EP3993873A1 - Mammary tumor virus suppression - Google Patents
Mammary tumor virus suppressionInfo
- Publication number
- EP3993873A1 EP3993873A1 EP20834735.1A EP20834735A EP3993873A1 EP 3993873 A1 EP3993873 A1 EP 3993873A1 EP 20834735 A EP20834735 A EP 20834735A EP 3993873 A1 EP3993873 A1 EP 3993873A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mtv
- dosage
- protein
- vaccine
- administering
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Classifications
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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
- A61K39/12—Viral antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- A61K2039/812—Breast
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/12011—Betaretrovirus, e.g. mouse mammary tumour virus
- C12N2740/12022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/12011—Betaretrovirus, e.g. mouse mammary tumour virus
- C12N2740/12034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- SEQ. 1 Illustrates an example Pr75gag polyprotein sequence.
- SEQ. 2 Illustrates an example transitional protein plO sequence.
- SEQ. 3 Illustrates an artificial cDNA sequence encoding a modified plO transitional protein.
- Embodiments of the invention generally fall into the category of suppression of viral replication.
- a protease inhibitor is used to control viral replication to prevent recurrence or metastasis in patients with invasive viral-mediated cancers.
- the protease inhibitor is combined with a cDNA produced peptide.
- MTV mammary tumor virus
- MMTV Mouse Mammary Tumor Virus
- MTV MTV belongs to a group globally recognized as oncogenic. As such, it acts through insertional mutagenesis, ultimately producing a tumor in its target tissue.
- MMTV strains vary according to species of mouse, which itself varies by geography and historical custom.
- the observance of the parallel trends in MMTV expression and human breast cancer led to a probable associative link between the two. Areas that have higher concentrations of rodents and have had them for a longer period of time show increased virulence and increased rates of cancer.
- the incidence and manifestation of breast cancer in humans can be directly correlated to the species of mouse endemic to a given area. Regions where mouse populations are generally low, like East Asia, have lower overall breast cancer rates, and those populations have tumors that exhibit very low virus positivity (Khan, 2008; San, 2017).
- a hormonally-activated and regulated retrovirus the genetic code of MTV is fully deciphered for variants found in some mammalian species.
- the genetic code of the deciphered variants share a common genetic architecture with many other retroviruses with major expression groups comprising: long terminal repeats (LTR); group antigen polyproteins (GAG); reverse transcriptases and polymerases (POL); and, envelope proteins (ENV).
- LTR long terminal repeats
- GAG group antigen polyproteins
- POL reverse transcriptases and polymerases
- ENV envelope proteins
- Figure 1 provides an illustration of this generalized architectural structure for MTV.
- the proteins that compose the GAG group generally form the viral core structure, RNA genome binding proteins, and are the major proteins comprising the nucleoprotein core.
- the GAG group may also encode viral matrix, capsid, and nucleoproteins.
- the POL reverse transcriptase is the essential enzyme that carries out the reverse transcription process that takes the viral RNA genome to a double-stranded DNA pre integrated form.
- the ENV group encodes for host cell transmembrane and surface-receptor subunits, and regulatory subunits found on the endoplasmic reticulum of the host cell in addition to the proteins that form the viral envelope.
- the MMTV virus while endemic to mice, appears to be acquired within the species itself.
- An antigenic component, the gp52 envelope protein can reliably be found in the blood and reproductive organs of infected mice (Arthur, 1978), as can antibodies to envelope proteins such as gp52.
- the virus is passed through breast milk, urine, feces, and/or saliva, and it travels liberally until it finds hormone-dependent tissues to infect, with breast being the preferred target. Once inside a cell, the virus randomly inserts into a series of integration sites (Faschinger, 2008), ultimately meeting an oncogene and producing the necessary frameshift to cause a cancer- producing mutation (Moore, 1987).
- HMTV Human Mammary Tumor Virus
- HMTV ductal carcinoma in situ
- DCIS ductal carcinoma in situ
- the virus may be somewhat elusive, owing to the fact that it is present in low concentrations (Bindra, 2007), and serves as a relatively remote precursor to oncogenesis (Nartey, 2017).
- Viral acquisition predates tumor formation by one to eleven years (Lawson, 2017), with the virus itself possibly becoming less virulent after initial mutagenesis.
- viral particles can be detected in tumor tissue and breast milk (Nartey, 2014), demonstrating a predilection for that organ system.
- the affinity for breast tissue includes male subjects as well, in whom particles have been isolated from benign cases of gynecomastia (Ford, 2004).
- HMTV shares homology with MMTV in both form and action and the two share similar genetic sequences.
- “homolog” and its derivatives are, unless specified with a percentage, used as commonly understood by practitioners in the field of biochemistry in that proteins sharing similar behavioral properties, structural motifs, or performing similar functions with conserved domains across a family are said to be“homologous” to each other.
- sequence data for DNA or RNA may be more or less“homologous” in that shared identities across species are said to be“homologous.”
- homologous is interpreted to mean a comparison of sequences (DNA, RNA, peptide) with sequences above a certain percentage similarity or bearing certain conserved structural motifs at key positions said to be“homologous” with other sequences.
- RNA segments known to originate from MMTV (Axel, 1962).
- the HMTV virus inserts similarly into the genome at random sites, ultimately inciting comparable mutations by activating various oncogenes (Callahan, 2012).
- Representatives of the envelope protein can be localized to the host cell membrane, but are more prominent in cellular cytoplasm (Tomana, 1981).
- transcription processes read through an MTV genome and mRNA is polyadenylated and processed using signals in transcribed regions from the 3' LTR at the end of the transcribed RNA.
- the full-length message can be spliced to lead to production of envelope proteins (or other proteins depending upon retroviral class).
