the not to 100% conserved nucleotides in the histone stem-loop sequences according to at least one of specific formulae (I) or (la) to (Ih) or (II) or (Ha) to (llh) or with a naturally occurring histone stem-loop sequence.
- a particular preferred histone stem-loop sequence is the sequence according to SEQ ID NO: 70 CAAAGGCTCTTTTCAGAGCCACCA or more preferably the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO: 70:
- CAAAGGCUCUUUUCAGAGCCACCA (SEQ ID NO: 71 ).
- the histone stem loop sequence does not contain the loop sequence 5'-UUUC-3'. More specifically, the histone stem loop does not contain the steml sequence 5'-GGCUCU-3' and/or the stem2 sequence 5'-AGAGCC-3', respectively. In another preferred embodiment, the stem loop sequence does not contain the loop sequence 5'- CCUGCCC-3' or the loop sequence 5'-UGAAU-3'. More specifically, the stem loop does not contain the steml sequence 5'-CCUGAGC-3' or does not contain the steml sequence 5'- ACCUUUCUCCA-3' and/or the stem2 sequence 5'-GCUCAGG-3' or 5'-UGGAGAAAGGU-3', respectively.
- stem loop sequences are preferably not derived from a mammalian insulin receptor 3'-untranslated region.
- the at least one mRNA according to the invention may not contain histone stem loop processing signals, in particular not those derived from mouse histone gene H2A614 gene (H2kA614).
- the at least one mRNA of the composition according to the present invention does not contain one or two or at least one or all but one or all of the components of the group consisting of: a sequence encoding a ribozyme (preferably a self-splicing ribozyme), a viral nucleic acid sequence, a histone stem-loop processing signal, in particular a histone- stem loop processing sequence derived from mouse histone H2A614 gene, a Neo gene, an inactivated promoter sequence and an inactivated enhancer sequence.
- a encoding a ribozyme preferably a self-splicing ribozyme
- a viral nucleic acid sequence a histone stem-loop processing signal, in particular a histone- stem loop processing sequence derived from mouse histone H2A614 gene, a Neo gene, an inactivated promoter sequence and an inactivated enhancer sequence.
- a histone stem-loop processing signal in particular a histone- stem loop processing sequence derived from
- the at least one mRNA according to the invention does not contain a ribozyme, preferably a self-splicing ribozyme, and one of the group consisting of: a Neo gene, an inactivated promoter sequence, an inactivated enhancer sequence, a histone stem-loop processing signal, in particular a histone-stem loop processing sequence derived from mouse histone H2A614 gene.
- the mRNA may in a preferred mode neither contain a ribozyme, preferably a self-splicing ribozyme, nor a Neo gene or, alternatively, neither a ribozyme, preferably a self-splicing ribozyme, nor any resistance gene (e.g.
- the at least one mRNA of the invention may neither contain a ribozyme, preferably a self-splicing ribozyme nor a histone stem-loop processing signal, in particular a histone-stem loop processing sequence derived from mouse histone H2A614 gene
- the at least one mRNA of the composition according to the invention optionally comprises a polyadenylation signal which is defined herein as a signal which conveys polyadenylation to a (transcribed) mRNA by specific protein factors (e.g. cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF), cleavage factors I and II (CF I and CF II), poly(A) polymerase (PAP)).
- CPSF cleavage and polyadenylation specificity factor
- CstF cleavage stimulation factor
- CF I and CF II cleavage factors I and II
- PAP poly(A) polymerase
- a consensus polyadenylation signal is preferred comprising the NN(U/T)ANA consensus sequence.
- the polyadenylation signal comprises one of the following sequences: AA(U/T)AAA or A(U/T)(U/T)AAA (wherein uridine is usually present in RNA and thymidine is usually present in DNA).
- the polyadenylation signal used in the at least one mRNA according to the invention does not correspond to the U3 snRNA, U5, the polyadenylation processing signal from human gene G-CSF, or the SV40 polyadenylation signal sequences.
- the above polyadenylation signals are not combined with any antibiotics resistance gene (or any other reporter, marker or selection gene), in particular not with the resistance neo gene (neomycin phosphotransferase).
- any of the above polyadenylation signals are preferably not combined with the histone stem loop or the histone stem loop processing signal from mouse histone gene H2A614 in the at least one mRNA according to the invention.
- the at least one mRNA of the composition of the present invention may be modified, and thus stabilized by modifying the G/C content of the mRNA, preferably of the coding region of the at least one mRNA.
- the G/C content of the coding region of the at least one mRNA of the composition of the present invention is modified, particularly increased, compared to the G/C content of the coding region of its particular wild-type mRNA, i.e. the unmodified mRNA.
- the amino acid sequence encoded by the at least one mRNA is preferably not modified as compared to the amino acid sequence encoded by the particular wild-type mRNA.
- This modification of the at least one mRNA of the composition of the present invention is based on the fact that the sequence of any mRNA region to be translated is important for efficient translation of that mRNA.
- the composition and the sequence of various nucleotides are important.
- sequences having an increased G (guanosine)/C (cytosine) content are more stable than sequences having an increased A (adenosine)/U (uracil) content.
- the codons of the mRNA are therefore varied compared to the respective wild-type mRNA, while retaining the translated amino acid sequence, such that they include an increased amount of G/C nucleotides.
- the most favorable codons for the stability can be determined (so-called alternative codon usage).
- codons which contain exclusively G or C nucleotides no modification of the codon is necessary.
- the codons for Pro (CCC or CCG), Arg (CGC or CGG), Ala (GCC or GCG) and Gly (GGC or GGG) require no modification, since no A or U is present.
- codons which contain A and/or U nucleotides can be modified by substitution of other codons which code for the same amino acids but contain no A and/or U.
- the codons for Pro can be modified from CCU or CCA to CCC or CCG; the codons for Arg can be modified from CGU or CGA or AGA or AGG to CGC or CGG; the codons for Ala can be modified from GCU or GCA to GCC or GCG; the codons for Gly can be modified from GGU or GGA to GGC or GGG.
- the codons for Pro can be modified from CCU or CCA to CCC or CCG; the codons for Arg can be modified from CGU or CGA or AGA or AGG to CGC or CGG; the codons for Ala can be modified from GCU or GCA to GCC or GCG; the codons for Gly can be modified from GGU or GGA to GGC or GGG.
- the codons for Phe can be modified from UUU to UUC; the codons for Leu can be modified from UUA, UUG, CUU or CUA to CUC or CUG; the codons for Ser can be modified from UCU or UCA or AGU to UCC, UCG or AGC; the codon for Tyr can be modified from UAU to UAC; the codon for Cys can be modified from UGU to UGC; the codon for His can be modified from CAU to CAC; the codon for Gin can be modified from CAA to CAG; the codons for lie can be modified from AUU or AUA to AUC; the codons for Thr can be modified from ACU or ACA to ACC or ACG; the codon for Asn can be modified from AAU to AAC; the codon for Lys can be modified from AAA to AAG; the codons for Val can be modified from GUU or GUA to GUC or GUG; the codon for Asp can be modified from GAU to GAC;
- the G/C content of the coding region of the at least one mRNA of the composition of the present invention is increased by at least 7%, more preferably by at least 1 5%, particularly preferably by at least 20%, compared to the G/C content of the coded region of the wild- type mRNA which codes for an antigen, antigenic protein or antigenic peptide as deinined herein or its fragment or variant thereof.
- At least 5%, 10%, 20%, 30%, 40%, 50%, 60%, more preferably at least 70 %, even more preferably at least 80% and most preferably at least 90%, 95% or even 100% of the substitutable codons in the region coding for an antigen, antigenic protein or antigenic peptide as defined herein or its fragment or variant thereof or the whole sequence of the wild type mRNA sequence are substituted, thereby increasing the GC/content of said sequence.
- a further preferred modification of the at least one mRNA of the composition of the present invention is based on the finding that the translation efficiency is also determined by a different frequency in the occurrence of tRNAs in cells.
- the corresponding modified at least one mRNA sequence is translated to a significantly poorer degree than in the case where codons coding for relatively "frequent" tRNAs are present.
- the region which codes for the antigen is modified compared to the corresponding region of the wild-type mRNA such that at least one codon of the wild type sequence which codes for a tRNA which is relatively rare in the cell is exchanged for a codon which codes for a tRNA which is relatively frequent in the cell and carries the same amino acid as the relatively rare tRNA.
- the sequences of the at least one mRNA of the composition of the present invention is modified such that codons for which frequently occurring tRNAs are available are inserted.
- the Gly codon which uses the tRNA which occurs the most frequently in the (human) cell, are particularly preferred.
- This preferred embodiment allows provision of a particularly efficiently translated and stabilized (modified) at least one mRNA of the composition of the present invention.
- a modified at least one mRNA of the composition of the present invention as described above can be carried out using the computer program explained in WO 02/098443 - the disclosure content of which is included in its full scope in the present invention.
- the nucleotide sequence of any desired mRNA can be modified with the aid of the genetic code or the degenerative nature thereof such that a maximum G/C content results, in combination with the use of codons which code for tRNAs occurring as frequently as possible in the cell, the amino acid sequence coded by the modified at least one mRNA preferably not being modified compared to the non-modified sequence.
- the A/U content in the environment of the ribosome binding site of the at least one (m)RNA of the composition of the present invention is increased compared to the A/U content in the environment of the ribosome binding site of its particular wild-type mRNA.
- This modification increases the efficiency of ribosome binding to the at least one mRNA.
- the at least one mRNA of the composition of the present invention may be modified with respect to potentially destabilizing sequence elements.
- the coding region and/or the 5 ' and/or 3' untranslated region of this at least one mRNA may be modified compared to the particular wild type mRNA such that it contains no destabilizing sequence elements, the coded amino acid sequence of the modified at least one mRNA preferably not being modified compared to its particular wild type mRNA.
- DSE destabilizing sequence elements
- Such destabilizing sequences are e.g. AU-rich sequences (AURES), which occur in 3'-UTR sections of numerous unstable RNAs (Caput et al., Proc. Natl. Acad. Sci. USA 1986, 83: 1 670 to 1 674).
- the at least one mRNA of the composition of the present invention is therefore preferably modified compared to the wild type mRNA such that the at least one mRNA contains no such destabilizing sequences.
- sequence motifs which are recognized by possible endonucleases, e.g. the sequence GAACAAG, which is contained in the 3'-UTR segment of the gene which codes for the transferrin receptor (Binder et al., EMBO J.
- the at least one mRNA of the composition of the present invention has, in a modified form, at least one IRES as defined above and/or at least one 5' and/or 3' stabilizing sequence, in a modified form, e.g. to enhance ribosome binding or to allow expression of different encoded antigens located on an at least one (bi- or even multicistronic) mRNA of the composition of the present invention.
- the at least one mRNA of the composition of the present invention furthermore preferably has at least one 5 ' and/or 3' stabi lizing sequence.
- stabilizing sequences in the 5' and/or 3' untranslated regions have the effect of increasing the half-life of the at least one mRNA in the cytosol.
- These stabilizing sequences can have 1 00% sequence homology to naturally occurring sequences which occur in viruses, bacteria and eukaryotes, but can also be partly or completely synthetic.
- the untranslated sequences (UTR) of the ⁇ -globin gene e.g. from Homo sapiens or Xenopus laevis may be mentioned as an example of stabi lizing sequences which can be used in the present invention for a stabilized mRNA.
- a stabilizing sequence has the general formula (C/U)CCANxCCC(U/A)PyxUC(C U)CC (SEQ ID NO: 68), which is contained in the 3'UTR of the very stable mRNA which codes for a-globin, a(l)-collagen, 1 5-lipoxygenase or for tyrosine hydroxylase (cf. Holcik et al., Proc. Natl. Acad. Sci. USA 1 997, 94: 241 0 to 2414).
- Such stabi lizing sequences can of course be used individual ly or in combination with one another and also in combination with other stabilizing sequences known to a person skilled in the art.
- the at least one mRNA of the composition of the present invention is therefore preferably present as globin UTR (untranslated regions)-stabil ized mRNA, in particular as a-globin UTR-stabilized mRNA.
- the at least one mRNA of the composition comprises a stabi lizing sequence in the 3'-UTR derived from the center, a- complex-binding portion of the 3'UTR of an ⁇ -globin gene, such as of a human a-globin gene, preferably according to SEQ ID NO: 69:
- ⁇ -globin gene also named herein as "muag"
- GCCCCAUGGGCCUCCCAACGGGCCCUCCUCCCCUCCUUGCACCG (SEQ ID NO: 69)
- substitutions, additions or eliminations of bases are preferably carried out with the at least one mRNA of the composition of the present invention, using a DNA matrix for preparation of the at least one mRNA of the composition of the present invention by techniques of the well known site directed mutagenesis or with an oligonucleotide ligation strategy (see e.g. Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 3rd ed., Cold Spring Harbor, NY, 2001 ).
- a corresponding DNA molecule may be transcribed in vitro.
- This DNA matrix preferably comprises a suitable promoter, e.g.
- a T7 or SP6 promoter for in vitro transcription, which is followed by the desired nucleotide sequence for the at least one mRNA to be prepared and a termination signal for in vitro transcription.
- the DNA molecule which forms the matrix of an at least one mRNA of interest, may be prepared by fermentative proliferation and subsequent isolation as part of a plasmid which can be replicated in bacteria. Plasmids which may be mentioned as suitable for the present invention are e.g. the plasmids pT7Ts (GenBank accession number U26404; Lai et al., Development 1995, 121 : 2349 to 2360), pGEM® series, e.g.
- pGEM®-1 GenBank accession number X65300; from Promega
- pSP64 GeneBank accession number X65327
- Mezei and Storts Purification of PCR Products, in: Griffin and Griffin (ed.), PCR Technology: Current Innovation, CRC Press, Boca Raton, FL, 2001 .
- the stabilization of the at least one mRNA of the composition of the present invention can likewise by carried out by associating or complexing the at least one mRNA with, or binding it to, a cationic compound, in particular a polycationic compound, for example a (poly)cationic peptide or protein.
- a cationic compound in particular a polycationic compound, for example a (poly)cationic peptide or protein.
- a cationic compound for example a (poly)cationic peptide or protein.
- a cationic compound in particular a polycationic compound, for example a (poly)cationic peptide or protein.
- protamine, nucleoline, spermin or spermidine as the polycationic, nucleic-acid-binding protein to the mRNA is particularly effective.
- other cationic peptides or proteins such as poly-L-lysine or histones, is likewise possible.
- cationic substances which can be used for stabilizing the mRNA of the composition of the present invention include cationic polysaccharides, for example chitosan, polybrene, polyethyleneimine (PEI) or poly-L-lysine (PLL), etc..
- cationic polysaccharides for example chitosan, polybrene, polyethyleneimine (PEI) or poly-L-lysine (PLL), etc.
- Association or complexing of the at least one mRNA of the inventive composition with cationic compounds e.g. cationic proteins or cationic lipids, e.g.
- oligofectamine as a lipid based complexation reagent preferably increases the transfer of the at least one mRNA present as a pharmaceutically active component into the cells to be treated or into the organism to be treated. It is also referred to the disclosure herein with regard to the stabilizing effect for the at least one mRNA of the composition of the present invention by complexation, which holds for the stabilization of RNA as well.
- the at least one mRNA of the composition may additionally or alternatively encode a secretory signal peptide.
- signal peptides are sequences, which typically exhibit a length of about 1 5 to 30 amino acids and are preferably located at the N-terminus of the encoded peptide, without being limited thereto.
- Signal peptides as defined herein preferably allow the transport of the antigen, antigenic protein or antigenic peptide as encoded by the at least one mRNA of the composition into a defined cellular association, preferably the cell surface, the endoplasmic reticulum (ER) or the endosomal-lysosomal association.
- secretory signal peptide sequences as defined herein include, without being limited thereto, signal sequences of classical or non-classical MHC-molecules (e.g. signal sequences of MHC I and II molecules, e.g. of the MHC class I molecule HLA-A*0201 ), signal sequences of cytokines or immunoglobulines as defined herein, signal sequences of the invariant chain of immunoglobulines or antibodies as defined herein, signal sequences of Lampl , Tapasin, Erp57, Calretikulin, Calnexin, and further membrane associated proteins or of proteins associated with the endoplasmic reticulum (ER) or the endosomal-lysosomal juxtapos.
- signal sequences of MHC class I molecule HLA-A*0201 may be used according to the present invention.
- any of the above modifications may be applied to the at least one mRNA of the composition of the present invention, and further to any (m)RNA as used in the context of the present invention and may be, if suitable or necessary, be combined with each other in any combination, provided, these combinations of modifications do not interfere with each other in the respective RNA.
- a person skilled in the art will be able to take his choice accordingly.
- the composition comprises at least one mRNA that has been modified as described herewithin, which comprises at least one coding sequence selected from RNA sequences being identical or at least 80% identical to the RNA sequence of SEQ ID NOs: 3, 6, 9, 12, 1 5, 1 8, 82, 83, 84, or 85. Even more preferably, the composition comprises six mRNAs, wherein the coding sequence in each mRNA is identical or at least 80% identical to one of the RNA sequences according to SEQ ID NOs: 3, 6, 9, 12, 15,18, 82, 83, 84, or 85.
- each of the six antigens of the composition of the present invention may be encoded by one (monocistronic) mRNA.
- the composition of the present invention may contain six (monocistronic) mRNAs, wherein each of these six (monocistronic) mRNAs, may encode just one antigen as defined above.
- the composition comprises six mRNAs, each of which has been modified as described herewithin, wherein one mRNA encodes PSA, one mRNA encodes PSMA, one mRNA encodes PSCA, one mRNA encodes STEAP, one mRNA encodes PAP and one mRNA encodes MUC1 or fragments or variants thereof, respectively.
- the composition comprises six mRNAs, wherein one mRNA encodes PSA and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 3 or 82, one mRNA encodes PSMA and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 6 or 83, one mRNA encodes PSCA and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 9 or 84, one mRNA encodes STEAP and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 12 or 85, one mRNA encodes PAP and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 15 and one mRNA encodes MUC1 and comprises a coding sequence identical or at least 80% identical to SEQ ID NO: 18 (or fragments or variants of each of these sequences) and optionally further excipients.
- the composition comprises at least one mRNA, which is identical or at least 80% identical to the RNA sequence of SEQ ID NOs: 1 , 4, 7, 10, 13 or 1 6. Even more preferably, the composition comprises six mRNAs, wherein each mRNA is identical or at least 80% identical to one of the RNA sequences according to SEQ ID NOs: 1 , 4, 7, 1 0, 1 3 or 1 6.