- Unspliced full-length mRNA can give rise to GAG-POL precursor polyproteins.
- GAG and POL proteins, and other MTV proteins, or protein subunits may first arise from translated mRNA polypeptide precursor molecules. Multiple precursors are possible and may contain multiple proteins or protein subunits.
- a viral protease cleaves the precursor into multiple subunits with varying functions.
- An ENV protein complex may be translated from mRNA segments into multiple precursors which are then cleaved by endogenous proteases to yield multiple subunits that assemble into a mature surface glycoprotein.
- Translated proteins assemble a retroviral particle at the host cell surface.
- Full-length genomic unspliced mRNA (containing a packaging signal termed Psi) is bound by GAG-derived proteins and incorporated into the budding particle.
- Psi packaging signal
- the general structure of a mature MTV particle is characterized by prominent surface protein“spikes” and a dense acentric nucleocapsid.
- HERV Human Endogenous Retroviruses
- MTV behaves in a fashion more consistent as an exogenous particle (Ford, 2004; Melana, 2007).
- the measured immunogenicity against MTV is consistent with that of an acquired infection, and is maximal during disease latency (Black, 1976).
- the retrovirus replication cycle is characterized by conversion of the single-strand
- RNA viral genome into double-strand proviral DNA by the multiple enzymatic activities of the virus-associated reverse transcriptase Integration of MMTV proviral DNA into the genome of host cells is required for the expression of viral proteins. In both infected mouse mammary glands as wells as heterologous cells MMTV proviral DNA is integrated into a large number of apparently random sites. Integration of MMTV proviruses containing transcriptionally active long terminal repeats (LTR) near some cellular genes (proto-oncogenes) involved with oncogenesis can result in over-expression of these genes resulting in cellular transformation and clonal expansion of tumor cells. Thus, the long latency of MMTV-induced carcinogenesis is explained in part by the necessity for proviruses to integrate into oncogenetic sites.
- LTR transcriptionally active long terminal repeats
- mice While mice are ubiquitous and are known to be present in both homes and food storage facilities, MTV appears to require more intimate contact for effective transmission.
- Various efforts to detect MTV in other species have shown that correlates are found in primates, feline and canine species, in addition to the well-known mouse model (Szabo, 2005).
- Cross species transmission is possible, as evidenced by the acquisition of MMTV in lab personnel who performed frequent handling of infected mice (Dion, 1986).
- MTV appears to require repeated and frequent exposure for effective transmission.
- domesticated pets have become the prime targets for study, and the prime suspects as vectors.
- MTV particles are found in the non-cancer cells of house pets, with sequences similar to those of infected mice (Hsu, 2010). Pet-human interaction being frequent and extensive, studies then proceeded to identify the most common mode of transmission between them. Given that MTV has been detected in various body fluids, saliva was next to be evaluated for its virulent potential.
- an MTV vaccine capable of inducing immunity in humans and in human-associated animals. Further, as the oncogenic properties of exogenous MTV are only recently recognized, there is a need to develop treatments effective at lowering viral particle load and/or activity.
- An embodiment of the invention is a method of reducing breast cancer recurrence via prevention of MTV transcription in breast tissue via administration of a protease inhibitor.
- Other compositions contemplated as part of various embodiments of the instant invention provide a means for stabilizing or reducing the amount of virus present in a human or other animal.
- the patient Upon discovery of MTV the patient is then administered an antiretroviral medication.
- the antiretroviral medication is a protease inhibitor.
- the antiretroviral treatment may be one or more selected from the group of: nucleoside analogue reverse transcriptase inhibitors, nucleotide analogue reverse transcriptase inhibitors, non nucleoside reverse transcriptase inhibitors.
- the antiretroviral medication such as a protease inhibitor
- the test for MTV presence is an antibody titer test.
- the antibody test relies on antibodies raised in response to at least one of : GP52, a transition protein, and pl4.
- the transition protein is plO.
- a patient with a breast cancer diagnosis, or a patient with breast cancer risk factors is treated with an antiretroviral medication. In still other embodiments this treatment is combined with the administration of MTV transition proteins or transition protein peptides.
- a cDNA encoding an MTV transition protein is provided. The protein may be myristoylated and, likewise, the cDNA may encode for this modification. Also provided are cDNA molecules encoding MTV transition protein peptide chains of greater or lesser length with or without a myristol. The transition protein or transition protein peptide chains may then be incorporated as part of an MTV vaccine or treatment regimen administered to a patient for control of MTV particle count or viral activity.
- POL, and LTR may encode for multiple proteins, subunits, glycosylation sites, or signaling factors.
- Vaccines also include a variety of ingredients besides classifying antigens and can include: stabilizers, adjuvants, antibiotics, and preservatives. Those skilled in the art of pharmaceutical preparation are able to select appropriate additional ingredients in the course of standard practice.
- the term“vaccine” is used as ordinarily understood and may also contain a secondary descriptor describing the antigenic component eliciting the desired immune response along with the associated ingredients tailored to the desired effect. It is further understood that a vaccine may be all or part of a“pharmaceutical preparation” as herein defined and may incorporate a combination of natural and synthetic components.
- Vaccines may be monovalent or polyvalent.
- a monovalent vaccine contains a single strain of a single antigen (e.g. Measles vaccine), whereas a polyvalent vaccine contains two or more strains/serotypes of the same antigen (e.g. OPV).
- antigens may be combined in a single injection that can prevent different diseases or that protect against multiple strains of infectious agents causing the same disease (e.g. combination vaccine DPT combining diphtheria, pertussis, and tetanus antigens).
- combination vaccines can be useful to overcome the logistic constraints of multiple injections and accommodate for a patient’s fear of needles and pain.