- the composition comprises six mRNAs, wherein one mRNA encodes PSA and is identical or at least 80% identical to SEQ ID NO: 1 , one mRNA encodes PSMA and is identical or at least 80% identical to SEQ ID NO: 4, one mRNA encodes PSCA and is identical or at least 80% identical to SEQ ID NO: 7, one mRNA encodes STEAP and is identical or at least 80% identical to SEQ ID NO: 10, one mRNA encodes PAP and is identical or at least 80% identical to SEQ ID NO: 1 3 and one mRNA encodes MUC1 and is identical or at least 80% identical to SEQ ID NO: 1 6 (or fragments or variants of each of these sequences) and optionally further excipients.
- the at least one mRNA of the compositions described above comprises a histone stem-loop in the 3' UTR region.
- the composition comprises six mRNAs, wherein each of the mRNAs comprises a histone stem-loop as defined herewithin.
- the composition comprises six mRNAs, wherein one mRNA encodes PSA and is identical or at least 80% identical to SEQ ID NO: 1 9, one mRNA encodes PSMA and is identical or at least 80% identical to SEQ ID NO: 20, one mRNA encodes PSCA and is identical or at least 80% identical to SEQ ID NO: 21 , one mRNA encodes STEAP and is identical or at least 80% identical to SEQ ID NO: 22, one mRNA encodes PAP and is identical or at least 80% identical to SEQ ID NO: 23 and one mRNA encodes MUC1 and is identical or at least 80% identical to SEQ ID NO: 24 (or fragments or variants of each of these sequences) and optional ly further excipients.
- the composition according to the invention may comprise an adjuvant in order to enhance the immunostimulatory properties of the composition.
- an adjuvant may be understood as any compound, which is suitable to support administration and delivery of the composition according to the invention.
- an adjuvant may, without being bound thereto, initiate or increase an immune response of the innate immune system, i.e. a non-specific immune response.
- the composition according to the invention typically initiates an adaptive immune response due to the at least six antigens encoded by the at least one mRNA contained in the inventive composition.
- the composition accordi ng to the invention may generate an (supportive) innate immune response due to addition of an adjuvant as defined herein to the composition according to the invention.
- Such an adjuvant may be selected from any adjuvant known to a ski lled person and suitable for the present case, i.e. supporting the induction of an immune response in a mammal.
- the adjuvant may be selected from the group consisting of, without being limited thereto, TDM, MDP, muramyl dipeptide, pluronics, alum solution, aluminium hydroxide, ADJ UMERTM (polyphosphazene); aluminium phosphate gel; glucans from algae; algammulin; aluminium hydroxide gel (alum); highly protei n-adsorbing aluminium hydroxide gel; low viscosity aluminium hydroxide gel; AF or SPT (emulsion of squalane (5%), Tween 80 (0.2%), Pluronic L1 21 (1 .25%), phosphate-buffered saline, pH 7.4); AVRIDINETM (propanediamine); BAY R1 005TM ((N-(2-deoxy)
- DMPC dehydroepiandrosterone
- DMPG dimethyldioctadecylammonium chloride
- ZnPro-8 zinc-L-proline salt complex
- GMDP N-acetylglucosaminyl-(b1 -4)-N-acetylmuramyl-L-aIanyl-D- isoglutamine
- imiquimod (1 -
- TM liposomes
- LOXORIBINETM (7-allyl-8-oxoguanosine); LT oral adjuvant (E.coli labile enterotoxin-protoxin); microspheres and microparticles of any composition; MF59TM; (squalene-water emulsion); MONTANIDE ISA 51 TM (purified incomplete Freund's adjuvant); MONTANIDE ISA 720TM (metabolisable oil adjuvant); MPLTM (3-Q-desacyl-4'-monophosphoryl lipid A); MTP-PE and MTP-PE liposomes ((N- acetyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1 ,2-dipalmitoyl-sn-glycero-3- (hydroxyphosphoryloxy))-ethylamide, monosodium salt); MURAMETIDETM (Nac-Mur-L- Ala-D-Gln-OC
- Suitable adjuvants may also be selected from cationic or polycationic compounds wherein the adjuvant is preferably prepared upon complexing the at least one mRNA of the inventive composition with the cationic or polycationic compound. Association or complexing the at least one mRNA of the composition with cationic or polycationic compounds as defined herein preferably provides adjuvant properties and confers a stabilizing effect to the at least one mRNA of the composition.
- Particularly preferredcationic or polycationic compounds are selected from cationic or polycationic peptides or proteins, including protamine, nucleoline, spermin or spermidine, or other cationic peptides or proteins, such as poly-L-lysine (PLL), poly-arginine, basic polypeptides, cell penetrating peptides (CPPs), including HIV-binding peptides, Tat, HIV-1 Tat (HIV), Tat- derived peptides, Penetratin, VP22 derived or analog peptides, HSV VP22 (Herpes simplex), MAP, KALA or protein transduction domains (PTDs, PpT620, prol in-rich peptides, argi nine- rich peptides, lysine-rich peptides, MPG-peptide(s), Pep-1 , L-oligomers, Calcitonin peptide(s), Antennapedia-derived peptides (particularly from Drosophil
- cationic or polycationic compounds may include cationic polysaccharides, for example chitosan, polybrene, cationic polymers, e.g. polyethyleneimine (PEI), cationic lipids, e.g.
- cationic polysaccharides for example chitosan, polybrene, cationic polymers, e.g. polyethyleneimine (PEI), cationic lipids, e.g.
- PEI polyethyleneimine
- DOTMA 1 -(2,3-sioleyloxy)propyl) - ⁇ , ⁇ , ⁇ -trimethylammonium chloride
- DMRIE di-CI 4- amidine
- DOTIM 1,3-sioleyloxy)propyl) - ⁇ , ⁇ , ⁇ -trimethylammonium chloride
- DOPE Dioleyl phosphatidylethanol-amine
- DOSPA DODAB
- DOIC DOIC
- DMEPC DOGS: Dioctadecylamidoglicylspermin
- DIMRI Dimyristo-oxypropyl dimethyl hydroxyethyl ammonium bromide
- DOTAP dioleoyloxy-3-(trimethylammonio)propane
- DC-6-14 O,O- ditetradecanoyl-N-( -trimethylammonioacetyl)diethanolamine chloride
- CLIP1 rac- (2,3- dioctadecyloxypropyl)(2-hydroxyethy
- modified polyaminoacids such as -aminoacid- polymers or reversed polyamides, etc.
- modified polyethylenes such as PVP (poly(N-ethyl- 4-vinylpyridinium bromide)), etc.
- modified acrylates such as pDMAEMA (poly(dimethylaminoethyl methylacrylate)), etc.
- modified Amidoamines such as pAMAM (poly(amidoamine)), etc., modified polybetaaminoester (PBAE), such as diamine end modified 1 ,4 butanediol diacrylate-co-5-amino-1 -pentanol polymers, etc.
- dendrimers such as polypropylamine dendrimers or pAMAM based dendrimers, etc.
- polyimine(s) such as PEI: poly(ethyleneimine), poly(propyleneimine), etc.
- polyallylamine sugar backbone based polymers
- oligoarginines in this context are e.g. Arg7, Arg8, Arg9, Arg7, H3R9, R9H3, H3R9H3, YSSR9SSY, (RKH)4, Y(RKH)2R, etc.
- the ratio of the RNA to the cationic or polycationic compound in the adjuvant component may be calculated on the basis of the nitrogen/phosphate ratio (N/P-ratio) of the entire RNA complex, i.e. the ratio of positively charged (nitrogen) atoms of the cationic or polycationic compound to the negatively charged phosphate atoms of the nucleic acids.
- N/P-ratio nitrogen/phosphate ratio
- 1 pg RNA typically contains about 3 nmol phosphate residues, provided the RNA exhibits a statistical distribution of bases.
- 1 pg peptide typically contains about x nmol nitrogen residues, dependent on the molecular weight and the number of basic amino acids.
- protamine molecular weight about 4250 g/mol, 21 nitrogen atoms, when protamine from salmon is used
- N/P ratio of about 0.81 can be calculated.
- mass ratio of about 8:1 RNA/protamine an N/P ratio of about 0.2 can be calculated.
- an N/P-ratio is preferably in the range of about 0.1 -10, preferably in a range of about 0.3-4 and most preferably in a range of about 0.5-2 or 0.7-2 regarding the ratio of RNA:peptide in the complex, and most preferably in the range of about 0.7-1 .5.
- the composition is obtained in two separate steps in order to obtain both, an efficient immunostimulatory effect and efficient translation of the at least one mRNA according to the invention.
- a so called "adjuvant component" is prepared by complexing - in a first step - the at least one mRNA of the adjuvant component with a cationic or polycationic compound in a specific ratio to form a stable complex.
- a cationic or polycationic compound it is important, that no free cationic or polycationic compound or only a neglibly small amount remains in the adjuvant component after complexing the mRNA.
- the ratio of the mRNA and the cationic or polycationic compound in the adjuvant component is typically selected in a range that the mRNA is entirely complexed and no free cationic or polycationic compound or only a neclectably small amount remains in the composition.
- the ratio of the adjuvant component i.e.
- the ratio of the mRNA to the cationic or polycationic compound is selected from a range of about 6:1 (w/w) to about 0,25:1 (w/w), more preferably from about 5:1 (w/w) to about 0,5:1 (w/w), even more preferably of about 4:1 (w/w) to about 1 :1 (w/w) or of about 3:1 (w/w) to about 1 :1 (w/w), and most preferably a ratio of about 3:1 (w/w) to about 2:1 (w/w).
- the at least one mRNA encoding the antigens according to the invention is added in a second step to the complexed mRNA of the adjuvant component in order to form the (immunostimulatory) composition of the invention.
- the at least one mRNA of the invention is added as free mRNA, i.e. mRNA, which is not complexed by other compounds.
- the at least one free mRNA is not complexed and will preferably not undergo any detectable or significant complexation reaction upon the addition of the adjuvant component. This is due to the strong binding of the cationic or polycationic compound to the above described at least one mRNA in the adjuvant component.
- the at least one free mRNA, encoding at least one of the antigens according to the invention is added to the "adjuvant component", preferably no free or substantially no free cationic or polycationic compound is present, which may form a complex with the at least one free mRNA. Accordingly, an efficient translation of the at least one free mRNA of the inventive composition is possible in vivo.
- the at least one free mRNA may occur as a mono-, di-, or multicistronic mRNA, i.e. an mRNA which carries the coding sequences of one or more proteins.
- Such coding sequences in di-, or even multicistronic mRNA may be separated by at least one IRES sequence, e.g. as defined herein.
- the at least one free mRNA, which is comprised in the inventive composition may be identical or different to the at least one mRNA of the adjuvant component of the inventive composition, depending on the specific requirements of therapy. Even more preferably, the at least one free mRNA, which is comprised in the inventive composition, is identical to the at least one mRNA of the adjuvant component of the inventive immunostimulatory composition.
- the composition comprises at least one mRNA, wherein at least one mRNA is encoding the antigens as defined above and wherein said mRNA is present in the composition partially as free mRNA and partially as complexed mRNA.
- the at least one mRNA encoding one or more antigens as defined above is complexed as described above and the same at least one mRNA is then added as free mRNA, wherein preferably the compound, which is used for complexing the mRNA is not present in free form in the composition at the moment of addition of the free mRNA component.
- the ratio of the first component (i.e. the adjuvant component comprising or consisting of the at least one mRNA complexed with a cationic or polycationic compound) and the second component (i.e. the at least one free mRNA) may be selected in the inventive composition according to the specific requirements of a particular therapy.
- the ratio of the adjuvant component and the at least one free mRNA (adjuvant component : free RNA) of the inventive composition is selected such that a significant stimulation of the innate immune system is elicited due to the adjuvant component.
- the ratio is selected such that a significant amount of the at least one free mRNA can be provided in vivo leading to an efficient translation and concentration of the expressed protein in vivo, e.g. the antigens as defined above.
- the ratio of the mRNA in the adjuvant component : free mRNA in the inventive composition is selected from a range of about 5:1 (w/w) to about 1 :10 (w/w), more preferably from a range of about 4:1 (w/w) to about 1 :8 (w/w), even more preferably from a range of about 3:1 (w/w) to about 1 :5 (w/w) or 1 :3 (w/w), and most preferably the ratio of the RNA in the adjuvant component : free mRNA in the inventive composition is selected from a ratio of about 1 :1 (w/w).
- the ratio of the first component (i.e. the adjuvant component comprising or consisting of the at least one mRNA complexed with a cationic or polycationic compound) and the second component (i.e. the at least one free mRNA) may be calculated on the basis of the nitrogen/phosphate ratio (N/P-ratio) of the entire mRNA complex.
- N/P-ratio is preferably in the range of about 0.1 -10, preferably in a range of about 0.3-4 and most preferably in a range of about 0.5-2 or 0.7-2 regarding the ratio of RNA:peptide in the complex, and most preferably in the range of about 0.7-1 .5.
- the ratio of the first component i.e. the adjuvant component comprising or consisting of the at least one mRNA complexed with a cationic or polycationic compound
- the second component i.e. the at least one free mRNA
- the ratio of the first component and the second component may also be selected in the inventive composition on the basis of the molar ratio of both mRNAs to each other, i.e. the mRNA of the adjuvant component, being complexed with a cationic or polycationic compound and the at least one free mRNA of the second component.
- the molar ratio of the mRNA of the adjuvant component to the at least one free mRNA of the second component may be selected such, that the molar ratio suffices the above (w/w) and/or N/P-definitions. More preferably, the molar ratio of the mRNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g.
- the molar ratio of the mRNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g. from a range of about 0.01 :1 to 1 :0.01. Most preferably, the molar ratio of the at least one mRNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g. from a molar ratio of about 1:1. Any of the above definitions with regard to (w/w) and/or N/P ratio may also apply.
- the present invention may provide a vaccine which is based on at least one mRNA, preferably at least six distinct mRNA species, encoding at least the above defined antigens PSMA, PSA, PSCA, STEAP, PAP and MUC-1 .
- the inventive vaccine is based on the same components as the composition as defined above. Insofar, it may be referred to the above disclosure defining the inventive composition.
- the inventive vaccine may, however, be provided in physically separate form and may be administered by separate administration steps.
- the inventive vaccine may correspond to the inventive composition, if the mRNA components are provided by one single composition. However, the inventive vaccine may e.g. be provided physically separated.
- the mRNA species may be provided such that two separate compositions, which may contain at least one mRNA species each (e.g. three distinct mRNA species) encoding three distinct antigens, are provided, which may or may not be combined.
- the inventive vaccine may be a combination of three distinct compositions, each composition comprising at least one mRNA encoding two of the above six antigens.
- the vaccine may be provided as a combination of at least one mRNA, preferably six mRNAs, each encoding one of the above defined six antigens.
- the vaccine may be combined to provide one single composition prior to its use or it may be used such that more than one administration is required to administer the distinct mRNA species coding for the above defined six distinct antigens.
- the vaccine contains at least one mRNA molecule, typically at least two, three, four, five or six mRNA molecules, encoding the above defined six antigens, it may e.g. be administered by one single administration (combining all mRNA species), by two separate administrations (e.g. each administration administering mRNA molecules encoding for three of the above six antigens), by three, four, five or six administrations (in case all of the mRNA species encode one of the above defined six antigens and are provided physically separate).
- any combination of mono-, bi- or multicistronic mRNAs encoding the above defined six antigens (and optionally further antigens), provided as separate entities (contai ning one mRNA species) or as combined entity (containing more than one mRNA species), is understood as a vaccine according to the present invention.
- each of the antigens according to the invention is provided as an individual (monocistronic) mRNA, which is administered separately.
- the entities of the vacci ne may be provided in liquid and or in dry (e.g. lyophylized) form. They may contain further components, in particular further components al lowing for its pharmaceutical use.
- the inventive vaccine or the inventive composition may, e.g., additionally contain a pharmaceutically acceptable carrier and/or further auxi liary substances and additives and/or adjuvants.
- the inventive vaccine or composition typical ly comprises a safe and effective amount of the at least one mRNA of the composition as defined above encoding the antigens as defined above.
- safe and effective amount means an amount of the at least one mRNA of the composition or the vaccine as defi ned above, that is sufficient to significantly induce a positive modification of prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers and diseases or disorders related thereto.
- PCa prostate cancer
- adenocarcinoma locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers and diseases or disorders related thereto.
- the expression "safe and effective amount” preferably means an amount of the mRNA (and thus of the encoded antigens) that is suitable for stimulating the adaptive immune system in such a manner that no excessive or damaging immune reactions are achieved but, preferably, also no such immune reactions below a measurable level.
- a "safe and effective amount" of the at least one mRNA of the composition or vaccine as defined above may furthermore be selected in dependence of the type of mRNA, e.g.
- a "safe and effective amount" of the at least one mRNA of the composition or the vaccine as defined above will furthermore vary in connection with the particular condition to be treated and also with the age and physical condition of the patient to be treated, the severity of the condition, the duration of the treatment, the nature of the accompanying therapy, of the particular pharmaceutically acceptable carrier used, and similar factors, within the knowledge and experience of the accompanying doctor.
- the vaccine or composition according to the invention can be used according to the invention for human and also for veterinary medical purposes, as a pharmaceutical composition or as a vaccine.
- the at least one mRNA of the composition, vaccine or kit of parts according to the invention is provided in lyophi lized form.
- the at least one lyophilized mRNA is reconstituted in a suitable buffer, advantageously based on an aqueous carrier, prior to administration, e.g. Ringer-Lactate solution, which is preferred, Ringer solution, a phosphate buffer solution.
- the composition, the vaccine or the kit of parts according to the invention contains six mRNAs, which are provided separately in lyophi lized form (optional ly together with at least one further additive) and which are preferably reconstituted separately in a suitable buffer (such as Ringer-Lactate solution) prior to its use so as to allow individual administration of each of the six (monocistronic) mRNAs.
- a suitable buffer such as Ringer-Lactate solution
- the vaccine or composition according to the invention may typically contain a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier as used herein preferably includes the liquid or non-liquid basis of the inventive composition or vaccine. If the inventive composition or vaccine is provided in liquid form, the carrier will be water, typically pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g phosphate, citrate etc. buffered solutions.
- water or preferably a buffer preferably an aqueous buffer
- a sodium salt preferably at least 50 mM of a sodium salt
- a calcium salt preferably at least 0,01 mM of a calcium salt
- optionally a potassium salt preferably at least 3 mM of a potassium salt.
- the sodium, calcium and, optionally, potassium salts may occur in the form of their halogenides, e.g. chlorides, iodides, or bromides, in the form of their hydroxides, carbonates, hydrogen carbonates, or sulfates, etc.
- examples of sodium salts include e.g.
- the buffer suitable for injection purposes as defined above may contain salts selected from sodium chloride (NaCI), calcium chloride (CaCl2) and optionally potassium chloride (KCI), wherein further anions may be present additional to the chlorides.