- the term“polyvalent vaccine” refers to multiple antigen types that may derive from a single or multiple disease vectors whereas a“combination vaccine” refers to a vaccine with multiple antigens targeting at least two or more diseases.
- a“polyvalent vaccine” may have multiple antigens but only provide immunity to a single disease whereas a “combination vaccine” may contain a single type of antigen from two or more disease vectors and give rise to an immunity for those two or more diseases.
- the term “patient” reflects a human or animal subject to whom a medical treatment is provided either for modification of a disease state or as a prophylactic preventative of disease.
- LAV live attenuated vaccines
- pathogens virus or bacteria
- Inactivated vaccines are made from microorganisms (viruses, bacteria, other) that have been killed through physical or chemical processes. These killed organisms cannot cause disease.
- Subunit vaccines like inactivated whole-cell vaccines do not contain live components of the pathogen. They differ from inactivated whole-cell vaccines, by containing only the antigenic parts of the pathogen. Protein based subunit vaccines present an antigen to the immune system without viral particles, using a specific, isolated protein of the pathogen. Some bacteria when infecting humans are often protected by a polysaccharide (sugar) capsule that helps the organism evade the human defense systems especially in infants and young children. Polysaccharide vaccines create a response against the molecules in the pathogen’s capsule. Conjugate subunit vaccines also create a response against the molecules in the pathogen’ s capsule. In comparison to plain polysaccharide vaccines, they benefit from a technology that binds the polysaccharide to a carrier protein that can induce a long-term protective response.
- Toxoid vaccines are based on the toxin produced by certain bacteria (e.g. tetanus or diphtheria).
- the toxin invades the bloodstream and is largely responsible for the symptoms of the disease.
- a protein-based toxin is rendered harmless (toxoid) and used as the antigen in the vaccine to elicit immunity.
- the toxoid is often adsorbed to aluminum or calcium salts, which serve as adjuvants.
- a live vaccine can have different associated ingredients than a subunit-based vaccine. Both are vaccines and raise an immune response in patients but with different antigens. Or, in the alternative, two live vaccines may have the same antigen but varied ingredients (e.g., in response to administration requirements). Or, in other embodiments, the vaccine may have the same antigen (e.g., an ENV protein or protein subunit) that is derived from one or more sources (e.g., an ENV protein from a human and one from a cat). In other embodiments, two or more antigenic components may be combined to increase immune system response greater than an individual antigen alone (e.g., an ENV protein combined with a protein precursor). Additionally, antigens for MTV may be combined with other antigens for other diseases into a mono or poly valent combination vaccine.
- antigens and derivatives are defined as the components typically derived from the structure of disease-causing organisms, which are recognized as“foreign” by the immune system and trigger a protective immune response to the vaccine.
- the antigen component does not have to be made by the disease-causing organism in order to be used.
- viral proteins or protein precursors may be manufactured and purified using bacterial, fungal, cell free, or other vector-based systems in bulk and then purified for use in a vaccine serum or other pharmaceutical preparation.
- Vaccines may be administered through multiple routes at least including: intramuscular injection, subcutaneous injection, intradermal injection, orally, or through intranasal sprays. It is understood that each route of administration may require its own mix of antigens and associated ingredients.
- an“syn” such as synMTV or synENV, synPOL, etc. to differentiate from naturally occurring versions.
- an synENV protein may be derived from a genetic sequence identical to or modified from (e.g., introns removed, different starter code and reading frame, different promoters etc.) a naturally occurring sequence but produced in an alternative system of protein expression (e.g., in yeast or e. coli , etc.).
- the amino acid sequences, and underlying genetics, for each protein may vary across viral sub-species found in different mammalian species.
- synProteins or synProtein subunits may be derived in whole or in part from single or multiple viral sub-types (e.g., human sequence synProtein combined with a homologous canine synProtein to form a polyvalent vaccine protective against both HMTV and canine MTV virus particles).
- an engineered vaccine is created by synthesizing and purifying an EP3-pl4-plO peptide chain.
- the peptides, in haptan formulation, are coupled to keyhole limpet hemocyanin (KLH) and extensively dialyzed. Moles of conjugated peptide/mole of KLH are determined by amino acid analysis and range between 700 and 1,000. Positive and negative controls consist of gp52, purified from C3H-MMTV and a scrambled peptide sequence coupled to KLH respectively.
- Still other embodiments may employ different carrier proteins including at least: Concholepas concholepas hemocyanin, bovine serum albumin (BSA), cationized BSA, or ovalbumin, and any other carrier proteins.
- BSA bovine serum albumin
- multiple antigens for instance from other viral-mediated cancers or tumor-associated antigens, or for other diseases which may be vaccinated against, may also be attached to one or more carrier proteins and combined to form a polyvalent combination vaccine.
- the vaccine is administered to patients either as a prophylactic preventative or, in the case of patients with a known MTV exposure as a means of inducing or bolstering an immune response.
- the MTV envelope (ENV) class of proteins is known to have conserved domain elements across variants of the virus detected across multiple species.
- the ENV proteins may comprise those that are signaling peptides, those that are specific to the outer membrane of the virus particle, those specific to the endoplasmic reticulum, and those that are trans-membrane anchors.
- the polymerase (POL) protein class may comprise both a polymerase and/or a reverse transcriptase and an associated signaling factor.
- the group antigen (GAG) proteins form the viral core structure, RNA genome binding proteins, and are the major proteins comprising the nucleoprotein core particle. The POL and GAG group proteins are likewise thought to have conserved cross-species elements.
- variants within and between the above genetic motifs may account for viral traits such as specificity, genetic integration location, surface protein structures, species specificity, etc.
- viral traits such as specificity, genetic integration location, surface protein structures, species specificity, etc.