- NaCI sodium chloride
- CaCl2 calcium chloride
- KCI optionally potassium chloride
- CaCl2 can also be replaced by another salt like KCI.
- the salts in the injection buffer are present in a concentration of at least 50 mM sodium chloride (NaCI), at least 3 mM potassium chloride (KCI) and at least 0,01 mM calcium chloride (CaCl2).
- the injection buffer may be hypertonic, isotonic or hypotonic with reference to the specific reference medium, i.e. the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the afore mentioned salts may be used, which do not lead to damage of cells due to osmosis or other concentration effects.
- Reference media are e.g.
- liquids such as blood, lymph, cytosolic liquids, or other body liquids, or e.g. liquids, which may be used as reference media in “in vitro” methods, such as common buffers or liquids.
- common buffers or liquids are known to a skilled person. Ringer- Lactate solution is particularly preferred as a liquid basis.
- compatible solid or liquid fillers or diluents or encapsulating compounds may be used as well, which are suitable for administration to a person.
- the term "compatible” as used herein means that the constituents of the inventive composition or vaccine are capable of being mixed with the the at least one mRNA, in such a manner that no interaction occurs which would substantially reduce the pharmaceutical effectiveness of the inventive composition or vaccine under typical use conditions.
- Pharmaceutically acceptable carriers, fillers and diluents must, of course, have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to a person to be treated.
- Some examples of compounds which can be used as pharmaceutically acceptable carriers, fillers or constituents thereof are sugars, such as, for example, lactose, glucose, trehalose and sucrose; starches, such as, for example, corn starch or potato starch; dextrose; cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt- gelatin; tallow; solid glidants, such as, for example, stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as, for example, groundnut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil from theobroma; polyols, such as, for example, polypropylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid.
- sugars such as, for example, lactose, glucose, trehalose
- the choice of a pharmaceutically acceptable carrier is determined in principle by the manner, in which the inventive composition or vaccine is administered.
- the inventive composition or vaccine can be administered, for example, systemically or locally.
- Routes for systemic administration in general include, for example, transdermal, oral, parenteral routes, including subcutaneous, intravenous, intramuscular, intraarterial, intradermal and intraperitoneal injections and/or intranasal administration routes.
- Routes for local administration in general include, for example, topical administration routes but also intradermal, transdermal, subcutaneous, or intramuscular injections or intralesional, intracranial, intrapulmonal, intracardial, and sublingual injections.
- vaccines may be administered by an intradermal, subcutaneous, or intramuscular route, preferably by injection, which may be needle-free and/or needle injection.
- the inventive composition or vaccine is administered by jet injection which is one specific form of needle-free injection.
- Jet injection refers to a needle-free injection method, wherein a fluid containing the at least one mRNA, the composition or vaccine according to the invention and, optionally, further suitable excipients is forced through an orifice, thus generating an ultra-fine liquid stream of high pressure that is capable of penetrating mammalian skin and, depending on the injection settings, subcutaneous tissue or muscle tissue.
- the liquid stream forms a hole in the skin, through which the liquid stream is pushed into the target tissue.
- jet injection is used for intradermal, subcutaneous or intramuscular injection of the composition or vaccine according to the invention.
- jet injection is used for intramuscular injection of the composition or vaccine.
- jet injection is used for intradermal injection of the composition or vaccine.
- compositions/vaccines are therefore preferably formulated in liquid or solid form.
- the suitable amount of the inventive composition or vaccine to be administered can be determined by routine experiments with animal models. Such models include, without implying any limitation, rabbit, sheep, mouse, rat, dog and non-human primate models.
- Preferred unit dose forms for injection include sterile solutions of water, physiological saline or mixtures thereof. The pH of such solutions should be adjusted to about 7.4.
- Suitable carriers for injection include hydrogels, devices for controlled or delayed release, polylactic acid and collagen matrices.
- Suitable pharmaceutically acceptable carriers for topical application include those which are suitable for use in lotions, creams, gels and the like. If the inventive composition or vaccine is to be administered perorally, tablets, capsules and the like are the preferred unit dose form.
- the pharmaceutically acceptable carriers for the preparation of unit dose forms which can be used for oral administration are well known in the prior art. The choice thereof will depend on secondary considerations such as taste, costs and storability, which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art.
- the inventive vaccine or composition can additionally contain one or more auxiliary substances in order to further increase the immunogenicity.
- a synergistic action of the at least one mRNA of the composition or vaccine as defined above and of an auxiliary substance, which may be optionally be co-formulated (or separately formulated) with the inventive vaccine or composition as described above, is preferably achieved thereby.
- various mechanisms can come into consideration in this respect. For example, compounds that permit the maturation of dendritic cells (DCs), for example lipopolysaccharides, TNF-alpha or CD40 ligand, form a first class of suitable auxiliary substances.
- DCs dendritic cells
- TNF-alpha or CD40 ligand form a first class of suitable auxiliary substances.
- auxiliary substance any agent that influences the immune system in the manner of a "danger signal" (LPS, GP96, etc.) or cytokines, such as GM-CFS, which allow an immune response produced by the immune-stimulating adjuvant according to the invention to be enhanced and/or influenced in a targeted manner.
- a "danger signal” LPS, GP96, etc.
- cytokines such as GM-CFS
- auxiliary substances are cytokines, such as monokines, lymphokines, interleukins or chemokines, that - additional to induction of the adaptive immune response by the encoded at least six antigens - promote the innate immune response, such as IL-1 , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-1 0, IL-12, IL-1 3, IL-14, IL-1 5, IL-1 6, IL-1 7, IL-18, IL-1 9, IL-20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31 , IL-32, IL-33, INF-alpha, IFN-beta, INF-gamma, GM- CSF, G-CSF, M-CSF, LT-beta or TNF-alpha, growth factors
- emulsifiers such as, for example, Tween ; wetting agents, such as, for example, sodium lauryl sulfate; colouring agents; taste-imparting agents, pharmaceutical carriers; tablet- forming agents; stabilizers; antioxidants; preservatives.
- the inventive vaccine or composition can also additionally contain any further compound, which is known to be immune-stimulating due to its binding affinity (as ligands) to human Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR1 0, or due to its binding affinity (as ligands) to murine Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR1 1 , TLR12 or TLR1 3.
- any further compound which is known to be immune-stimulating due to its binding affinity (as ligands) to human Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR1 1 , TLR12 or TLR1 3.
- CpG nucleic acids in particular CpG-RNA or CpG-DNA.
- a CpG- RNA or CpG-DNA can be a single-stranded CpG-DNA (ss CpG-DNA), a double-stranded CpG-DNA (dsDNA), a single-stranded CpG-RNA (ss CpG-RNA) or a double-stranded CpG- RNA (ds CpG-RNA).
- the CpG nucleic acid is preferably in the form of CpG-RNA, more preferably in the form of single-stranded CpG-RNA (ss CpG-RNA).
- the CpG nucleic acid preferably contains at least one or more (mitogenic) cytosine/guanine dinucleotide sequence(s) (CpG motif(s)).
- CpG motif(s) cytosine/guanine dinucleotide sequence(s)
- at least one CpG motif contained in these sequences that is to say the C (cytosine) and the G (guanine) of the CpG motif, is unmethylated. All further cytosines or guanines optionally contained in these sequences can be either methylated or unmethylated.
- the C (cytosine) and the G (guanine) of the CpG motif can also be present in methylated form.
- the above compounds are formulated and administered separately from the above composition or vaccine (of the invention) containing the at least one mRNA encoding at least the above defined six antigens.
- the inventive composition or the inventive vaccine may be used according to the present invention (for the preparation of a medicament) for the treatment of prostate cancer (PCa), preferably prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers and diseases or disorders related thereto.
- PCa prostate cancer
- adenocarcinoma locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers and diseases or disorders related thereto.
- the inventive vaccine or the inventive composition containing the at least one mRNA encoding the antigens as defined herein may be used for the treatment of prostate cancer (PCa), preferably prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- PCa prostate cancer
- adenocarcinoma locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- PCa prostate cancer
- a method typically comprises an optional first step of preparing the inventive composition, or the inventive vaccine, and a second step, comprising administering (a pharmaceutically effective amount of) said inventive composition or said inventive vaccine to a patient in need thereof.
- a subject in need thereof will typically be a male mammal.
- the mammal is preferably selected from the group comprising, without being limited thereto, e.g. goat, cattle, swine, dog, cat, donkey, monkey, ape, a rodent such as a mouse, hamster, rabbit and, particularly, human, wherein the mammal typically suffers from prostate cancer (PCa), preferably prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- PCa prostate cancer
- prostate adenocarcinoma locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- composition or vaccine according to the invention has beneficial effects for the treatment of subjects with castrate-refractory metastatic adenocarcinoma of the prostate with progressive disease.
- the subjects have undergone surgical castration or androgen suppression therapy (including a gonadotropin-releasing hormone (GNRH) agonist or antagonist).
- GNRH gonadotropin-releasing hormone
- subjects are treated with a progressive disease status even after at least one second-line anti-hormonal manipulation (e.g. antiandrogen). More preferably, subjects are selected that have a serum testosterone level of ⁇ 50 ng/dL or ⁇ 1 .7 nmol/dL.
- Disease progression may be characterized, for example, by two consecutive rises of PSA, measured at least 1 week apart, resulting at least in a 50% increase over the nadir and a PSA > 2 ng/ml. Progression of the disease may also be assessed radiological ly by means known in the art.
- composition or vaccine according to the invention has beneficial effects for the (neoadjuvant) treatment of subjects suffering from prostate cancer prior und subsequent of prostatectomy.