- one may target a vaccine to protect against an MTV exposure in various species. This may be accomplished by either deriving viral proteins from the target species of interest or utilizing synProteins or synProtein subunits derived from species-specific sequence data.
- a target species may be one whose MTV viral protein sequences, although homologous, differ enough from the primary MTV antigen in a vaccine that a separate antigen is required to raise or enhance an immune response either in the species of interest or to increase an immune response, for example in a human, in reaction to an exposure of an MTV variant from the target species.
- a human MTV vaccine with a transition protein may include additional MTV polypeptide antigens whose sequences are derived from human companion species such as a dog, cat, ferret, etc.
- the vaccine may also possibly be administered to the human-companion animal to reduce viral load in the animal (and hence exposure to the human), the additional MTV component also strengthens the immune response of the human to the target species variant of MTV.
- another embodiment of the invention comprises an MTV vaccine derived from attenuated or inactivated MTV particles derived from either single or multiple species.
- Other embodiment vaccines are derived from synProteins and synProtein subunits of the ENV, POL, and GAG protein classes.
- An additional embodiment is composed of synProteins and/or synProtein subunits derived from cross-species conserved sequences. For example, some portions of the sequence of the gp52 ENV protein are known to be conserved across MTV variants.
- a synProtein subunit based on the conserved sequence could be used in a vaccine to induce immunity to MTV in multiple species, including human-associated animals such as dogs, cats, and other human-companion animals or increase the immune response in a human to MTV variants derived from the animals.
- derived from is used as ordinarily understood: that is, a sequence (DNA, RNA, or peptide) may be found across multiple species with minor variations while still preserving a high sequence identity.
- MTV protein plO in general, it is the unique mutations, sometimes in the form of single nucleotide polymorphisms (SNPs), that allow one skilled in the art to identify a plO sequence from a human, compared to another mammal, such as a mouse.
- SNPs single nucleotide polymorphisms
- “derived from” encompasses and contemplates the source of raw stock materials, binders, supports, carrier proteins, etc.
- a purified MTV virus from one or multiple species is combined with 1.2xlO 2 M formalin for a concentration of 1 :3,000 formaldehyde. It is then incubated in the dark at 4°C for 5 days (or room temperature for 72 h) and stored at 4°C. It is diluted to contain 50 ng protein m ⁇ 1 and emulsified with an equal volume of complete Freund’s adjuvant (CFA) or other pharmaceutically acceptable adjuvant. The preparation is then stored at -70°C until used.
- CFA complete Freund’s adjuvant
- the above serum is combined with one or more additional vaccine sera to form polyvalent, compound, or compound polyvalent vaccines targeted at one or more additional diseases.
- the resulting pharmaceutical preparation is then administered to a patient for either prophylactic or treatment purposes.
- MTV virus particles from one or multiple species may be subjected to fragmentation processes designed to break apart the virus into multiple protein and protein pieces (e.g., sonication, vibration, freeze-fracture, etc.). MTV proteins and/or protein subunits may then be collected, purified, and fixed in a vaccine preparation. Particular preparations may include purified ENV, POL, or GAG proteins or protein subunits. In a further embodiment the purified proteins may include plO, pl4, and gp52.
- RNA viruses in many families and genera express their genomes in ways which involve the synthesis and subsequent cleavage of polypeptide chains known as precursor polyproteins. This stratagem allows the activation of subsets of proteins with different biochemical functions from the same precursor polyprotein. Although the virus-encoded enzymes responsible for processing the polyproteins are structurally diverse, they are all highly specific for their substrates. The resulting processing cascade is a tightly controlled process, which in several cases involves the action of protein cofactors to modulate the activity of the proteinase. Antigens for use in a vaccine can derive from protein precursors.
- MTV proteins are synthesized with at least two major precursor polyproteins, for MMTV this includes: gPr75env containing gp52 and gp36; and, Pr75gag containing p27, pp20, pl4, and plO.
- SEQ. ID: 01 illustrates an example sequence for a Pr75gag precursor polyprotein, the cleavage products of which are schematically illustrated in Figure 2. Shown in Figure 2, for example, pl4 is a signal peptide subunit of an ENV protein. pl4 can also function in both oncogenic and an anti-oncogenic capacity depending on its phosphorylation status.
- plO is part of the same polyprotein precursor as pl4 and is also found as a cleavage product thereof.
- SEQ. ID: 02 illustrates an example sequence of a plO protein.
- transition protein describes a protein, that moves between the viral core and the viral envelope (i.e., from core to envelope or envelope to core). In an embodiment the transition protein may start at the viral core and then move to the viral envelope. The transition protein may thus remain at the underside of the envelope, may transition through the envelope to the exterior, or may span across the viral envelope. A transition protein may also be a protein subunit that forms part of a larger protein.
- an embodiment of the invention includes an MTV transition protein either alone or in combination with further MTV proteins.
- An MTV transition protein may also be synthetically generated and combined with other antigens or formed as part of a polyvalent, or compound polyvalent vaccine targeting one or multiple diseases and administered to a patient either prophylactically or as a modifier of a disease state.
- an MTV vaccine preparation containing one or more precursor proteins either derived from polyprotein cleavage products or directly created using alternative protein expression means.
- polyprotein cleavage products, plO, pl4, and, alone or in combination with each other may be combined with at least one ENV, GAG, or POL protein or protein derivative.
- Still other embodiments may include gp52, gp36, and p28 proteins. These may then be combined with an MTV transition protein, such as plO.