- the invention relates also to the use of the inventive composition or the at least one mRNA encoding the antigens as defined herein (for the preparation of an inventive vaccine), preferably for eliciting an immune response in a mammal, preferably for the treatment of prostate cancer (PCa), more preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration- resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- PCa prostate cancer
- PCa prostate cancer
- metastatic, castration-resistant hormone-refractory
- metastatic castration- resistant and non-metastatic castration-resistant prostate cancers and diseases or disorders related thereto.
- the invention also relates to the use of the inventive vaccine per se or the at least one mRNA encoding the antigens as defined herein for eliciting an adaptive immune response in a mammal, preferably for the treatment of prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- PCa prostate cancer
- prostate adenocarcinoma locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- Prevention or treatment of prostate adenocarcinoma may be carried out by administering the combination of antigens according to the invention, either in the form of the inventive composition or in the form of the inventive vaccine in order to elicite an immune response.
- the immunization protocol for the immunization of a subject against the combination of at least six antigens as defined herein typically comprises a series of single doses or dosages of the inventive composition or the inventive vaccine.
- a single dosage refers to the initial/first dose, a second dose or any futher doses, respectively, which are preferably administered in order to "boost" the immune reaction.
- each single dosage comprises the administration of all of the at least six antigens according to the invention, wherein the interval between the administration of two single dosages can vary from at least one day, preferably 2, 3, 4, 5, 6 or 7 days, to at least one week, preferably 2, 3, 4, 5, 6, 7 or 8 weeks.
- the intervals between single dosages may be constant or vary over the course of the immunization protocol, e.g. the intervals may be shorter in the beginning and longer towards the end of the protocol.
- the immunization protocol may extend over a period of time, which preferably lasts at least one week, more preferably several weeks (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 weeks), even more preferably several months (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 1 8 or 24 months).
- Each single dosage encompasses the administration of all of the at least six antigens as defined herein and may therefore involve at least one, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 injections.
- a single dosage typically comprises one injection.
- the minimum number of injections carried out during the administration of a single dosage corresponds to the number of separate components of the vaccine.
- the administration of a single dosage may encompass more than one injection for each component of the vaccine (e.g. a specific mRNA formulation comprising a mRNA encoding, for instance, one of the six antigens according to the invention).
- parts of the total volume of an individual component of the vaccine may be injected into different body parts, thus involving more than one injection.
- a single dosage of a vaccine comprising six separate mRNA formulations, each of which is administered in two different body parts comprises twelve injections.
- a single dosage comprises all injections required to administer all components of the vaccine, wherein a single component may be involve more than one injection as outlined above.
- the administration of a single dosage of the vaccine according to the invention encompasses more than one injection, the injection are carried out essentially simultaneously or concurrently, i.e. typically in a time-staggered fashion within the time-frame that is required for the practitioner to carry out the single injection steps, one after the other.
- the administration of a single dosage therefore preferably extends over a time period of several minutes, e.g. 2, 3, 4, 5, 10, 15, 30 or 60 minutes.
- Prevention or treatment of prostate adenocarcinoma may be carried out by administering the combination of antigens according to the invention, either in the form of the inventive composition or in the form of the inventive vaccine, concurrently, i.e. at once or in a time staggered manner, e.g. as a kit of parts, each part containing at least one mRNA preferably encoding different antigens.
- each of the antigens is administered separately, i.e.
- each antigen is administered to a different part or region of the body of the subject to be treated, preferably simultaneously or within the same short time-frame, respectively.
- the individual mRNAs are administered distributed over the subject's four limbs (i.e. left/right arm and leg).
- the administration (of all at least one mRNAs) occurs within an hour, more preferably within 30 minutes, even more preferably within 15, 10, 5, 4, 3, or 2 minutes or even within 1 minute.
- any of the administration routes may be used as defined above.
- PCa prostate cancer
- Administering of the inventive composition and/or the inventive vaccine may occur prior, concurrent and/or subsequent to administering another inventive composition and/or inventive vaccine as defined herein which may - in addition - contain another combination of mRNAs encoding different antigens, wherein each antigen encoded by the at least one mRNA of the inventive composition may preferably be suitable for the therapy of prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration- resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration- resistant prostate cancers, and diseases or disorders related thereto.
- PCa prostate cancer
- PCa prostate cancer
- prostate adenocarcinoma locally limited, locally advanced, metastatic, castration- resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration- resistant prostate cancers, and diseases or disorders related thereto.
- a therapy as defined herein may also comprise the modulation of a disease associated to prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non- metastatic castration-resistant prostate cancers, and of diseases or disorders related thereto.
- PCa prostate cancer
- adenocarcinoma locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non- metastatic castration-resistant prostate cancers, and of diseases or disorders related thereto.
- the present invention furthermore comprises the use of the inventive composition or the at least one mRNA encoding the antigens as defined herein (for the preparation of an (inventive) vaccine) for modulating, preferably to induce or enhance, an immune response in a mammal as defined above, more preferably to treat and/or to support the treatment of prostate cancer (PCa), preferably of a prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, or of diseases or disorders related thereto.
- PCa prostate cancer
- PCa prostate cancer
- metastatic castration-resistant and non-metastatic castration-resistant prostate cancers or of diseases or disorders related thereto.
- the treatment of prostate cancer (PCa) according to the present invention may be assisted by any approach or any combination approaches known from conventional prostate cancer therapy, such as surgery, radiation therapy, hormonal therapy, occasionally chemotherapy, proton therapy, or any combination thereof, and a therapy using the inventive composition as defined herein.
- Support of the treatment of prostate cancer (PCa) may be also envisaged in any of the other embodiments defined herein.
- any use of the inventive composition or vaccine in co-therapy with any of the above therapy approaches, in particular in combination with prostate surgery, hormonal (e.g. antiandrogen), and/or chemotherapy is within the scope of the present invention.
- a time staggered treatment may be e.g. administration of the inventive composition or the at least one mRNA encoding the antigens as defined herein or the inventive vaccine prior, concurrent and/or subsequent to a conventional therapy of prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non- metastatic castration-resistant prostate cancers, and diseases or disorders related thereto, e.g.
- PCa prostate cancer
- adenocarcinoma locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non- metastatic castration-resistant prostate cancers, and diseases or disorders related thereto, e.g.
- PCa prostate cancer
- a therapeutic suitable for the treatment of prostate cancer preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- Such time staggered treatment may be carried out using e.g. a kit, preferably a kit of parts as defi ned below.
- the administration of the i nventive composition or inventive vaccine is carried out prior and optional additionally subsequent to prostatectomy (neoadjuvant treatment).
- Time staggered treatment may additionally or alternatively also comprise an administration of the inventive composition or vaccine, preferably of the at least one mRNA encoding the antigens as defined above, in a form, wherein the at least one mRNA encoding the antigens as defined above, preferably forming part of the inventive composition or vaccine, is administered parallel, prior or subsequent to another at least one mRNA encoding the antigens as defined above, preferably forming part of the same inventive composition or vaccine.
- the administration (of all at least one mRNAs) occurs within an hour, more preferably within 30 minutes, even more preferably within 1 5, 1 0, 5, 4, 3, or 2 minutes or even within 1 minute.
- Such time staggered treatment may be carried out using e.g. a kit, preferably a kit of parts as defined below.
- the inventive composition or vaccine is admi nistered repeatedly, wherein each administration preferably comprises individual administration of the at least one mRNA according to the invention.
- the at least one mRNA may be administered more than once (e.g. 2 or 3 times).
- six mRNAs are administered at each time point, wherein each mRNA is admi nistered twice by injection, thus resulting in twelve injections distributed over the four limbs.
- kits particularly kits of parts, comprising the inventive composition, and/or the inventive vaccine, optionally a liquid vehicle for solubilising and optionally technical instructions with information on the administration and dosage of the inventive composition and/or the inventive vaccine.
- the technical instructions may contain information about administration and dosage of the inventive composition, and/or the inventive vaccine.
- kits preferably kits of parts, may be applied e.g.
- inventive composition for the preparation of an inventive medicament, preferably a vaccine
- inventive composition for the preparation of an inventive medicament, preferably a vaccine
- PCa prostate cancer
- a vaccine for the treatment of prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto.
- kits may also be applied for the use of at least one inventive composition (for the preparation of an inventive vaccine) for the treatment of prostate cancer (PCa), preferably of prostate adenocarcinoma, locally limited, locally advanced, metastatic, castration-resistant (hormone-refractory), metastatic castration-resistant and non-metastatic castration-resistant prostate cancers, and diseases or disorders related thereto, wherein the inventive composition) and/or the vaccine due to the encoded at least six antigens may be capable to induce or enhance an immune response in a mammal as defined above.
- Such kits may further be applied for the use of at least one inventive composition, (for the preparation of an inventive medicament, preferably a vaccine) for modulating, preferably for eliciting, e.g.
- Kits of parts may contain one or more identical or different inventive compositions and/or one or more identical or different inventive vaccines in different parts of the kit. Kits of parts may also contain an (e.g. one) inventive composition, an (e.g.
- kits of parts may be used, e.g. when a time staggered treatment is envisaged, e.g. when using different formulations and/or increasing concentrations of the inventive composition, the inventive vaccine and/or the at least one mRNA encoding the antigens as defined above during the same treatment in vivo. Kits of parts may also be used when a separated formulation or administration of at least one of the antigens of the inventive composition (i.e.
- kits of parts as a special form of kits are envisaged, wherein each part of the kit contains at least one preferably different antigen as defined above, al l parts of the kit of parts forming the inventive composition or the inventive vaccine as defined herein.
- Such specific kits of parts may particularly be suitable, e.g. if different antigens are formulated separately as different parts of the kits, but are then administered at once together or in a time staggered manner to the mammal in need thereof.
- the kit contains at least two parts containing the six m NAs according to the invention.
- all six mRNAs are provided in separate parts of the kit, wherein the mRNAs are preferably lyophilised.
- the kit further contains as a part a vehicle for solubilising the at least one mRNA, the vehicle preferably being Ringer-lactate solution. Any of the above kits may be used in a treatment as defined above.
- the present invention provides a composition for the treatment of prostate cancer (PCa), wherein the composition comprises at least one mRNA, encoding at least six antigens capable of eliciting an (adaptive) immune response in a mammal wherein the antigens are selected from the group consisting of PSA (Prostate-Specific Antigen), PSMA (Prostate- Specific Membrane Antigen), PSCA (Prostate Stem Cell Antigen), STEAP (Six Transmembrane Epithelial Antigen of the Prostate), PAP (Prostate Alkaline Phosphatase) and MUC1 (Mucin 1 ).
- PSA Prostate-Specific Antigen
- PSMA Prostate- Specific Membrane Antigen
- PSCA Prostate Stem Cell Antigen
- STEAP Small Transmembrane Epithelial Antigen of the Prostate
- PAP Prostate Alkaline Phosphatase
- MUC1 Moc 1
- mRNA as used in the inventive composition has additional considerable advantages over DNA expression systems e.g. in immune response, immunization or vaccination. These advantages include, inter alia, that mRNA introduced into a cell is not integrated into the genome. This avoids the risk of mutation of this gene, which otherwise may be completely or partially inactivated or give rise to misinformation. It further avoids other risks of using DNA as an agent to induce an immune response (e.g. as a vaccine) such as the induction of pathogenic anti-DNA antibodies in the patient into whom the foreign DNA has been introduced, so bringing about a (possibly fatal) immune response. In contrast, no anti-RNA antibodies have yet been detected.
- an immune response e.g. as a vaccine
- the mRNA contains the following sequence elements:
- CDS coding sequence
- the mRNA contains following sequence elements:
- Figure 7 depicts the mRNA sequence PSCA (GC)-muag-A64-C30 (SEQ ID NO: 7), encoding PSCA (prostate stem cell antigen).
- the mRNA contains following sequence elements:
- Figure 8 depicts the wild type coding sequence encoding PSCA (prostate stem cell antigen) according to SEQ ID NO: 8, i.e. the coding sequence (CDS) encoding PSCA (prostate stem cell antigen) without GC-optimized sequence.
- CDS coding sequence
- Figure 9 depicts the GC-optimized coding sequence encoding PSCA (prostate stem cell antigen) according to SEQ ID NO: 9.
- Figure 10 depicts the mRNA sequence STEAP (GQ-muag-A64-C30 (SEQ ID NO: 10), encoding for STEAP (Six Transmembrane Epithelial Antigen of the Prostate).
- the mRNA contains following sequence elements:
- Figure 1 1 depicts the wild type coding sequence encoding STEAP (Six Transmembrane
- Epithelial Antigen of the Prostate according to SEQ ID NO: 1 1 , i.e. the coding sequence (CDS) encoding STEAP (Six Transmembrane Epithelial Antigen of the Prostate) without GC-optimized sequence.
- CDS coding sequence
- the mRNA contains following sequence elements:
- ⁇ 64 Adenosin at the 3'-terminal end (poly-A-tail), 30 Cytosin at the 3'- terminal end (poly-C-tail). depicts the wild type coding sequence encoding PAP (prostate alkaline phosphatase) according to SEQ ID NO: 14, i.e. the coding sequence (CDS) encoding PAP (prostate alkaline phosphatase) without GC-optimized sequence. depicts the GC-optimized coding sequence encoding PAP (prostate alkaline phosphatase) according to SEQ ID NO: 1 5).
- mRNA sequence RNActive MUC1 5xVNTR (GC)-muag-A64-C30 (SEQ ID NO: 1 6; R1 71 5), encoding for MUC1 (Mucin 1 ).
- the mRNA contains following sequence elements:
- ⁇ 64 Adenosin at the 3'-terminal end (poly-A-tail), 30 Cytosin at the 3'- terminal end (poly-C-tail). depicts the wild type coding sequence encoding MUC1 (Mucin 1 ) according to SEQ ID NO: 1 7, i.e. the coding sequence (CDS) encoding MUC1 (Mucin 1 ) without GC-optimized sequence.
- Figure 18 depicts the GC-optimized coding sequence encoding MUC1 (Mucin 1 ) according to SEQ ID NO: 18.
- Figure 19 depicts the mRNA sequence PSA (GC)-muag-A64-C30-histoneSL (SEQ ID NO: 19).
- the mRNA contains following sequence elements:
- Figure 20 depicts the mRNA sequence PSMA (GC)-muag-A64-C30-histoneSL (SEQ ID NO:
- the mRNA contains following sequence elements:
- Figure 21 depicts the mRNA sequence CAP-PSCA (GC)-muag-A64-C30-histoneSL (SEQ ID NO:
- the mRNA contains following sequence elements: a GC-optimized coding sequence for stabilization and a better codon usage encoding PSCA according to SEQ ID NO: 9, the stabilizing sequence "muag" in the 3'-UTR according to SEQ ID No.69, ⁇ 64 Adenosin at the 3'-terminal end (poly-A-tail), ⁇ 30 Cytosin at the 3'- terminal end (poly-C-tail); and a histone stem-loop sequence according to SEQ ID No. 71 .
- Figure 22 depicts the mRNA sequence STEAP1 (GC)-muag-A64-C30-histoneSL (SEQ ID NO:
- the mRNA contains following sequence elements:
- FIG. 23 depicts the mRNA sequence PAP (GC)-muag-A64-C30-histoneSL (R2251 ) (SEQ ID NO: 23).
- the mRNA contains following sequence elements:
- the stabilizing sequence "muag" in the 3'-UTR according to SEQ ID No.69 ⁇ 64 Adenosin at the 3'-terminal end (poly-A-tail), ⁇ 30 Cytosin at the 3'- terminal end (poly-C-tail); and a histone stem-loop sequence according to SEQ ID No. 71 .
- Figure 24 depicts the mRNA sequence CAP-MUC1 5xVNTR (GC)-muag-A64-C30- histoneSL (R2312) (SEQ ID NO: 24).
- the mRNA contains following sequence elements:
- Figure 25 shows detection of a PAP-specific cellular immune response by ELISPOT.
- Figure 26 shows detection of a MUC1 -specific cellular immune response by ELISPOT.
- mice were vaccinated with 32pg MUC1 -RNActive® (MUC1 5xVNTR (GC)-muag-A64-C30; SEQ ID NO: 16; R1 715) on days 1 , 5, 8, 12 and 1 5.
- MUC1 5xVNTR GC
- R1 715 32pg MUC1 5xVNTR (GC)-muag-A64-C30; SEQ ID NO: 16; R1 715)
- Ex vivo ELISpot analysis of the secretion of IFN-gamma in splenocytes from vaccinated and control mice was performed on day 6 after last vaccination. Cells were stimulated on the plate either with MUC1 - derived peptide (predicted MHC-class I epitope) or with control peptide.
- the graph shows single data points for individual mice.
- FIG. 85 shows the protein sequence of PSA NP_001 639.1 according to SEQ ID NO: 76.
- FIG. 77 shows the protein sequence of PSMA (FOLH1 ) NP_004467.1 according to SEQ ID NO: 77. shows the protein sequence of PSCA ⁇ 43653.1 according to SEQ ID NO: 78. shows the protein sequence of STEAP NP_036581 .1 according to SEQ ID NO: 79. shows the protein sequence of PAP NP_001090.2 according to SEQ ID NO: 80.
- Figure 36 shows the protein sequence of MUC1 as deposited under accession number
- FIG. 37 shows the protein sequence of MUC1 5xVNTR according to SEQ ID NO: 86
- Figure 38 depicts the wildtype coding sequence encoding MUC1 according to SEQ ID NO: 1
- the DNA sequence corresponding to the native antigen encoding mRNA (sequences comprising the coding sequences corresponding to the RNA sequences according to Figures 2, 5, 8, 1 1 , 14 and 1 7, i.e. SEQ ID NOs: 2, 5, 8, 1 1 , 14 and 1 7) were GC-optimized for a better codon-usage obtaining a sequence comprising the coding sequences corresponding to the RNA sequences according to Figures 27, 28, 29, 30, 1 5 and 1 8, i.e. SEQ ID NOs: 82, 83, 84, 85, 1 5 and 1 8.
- the coding sequence was transferred into a GC-optimized construct (CureVac GmbH, Tubingen, Germany), which has been modified with a poly-A-tail and a poly-C-tail (A64-C30, respectively).
- the final constructs and the corresponding mRNAs were termed:
- the final constructs comprise a sequence corresponding to RNA sequences according to sequences as shown in Figures 1 , 4, 7, 10, 1 3 and 1 6 (SEQ ID NOs: 1 , 4, 7, 10, 1 3 and 1 6), respectively, which contain following sequence elements:
- GC-optimized CDS sequences were transferred in GC-optimized constructs, which have been modified with a poly-A-tail, a poly-C-tail and a histone-stem- loop sequence according to SEQ ID NO: 70.