- oncoviruses are possible sources of oncogenesis; these can include at least: Epstein-Barr Virus (EBV) (Ballard, 2015; Lebreque, 1995), human immunodeficiency virus (HIV), human papilloma virus (HPV), herpes simplex virus (HSV), and bovine leukemia virus (BLV) (Baltzell, 2018; Buehring, 2017). It is believed, without subscribing or limiting to a particular theory, and as briefly outlined above, that viruses often work together to potentiate each other and to cause disease in general. Oncogenic viruses in particular can work together to cause disease.
- EBV Epstein-Barr Virus
- HSV human immunodeficiency virus
- HPV human papilloma virus
- HSV herpes simplex virus
- BLV bovine leukemia virus
- RNA viruses tend to be unstable but highly virulent
- DNA viruses tend to be stable but not as aggressive.
- DNA and RNA viruses can work together, each building upon the strengths of the other to increase pathogenicity. It is believed that many viruses like HPV and HSV can make other viruses more virulent, and that certain combinations are particularly effective at inducing oncogenesis in patients.
- RNA viruses and DNA viruses may have a complimentary effect wherein the high replication and mutation rates of RNA viruses may be stabilized by the less mutagenic DNA viruses, allowing for optimal adaptability without loss of control.
- the highly active MTV RNA virus as discussed above, replicates quickly and randomly inserts into the genome, often producing no effect. Genomically-integrated MTV sequences can be found with little to no clinical relevance, and these are often misinterpreted as being endogenous. Once stabilized and directed by a DNA partner, the usually erratic agent can now target its source more effectively and remain consistent long enough to provoke oncogenesis. This is one possible mechanism for HPV/MTV synergy in cancer formation.
- embodiments of the invention are directed towards the treatment of breast, prostate, and other viral-mediated cancers or other synergestic diseases in humans and other animals.
- a protective immunity is formed in patients as a result of vaccination with MTV or synMTV either in whole, in part, or in combinations as part of live, attenuated, or subunit vaccines along with antigenic components of other oncogenic virus particles such as at least: EBV, HIV, HPV, HSV, and BLV.
- an MTV vaccine is administered to a patient diagnosed with a viral-mediated cancer with the effect of reducing the malignancy, spread, or recurrence of the viral-mediated cancer.
- a monovalent vaccine targeting a rabbit may use an MTV protein or protein particles purified from rabbit-specific MTV.
- a human targeting vaccine may use ENV protein purified from HMTV strains found in humans.
- a synthetically derived synProteins or hybrids may be created based upon a target species MTV genetic sequence.
- MTV derived POL or GAG proteins or protein subunits may be used.
- the vaccine may be composed of peptides derived from one or more conserved sequences found across target species, for example, human, mouse, canine, feline, bovine, and other human-companion animals.
- target species for example, human, mouse, canine, feline, bovine, and other human-companion animals.
- a multi-species MTV vaccine may be created.
- animal vaccination may be used in tandem with human vaccination to decrease the overall incidence of breast cancer and other viral mediated cancers in a human population by decreasing human exposure to MTV transmitted via animals.
- Another embodiment of the invention is a polyvalent vaccine comprised of multiple
- the components may be a mixture of natural and synthetically derived components, for example, a synthetic synENV mixed with a naturally occurring ENV or POL.
- the polyvalent vaccine may further contain precursor cleavage products such as plO, mplO (which is a plO peptide in myristoylated form with or without subsequent conformational changes), or pl4. These may further be combined with one or more transition proteins and may be further combined into a combination vaccine or suitable pharmaceutical preparation.
- An embodiment of the invention is a vaccine comprising an MTV transition protein administered to a patient.
- the MTV transition protein is plO.
- the vaccine further comprises additional antigens to form a combination vaccine.
- the vaccine contains at least one additional MTV component.
- the one additional MTV component is derived from at least one of: gp52, pl4, syngp52, MTV polymerase, synMTV polymerase, MTV transcriptase, synMTV transcriptase, MTV surface, synMTV surface, MTV transmembrane anchoring, synMTV transmembrane anchoring, MTV-associated polysaccharide, and synMTV-associated polysaccharide.
- the vaccine may further contain MTV derived ENV and POL. In still other embodiments at least one of the ENV, POL and MTV transition proteins is synthetically derived. In another embodiment the vaccine may also contain a polysaccharide. In still other embodiments the vaccine may comprise additional antigens to form a combination polyvalent vaccine. In certain embodiments the additional antigens are derived from at least one of: an oncovirus, and a tumor-associated antigen.
- the vaccine contains MTV polypeptides coupled to a carrier protein.
- the MTV polyeptides are EP3, pi 4, and an MTV transition protein; and, the carrier protein is KLH.
- the MTV transition protein is plO as exemplified in SEQ. ID: 2 or a homologous sequence with at least 90% identity thereof.
- the carrier protein is at least one selected from the group of KLH, Concholepas concholepas hemocyanin, BSA, Cationized BSA, and Ovalbumin.
- the vaccine also contains additional antigens to form a compound polyvalent vaccine.
- an MTV vaccine comprising EP3, plO, and pl4 bound to KLH along with any additional pharmaceutically acceptable compounds may be prophylactically provided to an MTV naive patient.
- the patient immune system mounts a response resulting in long term immunity from subsequent MTV exposure.
- compositions comprising MTV DNA, RNA and/or proteins described herein. These compositions may further comprise a pharmaceutically acceptable excipient, carrier, or diluent and do not contain any biologically harmful substances.
- the pharmaceutical compositions of the present invention may be formulated by one having ordinary skill in the art. Suitable pharmaceutical formulations are described in Remington's Pharmaceutical Sciences which is a standard reference text in the field which is herein incorporated by reference.
- the pharmaceutical compositions may further comprise coloring or stabilizing agents, osmotic agents, antibacterial agents, or any other substances as long as such substances do not interfere with the function of the composition.