- PSCA GC-muag-A64-C30-histoneSL (SEQ ID NO: 21 ),
- the final constructs comprise a sequence corresponding to RNA sequences according to sequences as shown in Figures 19, 20, 21 , 22, 23 and 24 (SEQ ID NOs: 1 9, 20, 21 , 22, 23 and 24), respectively, which contain following sequence elements:
- ⁇ 70 adenosine nucleotides at the 3'-terminal end (poly-A-tail), 30 cytosin nucleotides at the 3'- terminal end (poly-C-tail) and a histone stem-loop sequence according to SEQ ID NO: 71 .
- the mRNA sequences were prepared by in vitro transcription. Therefore, the recombinant plasmid DNA was linearized and subsequently in vitro transcribed using the T7 RNA polymerase. The DNA template was then degraded by DNase I digestion, and the mRNA was recovered by LiCI precipitation and further cleaned by HPLC extraction (PUREMessenger®, CureVac GmbH, Tubingen, Germany).
- Each mRNA encoding an antigen according to the invention was complexed with protamine by addition of protamine to the mRNA in the ratio (1 :2) (w/w) (adjuvant component). After incubation for 1 0 minutes, the same amount of free mRNA used as antigen-providing mRNA was added.
- the mRNA vaccine consists of GC-optimized mRNAs coding for PAP (SEQ ID NO: 1 3) or MUC1 (SEQ ID NO: 1 6), respectively.
- the mRNA was complexed with protamine by addition of protamine to the mRNA in the ratio (1 :2) (w/w) (adjuvant component). After incubation for 1 0 min, the same amount of free mRNA used as antigen-providing mRNA was added.
- C57BL/6 mice were vaccinated intradermally with 32 pg of one of the mRNA vaccines as described under 4.1 above. Control mice were treated injected intradermally with buffer (Ringer-lactate). Vaccination comprised five immunizations with 2 immunizations per week. The immune response was analysed 5 or 6 days after completion of the vaccination cycle.
- CTL cytotoxic T cell
- Splenocytes from mice vaccinated with the mRNA vaccine as described under 4.1 above and control mice were isolated 5 or 6 days after the last vaccination and then transferred into 96-well ELISPOT plates coated with an IFN-gamma capture antibody. The cells were then stimulated for 24 hours at 37°C using the following peptides:
- the cells were washed out of the plate and the IFN-gamma secreted by the cells was detected using a biotinylated secondary antibody against murine IFN-gamma, followed by streptavidin-AKP. Spots were visualized using BCIP/NBT substrate and counted using an automated ELISPOT reader (Immunospot Analyzer, CTL Analyzers LLC).
- the mRNA vaccine according to the invention consists of 6 individual, separately formulated GC-optimized mRNAs coding for KLK3/PSA (SEQ ID NO: 1 9), FOLH1 /PSMA (SEQ ID NO: 20), PSCA (SEQ ID NO: 21 ), STEAP (SEQ ID NO: 22), PAP (SEQ ID NO: 23) or MUC1 (SEQ ID NO: 24), respectively.
- Each mRNA was complexed with protamine by addition of protamine to the mRNA in the ratio (1 :2) (w/w) (adjuvant component). After incubation for 10 min, the same amount of free mRNA used as antigen-providing mRNA was added.
- each formulated mRNA was separately lyophilized.
- the mRNAs were dissolved in Ringer-Lactate.
- Each of the six components of the inventive vaccine comprises a formulated and lyophilized mRNA coding for one of the six antigens according to the invention.
- Components of the inventive vaccine :
- Component 1 1 60 pg mRNA coding for KLK3/PSA (SEQ ID NO: 19) complexed with protamine in the ratio (1 :2) (w/w) (adjuvant component) and 1 60 pg mRNA coding for KLK3/PSA (SEQ ID NO: 19)
- Component 2 1 60 pg mRNA coding for FOLH1/PSMA (SEQ ID NO: 20) complexed with protamine in the ratio (1 :2) (w/w) (adjuvant component) and 1 60 pg mRNA coding for FOLH1/PSMA (SEQ ID NO: 20)
- Component 3 1 60 pg mRNA coding for PSCA (SEQ ID NO: 21 ) complexed with protamine in the ratio (1 :2) (w/w) (adjuvant component) and 1 60 pg mRNA coding for PSCA (SEQ ID NO: 21 )
- Component 4 1 60 pg mRNA coding for STEAP (SEQ ID NO: 22) complexed with protamine in the ratio (1 :2) (w/w) (adjuvant component) and 1 60 pg mRNA coding for STEAP (SEQ ID NO: 22),
- Component 5 160 pg mRNA coding for PAP (SEQ ID NO: 23) complexed with protamine in the ratio (1 :2) (w/w) (adjuvant component) and 1 60 pg mRNA coding for PAP (SEQ ID NO: 23)
- Component 6 1 60 pg mRNA coding for MUC1 (SEQ ID NO: 24) complexed with protamine in the ratio (1 :2) (w/w) (adjuvant component) and 1 60 pg mRNA coding for MUC1 (SEQ ID NO: 24)
- An open-label, randomized phase II trial including the optional use of an injection device is conducted in patients with intermediate or high risk prostate cancer who receive 4 vaccinations with the inventive mRNA vaccine prepared according to Example 5.1 . within a 6-week period prior to radical prostatectomy (neoadjuvant treatment) or are observed without vaccination prior to surgery.
- Patients treated via conventional intradermal injection receive 320 pg of each mRNA according to Example 5.1 .
- Each component of the inventive vaccine was injected in 2 separate injection sites (1 60 pg mRNA/injection site).
- Patients injected by jet injection received only half of the dose (wherein the dose corresponds to 160 pg/component of the inventive vaccine), also injected in 2 separate injection sites (80 pg mRNA/injection site).
- Patients receive the vaccinations in weeks 1 , 2, 3 and 5. These patients undergo radical prostatectomy at least 1 week, but not later than 2 weeks after the 4th vaccination (week 6 or 7). After prostatectomy the patients optionally receive 2 further vaccinations with the inventive
- a Phase l/ll randomised double-blind placebo controlled multicentre study with an open label safety lead-in is conducted in patients with metastatic castration refractory prostate cancer.
- Treatment with the inventive vaccine is administered on Day 1 of weeks 1 , 2, 3, 5, 7, 9, 1 2, 1 5, 1 8 and 24, then every 6 weeks for up to 12 months fol lowing the first vaccination and then every 3 months.
- each of the 6 vaccine components is administered individual ly on the same day as 2 intradermal (i.d.) injections of 200 ⁇ each per component for a total of 12 injections.
- the inventive vaccine is immunogenic and induces a cellular and/or humoral immune response in 83% of the patients.
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- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Biophysics (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (11)
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AU2014310930A AU2014310930A1 (en) | 2013-08-21 | 2014-08-21 | Composition and vaccine for treating prostate cancer |
EP14755332.5A EP3035954A1 (en) | 2013-08-21 | 2014-08-21 | Composition and vaccine for treating prostate cancer |
SG11201510751YA SG11201510751YA (en) | 2013-08-21 | 2014-08-21 | Composition and vaccine for treating prostate cancer |
CN201480046124.1A CN105517566A (en) | 2013-08-21 | 2014-08-21 | Composition and vaccine for treating prostate cancer |
JP2016535367A JP2016532451A (en) | 2013-08-21 | 2014-08-21 | Compositions and vaccines for the treatment of prostate cancer |
CA2915904A CA2915904A1 (en) | 2013-08-21 | 2014-08-21 | Composition and vaccine for treating prostate cancer |
MX2016002153A MX2016002153A (en) | 2013-08-21 | 2014-08-21 | Composition and vaccine for treating prostate cancer. |
RU2016109938A RU2016109938A (en) | 2013-08-21 | 2014-08-21 | COMPOSITION AND VACCINE FOR TREATMENT OF PROSTATE CANCER |
KR1020167006937A KR20160043103A (en) | 2013-08-21 | 2014-08-21 | Composition and Vaccine for Treating Prostate Cancer |
BR112016000889A BR112016000889A2 (en) | 2013-08-21 | 2014-08-21 | composition and vaccine for prostate cancer treatment |
US15/048,126 US20160166668A1 (en) | 2013-08-21 | 2016-02-19 | Composition and vaccine for treating prostate cancer |
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EP2013002515 | 2013-08-21 | ||
EP2013002516 | 2013-08-21 | ||
EPPCT/EP2013/002516 | 2013-08-21 | ||
EPPCT/EP2013/002515 | 2013-08-21 |
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US15/048,126 Continuation US20160166668A1 (en) | 2013-08-21 | 2016-02-19 | Composition and vaccine for treating prostate cancer |
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WO2015024664A1 true WO2015024664A1 (en) | 2015-02-26 |
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PCT/EP2014/002297 WO2015024664A1 (en) | 2013-08-21 | 2014-08-21 | Composition and vaccine for treating prostate cancer |
Country Status (11)
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US (1) | US20160166668A1 (en) |
JP (2) | JP2016532451A (en) |
KR (1) | KR20160043103A (en) |
CN (1) | CN105517566A (en) |
AU (1) | AU2014310930A1 (en) |
BR (1) | BR112016000889A2 (en) |
CA (1) | CA2915904A1 (en) |
MX (1) | MX2016002153A (en) |
RU (1) | RU2016109938A (en) |
SG (2) | SG10201801433XA (en) |
WO (1) | WO2015024664A1 (en) |
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JP2018184422A (en) | 2018-11-22 |
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