- the pharmaceutical compositions of the instant invention can, for example, be formulated as a solution, suspension, or emulsion in association with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 5% human albumen. Liposomes may also be used.
- the vehicle may contain additives that maintain isotonicity (e.g., sodium chloride or mannitol) and chemical stability (e.g., buffers and preservatives).
- endotoxin contamination should be kept at a safe level, for example, less than 0.5ng mg 1 protein.
- preparations should meet sterility, pyrogenicity, general safety and purity standards as required by the United States Food and Drug Administration Office of Biological Standards.
- the formulations may be sterilized by commonly used techniques such as filtration.
- pharmaceutically acceptable refers to substances and compositions which do not produce an adverse, allergic, or otherwise untoward reaction when administered to an animal, or a human, as appropriate. A substance which caused or produced any of these adverse effects would be classified as“biologically harmful' within the scope of the present invention.
- compositions include, but are not limited to solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Except where incompatible with the invention the use of any conventional ingredient is contemplated. Furthermore, supplementary active ingredients which serve some other pharmacologically expedient purpose can also be incorporated into the instant compositions without departing from the broader scope of the instant invention.
- Another embodiment of the invention is a method of treating MTV where an MTV vaccine with an MTV transition protein is provided and administered to a patient.
- the vaccine is administered in conjunction with additional vaccines or other medical treatments as below described.
- the vaccine is administered to at least one of a human, and a human associated animal.
- the vaccine may be administered as a preventative prophylactic to induce an immune response in a naive host resulting in immunity to subsequent MTV exposure, or may be administered to an exposed patient for the purposes of bolstering an immune response to an extant viral presence. In such instances, either viral particle count or other measures of viral presence and/or activity are decreased as a result of vaccine administration.
- Protease inhibitors are an example of one class of retroviral medications. As described above, MTV reproduction relies upon production and then cleavage of precursor proteins. In general, a protease inhibitor prevents cleavage of the viral precursor protein by inhibiting the action of the viral protease responsible for the cleavage. Thus, viral loads in a host are decreased as the virus fails to replicate. Accordingly, an embodiment of the invention results in the decrease of MTV loads in a patient accomplished through the administration of protease inhibitors.
- Example protease inhibitors can include at least one of: atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfmavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), and, darunavir/cobicistat (Prezcobix) either alone or in combination with another protease inhibitor.
- a method of treating a patient exposed to MTV may include: determining through an antibody or other test patient exposure status to MTV; then administering either a treatment dose or a maintenance dose of a protease inhibitor.
- the protease inhibitor may be administered in conjunction with an MTV vaccine of the like described above thus decreasing viral load in a patient.
- the patient may, instead, have a cancer diagnosis, or present other cancer-associated risk factors, without measurement of MTV levels or detection of MTV presence.
- the diagnosed cancer may, for example, be breast cancer or prostate cancer, or another viral-mediated cancer.
- the patient may be analyzed for one or more risk factors (e.g., familial history, work history, past cancer status, etc.). Patients deemed above a given risk threshold may be deemed“high risk” and provided with anti retroviral medications as above described.
- a treatment dosage is used as commonly understood in the art as one calculated to immediately or gradually (the terms“immediately” or“gradually” understood to be qualitative and relative, not quantitative) reduce a high viral load in a patient.
- patient exposure to MTV is determined through the use of an antibody titer test.
- the antibody test may detect antibodies to at least one of: gp52, plO, and pl4.
- a maintenance dosage is one calculated to sustain a low or non-detectable limit of viral particles.
- An initial treatment dosage may be decreased to a maintenance dosage.
- a treatment dosage with one or more primary protease inhibitors may be effected and then replaced with a maintenance dosage of one or more secondary protease inhibitors.
- maintenance dosages may be increased or decreased as demanded by either viral load measurements or treatment protocols.
- ritonavir may be provided to a patient as a maintenance dosage in the range of 50-440 mg per day, or atazanvir at 300-400 mg per day.
- ritonavir may be used with a range of 50-400 mg per day combined with another protease inhibitor at 100-400 mg per day.
- Protease inhibitors may also be used in combination with chemotherapy drugs to first treat a cancer (e.g., breast cancer or other viral-mediated cancer) and then used singly to prevent cancer recurrence.
- dosage ranges explicitly contemplate every integer or part dosage amount (e.g., 1, 1.1, 1.2, 1.3, etc.) within the range including the initial and end amounts within the range. It is recognized that while ranges may list start and end points manufacturing tolerances and the like may result in products above or below range within a specified tolerance.
- a method of treating MTV exposure in a patient can comprise: determining the integer or part dosage amount (e.g., 1, 1.1, 1.2, 1.3, etc.) within
- the protease inhibitor may be administered in conjunction with an MTV vaccine.
- the MTV vaccine may contain a transition protein.
- the transition protein may be plO.
- the method described above may further be modified wherein the administration of the protease inhibitor is performed at a first treatment dosage and a second maintenance dosage.
- an MTV vaccine may be administered during the treatment dosage administration.
- the MTV vaccine may be administered when switching to a maintenance dosage.
- the maintenance dosage is in the range of 50-200 mg of medication per day.
- the method described above may be further modified wherein the protease inhibitor is administered in conjunction with chemotherapeutic agents in a cancerous patient.
- the protease inhibitor dosage may be altered from a treatment dosage to a maintenance dosage or switched to a second protease inhibitor at a maintenance dosage upon either cessation of chemotherapy treatments or remission of cancer.
- the cancer may be breast cancer, prostate cancer or another viral-mediated cancer.
- the protease inhibitor is at least one of: atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfmavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), and, darunavir/cobicistat (Prezcobix).
- ritonavir is combined with at least one more protease inhibitor.
- the ritonavir is combined with at least one of: atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfmavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), and, darunavir/cobicistat (Prezcobix).
- the protease inhibitor is ritonavier provided as a maintenance dosage in the range of 50-440 mg per day, or atazanvir at 300-400 mg per day.
- ritonavir may be used with a range of 50-400 mg per day and combined with another protease inhibitor at 100-400 mg per day.
- a patient is first tested for the presence of
- the patient Upon discovery of evidence of MTV exposure, the patient is then administered an antiretroviral medication.
- the antiretroviral medication is a protease inhibitor.
- the protease inhibitor is administered at a first dosage level, corresponding to a treatment level, and then altered to a second or more dosage level corresponding to a maintenance level.
- the test for MTV is an antibody test.
- the antibody test relies on antibodies raised in response to at least one of: GP52, a transition protein, and pl4.
- the transition protein is plO.
- a patient with MTV exposure may first be treated with ritonavir at a dosage of 70 mg per day, concomitantly an MTV vaccine with an MTV transition protein is administered.
- the net effect results in an overall decrease in patient MTV viral particle loading and/or measured activity.
- a second maintenance dosage of antiretroviral medications may be started.
- the net effect of the combined treatment is to halt the spread of an MTV viral-mediated cancer resulting in remission and/or the prevention of relapse.
- a patient with a cancer diagnosis is administered an antiretroviral medication.
- the antiretroviral medication is a protease inhibitor.
- the cancer diagnosis is for breast cancer.
- the cancer diagnosis is for a viral-mediated cancer.
- the protease inhibitor is administered at a first dosage level, corresponding to a treatment level, and then altered to a second or more dosage level corresponding to a second or more maintenance level. The method described above may further be modified wherein the administration of the protease inhibitor is performed at a first treatment dosage and a second maintenance dosage.
- an MTV vaccine may be administered during the treatment dosage administration.
- the MTV vaccine may be administered when switching to a maintenance dosage.
- the maintenance dosage is in the range of 50-200 mg of medication per day.
- the MTV vaccine contains an MTV transition protein.
- the effective dose and method of administration of a particular embodiment of the instant invention may vary based on the individual patient and stage of any present diseases (e.g., breast cancer, HIV, other co-morbidities), as well as other factors known to those of skill in the art.
- Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
- the dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
- Pharmaceutical compositions that exhibit large therapeutic indices are preferred.
- the data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
- the dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
- the exact dosage is chosen by an individual physician in view of a patient to be treated. Dosage and administration are adjusted to provide sufficient levels of embodiments of the instant invention to maintain the desired effect (e.g., elimination or reduction of MTV particles or activity in a host). Additional factors that may be taken into account include the severity of any disease state, age, weight, and gender of the patient; diet, time and frequency of the administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Short acting pharmaceutical compositions are administered daily whereas long acting pharmaceutical compositions are administered every 2, 3 to 4 days, every week, or once every two weeks or more. Depending on half-life and clearance rate of the particular formulation, the pharmaceutical compositions of the instant invention may be administered once, twice, three, four, five, six, seven, eight, nine, ten or more times per day.
- Normal dosage amounts may vary from approximately 1 to 100,000 micrograms, up to a total dose of about 10 grams, depending upon the route of administration. Desirable dosages include 250 pg, 500 pg, 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, and 10 g ⁇
- the dosage of peptide agents described herein is one that provides sufficient peptide agent to attain a desirable effect, including stimulation of the immune system to produce antibodies, and/or disruption of the production of MTV viral particles.
- the dose of the peptide agent preferably produces a tissue or blood concentration of both about 1 to 800 mM.
- Preferable doses produces a tissue or blood concentration of greater than about 10 mM to about 500 mM.
- Preferable doses are, for example, the amount of peptide required to achieve a tissue or blood concentration or both of 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 220 mM, 240 mM, 250 mM, 260 mM, 280 mM, 300 mM, 320 mM, 340 mM, 360 mM, 380 mM, 400 mM, 420 mM, 440 mM, 460 mM
- a constant infusion of embodiments of the invention can be provided so as to maintain a stable concentration of the therapeutic agents (e.g., modified MTV peptides, MTV transition proteins, additional proteins or peptides co-administered, and other medicines such as retrovirals as herein described).
- the therapeutic agents e.g., modified MTV peptides, MTV transition proteins, additional proteins or peptides co-administered, and other medicines such as retrovirals as herein described).
- Protein N-myristoylation is a cotranslational lipidic modification specific to the alpha-amino group of an N-terminal glycine residue of many eukaryotic and viral proteins.
- NMT N-myristoyltransf erase
- attachment of a myristoyl group increases specific protein-protein interactions leading to subcellular localization of myristoylated proteins with their signaling partners.
- the birth of the field of myristoylation a little over three decades ago, has led to the understanding of the significance of protein myristoylation in regulating cellular signaling pathways in several biological processes especially in carcinogenesis and, more recently, immune function.
- the myristate moiety participates in protein subcellular localization by facilitating protein-membrane interactions as well as protein-protein interactions.
- Myristoylated proteins are crucial components of a wide variety of functions, which include many signaling pathways, oncogenesis or viral replication.
- NMT N-myristoyltransferase
- CoA myristoyl-coenzyme A
- Myristic acid is a hydrophobic moiety, and as the cell microenvironment is hydrophilic, the myristoylated protein is inserted into hydrophobic regions within the cell namely on: lipid rafts, the plasma membrane, endoplasmic reticulum (ER), Golgi apparatus, nuclear membrane, and mitochondria. Thus, depending on the subcellular localization of the myristoylated protein, it can regulate diverse cellular functions. Myristoylated proteins are adapted to performing biological functions in signal transduction, cellular transformation, and oncogenesis. Myristic acid is not an abundant fatty acid, it accounts for less than 1% of the total fatty acid in the cell, introducing another form of regulation.
- myristoylated proteins and/or peptide chains derived therefrom may further enhance the antigenic properties when used in combinations with further adjuvants.
- modified proteins and/or protein peptide chains may be myristoylated and used alone or in pharmaceutical compositions as described above to trigger or enhance an immune response leading to decreased or eliminated viral particle loads and/or activity.
- myristoylation may provide a means of anchoring an antigenic protein or peptide chain into cell membranes or carrier molecules enhancing their presentment to the immune system for an increased immune response resulting in either lasting immunity in a patient or decreased viral loading and/or activity.
- a his-tag, or polyhistidine tag is a string of histidine residues added at either the N or C terminus of a recombinant protein. There can be from four to ten residues in a string, although commonly there are six histidine residues — a hexahistidine tag. Some recombinant proteins are engineered to have two or more hexahistidine tags.
- transition metal ions are immobilized on a resin matrix using a chelating agent such as iminodiacetic acid.
- a chelating agent such as iminodiacetic acid.
- the most common ion for his-tag purification of a recombinant protein is Ni2+, though Co2+, Cu2+, and Zn2+ are also used.
- the his-tag has a high affinity for these metal ions and binds strongly to the IMAC column. Most other proteins in the lysate will not bind to the resin or bind only weakly.
- the use of a his-tag and IMAC can often provide relatively pure recombinant protein directly from a crude lysate.
- Imidazole competes with the his-tag for binding to the metal-charged resin and thus is used for elution of the protein from an IMAC column.
- a low concentration of imidazole is added to both binding and wash buffers to interfere with the weak binding of other proteins and to elute any proteins that weakly bind.
- His-tagged protein is then eluted with a higher concentration of imidazole. Proteins with different numbers of poly histidine tags elute differently from nickel -affinity resin.
- proteins with a single hexahistidine tag may elute from a Ni-NTA column at 75 mM of imidazole whereas proteins with two hexahistadine tags may require 100 mM imidazole solution to elute from the same column.
- Some example alternatives to His-tag purification commonly include: HQ-tag
- HN-tag alternating histidine and asparagine
- HAT-tag which is a peptide tag
- Embodiments of the present invention provide for isolated cDNA, DNA, RNA, and polypeptides derived from viral transition proteins including those from HMTV and MMTV and human associated animals. Accordingly an embodiment of the present invention provides for a recombinant cDNA plasmid (a vector) which comprises MTV DNA at least 90% identical to SEQ ID No: 2.
- the plasmid vector further comprises a heterologous promoter operably linked to the MTV sequence (i.e., joined in the proper reading frame so as to be capable of producing functional MTV RNA and/or protein in vivo and in vitro).
- the vector which comprises the MTV DNA
- the MTV DNA is modified to include an N-terminal glycine residue capable of myristoylation.
- an artificial cDNA encoding a transition protein sequence comprises: a promoter sequence; a first position methionine; a second position glycine; a portion of or all of the sequence of a transition protein; one or more purification tags; a stop codon; and, the appropriate promoters and coding sequences for one or more additional genes for co-expression.
- the additional genes encoded include: myristoyl-CoA:protein N-myristoyl- transferase (NMT).
- NMT protein N-myristoyl- transferase
- the additional genes may further include methionine aminopeptidase.
- myristoylated transition protein peptide chain is 90% or more homologous with the peptide encoded by SEQ ID No: 2. In still other embodiments the myristoylated transition protein peptide chain is 10 or more contiguous amino acids as found in SEQ ID No: 2 or an acceptably homologous sequence.
- an example of an artificial cDNA sequence containing MTV protein plO is provided at SEQ ID No: 3.
- the plO sequence is altered to include an additional N- terminal glycine residue after an added initial methionine residue in order to enable myristoylation of the produced peptide.
- the sequence further includes a hexahistidine tag sequence with a 3x Gly linker. The sequence is left open to reflect the possibility of adding additional sequences.
- promotion sequences can include TATA box / Pribnow box sequences.
- the cDNA is incorporated into a vector, such as a plasmid, which is then subsequently expressed in the expression systems noted above for peptide / protein production.
- the peptide chains, with or without myristoylation are then purified and then incorporated into an acceptable pharmaceutical preparation as above disclosed.
- a“linker” sequence e.g., gly-gly-gly or gly-ser-gly
- the his-tag may then be removed.
- a purified transition protein peptide chain alone or in combination with a myristol group is combined into a pharmaceutical preparation as above described and administered to a patient with confirmed MTV exposure or, displaying MTV risk factors, or with a concomitant cancer diagnosis (viral-mediated or otherwise) with a resulting decrease in MTV viral load or activity.
- the pharmacologically active compounds of this invention can be processed in accordance with conventional methods of galenic pharmacy to produce medicinal agents for administration to patients (e.g., mammals including humans).
- the peptides with, or without, modification can be incorporated into a pharmaceutical composition.
- manufacture of pharmaceuticals or therapeutic agents that deliver the peptides or a nucleic acid sequence encoding a peptide by several routes is an embodiment.
- DNA, RNA, and viral vectors having sequences that encoding a transition protein peptide with antigenic properties are contemplated.
- Nucleic acids encoding a desired transition protein peptide can be administered alone or in combination with a transition protein peptide resulting in lowered MTV viral particle counts or lowered measurements of MTV virus activity either via direct action or enhanced immune response.
- sequence explicitly contemplates DNA, cDNA, RNA and resulting peptide chains encoded thereby in both sense and antisense directions. To know one is to know the others via the standard rules of complementarity and codon encoding as exemplified in standardized DNA, RNA, and amino acid codon tables.
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