WO2011026111A1 - Distribution par voie orale d'un vaccin au gros intestin pour induire une immunité mucosale - Google Patents
Distribution par voie orale d'un vaccin au gros intestin pour induire une immunité mucosale Download PDFInfo
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- WO2011026111A1 WO2011026111A1 PCT/US2010/047338 US2010047338W WO2011026111A1 WO 2011026111 A1 WO2011026111 A1 WO 2011026111A1 US 2010047338 W US2010047338 W US 2010047338W WO 2011026111 A1 WO2011026111 A1 WO 2011026111A1
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Definitions
- This disclosure relates to oral drug delivery, specifically to oral delivery of controlled release nanoparticles encapsulating a vaccine to the large intestine to induce mucosal immunity, including a protective immune response.
- STDs Sexually transmitted diseases
- HCV Human Immunodeficiency Virus
- HPV Human Papillomavirus
- HSV Herpes Simplex Virus
- STDs have put a significant burden on the health care of many countries, especially in the developing world.
- Vaccination of high-risk individuals to develop their own immune protection is the most cost-effective way to control infections and prevent disease from spreading. Effective vaccination relies largely on a robust vaccine, including powerful immune adjuvants, and a proper administration route.
- Vaccination of humans via the intrarectal or intracolorectal route is considered impractical and invasive. Additionally, delivery through parenteral routes would not be expected to deliver any given vaccines, such as non-live organisms, antigens and adjuvants in form of protein or peptide, to the large intestine immune system.
- an oral vaccination system that allows site-specific delivery of a vaccine to the large intestine as well as an enhanced immune response induced by the vaccine once delivered to the target site.
- an immunogenic composition that promotes efficient particle uptake at the large intestinal mucosal surface and provides immune protection of rectal and vaginal mucosa.
- the composition utilizes a polymer to encapsulate a target immunogen, such as an antigen from a pathogen of interest and a pH-sensitive coating (such as EUDRAGIT®, EUDRAGIT is a registered trademark of Evonik Rohm GmbH, Pharma Polymers, Darmstadt, Germany) to protect the encapsulated particles from degradation and uptake prior to reaching the large intestine.
- An immunostimulatory agent such as a Toll-like receptor ligand, is also included within the immunogenic composition and encapsulated with the target antigen by the polymer to further enhance the immune response induced by the target immunogen.
- Methods are disclosed for treating and/or inhibiting an infection by a pathogen of interest in a subject.
- the methods include selecting a subject for treatment that has, or is at risk for developing, an infection by a pathogen of interest.
- the subject is administered a therapeutically effective amount of a disclosed immunogenic composition into the upper gastrointestinal tract (for example by oral, gastric or duodenal administration), wherein the target immunogen in the immunogenic composition comprises one or more antigens present in the pathogen of interest.
- Oral administration is particularly advantageous because of its noninvasive nature.
- the methods are methods of treating or inhibiting a sexually transmitted disease or a mucosal cancer.
- an immunogenic composition formulated for oral administration includes nanoparticles and a microparticle carrier encapsulating the multiple nanoparticles.
- the nanoparticles include a polymer core encapsulating a therapeutically effective amount of a target immunogen and a therapeutically effective amount of one or more immunostimulatory agents.
- the microparticle carrier encapsulating the multiple nanoparticles includes a pH-sensitive copolymer matrix that is insoluble in acidic media, but dissolves by salt formation above pH 6.5, thereby forming an immunogenic composition capable of eliciting an immune response in a subject in the intestine.
- FIG. IA is a schematic showing an exemplary oral vaccine delivery system.
- FIG. IB is a schematic showing an exemplary method of oral vaccine delivery to the large intestinal mucosa.
- Intraluminal pH and GI ingestion travel time are indicated (distance not to scale). Mouse total GI transit time is shorter, approximately 8 hours.
- Nanoparticles are coated with acid-resistant EUDRAGIT® to form microparticles, which help the nanoparticles bypass the stomach low pH.
- the microparticle coating begins to dissolve at the highest pH point (terminal small intestine) before entering the large intestine and is completely dissolved to release contents in the large intestine. Mucosal uptake of released nanoparticles allows site- specific, local vaccination in the large intestine.
- FIGS 2A-2D illustrate intrarectal (i.c.r.) delivered nanoparticles enter the large intestinal mucosa and orally delivered FS30D/PLGA nanoparticle-releasing microparticles selectively target the large intestinal mucosa for uptake.
- FIG. 2A is a dot plot of a flow cytometry analysis showing colorectal mucosal uptake of PLGA nanoparticles after i.c.r. delivery of PLGA/FITC-BSA nanoparticles. Cells were isolated from the colorectum 2 days after administration and measured for FITC- positive cells (p ⁇ 0.02 between PLGA/FITC-BSA and PBS treated; results representative of three independent studies).
- FIG. 2B is a density plot of a flow cytometry analysis showing induction of antigen-specific colorectal mucosal T cells after i.c.r. delivery of PLGA nanoparticles encapsulating PCLUS3-18IIB and MALP2+poly(I:C)+CpG vaccine (PLGA/PeptAg+TLRL) or PLGA nanoparticles without the vaccine.
- colorectal cells were isolated and measured for P18-I10 specific CD8 + T cells by tetramer staining (p ⁇ 0.01 between
- FIG. 2C is a bar graph showing gut mucosal uptake of PLGA particles after oral delivery of FS30D/PLGA or L100-55/PLGA. Cells were isolated from the small and large intestine at day 2 for measurement of FITC-positive cells (** p ⁇ 0.02 on white bar indicates the difference from small intestine and *** p ⁇ 0.001 on black bar indicates the difference from small intestine; results are representative of two independent studies).
- FIG. 2D is a series of representative dot plots of flow cytometry from studies tabulated in FIG. 2C.
- FIG. 3A is a graph illustrating of particle size distribution of PLGA/FITC- BSA nanoparticles and a digital image of a scanning electron microscopy (SEM) image of micrographs of nanometer- size poly-lactic-co-glycolic acid (PLGA)/FITC- BSA nanoparticles. Image taken at 50,000x magnification.
- SEM scanning electron microscopy
- FIG. 3B is a graph showing the results of tests of the dissolution of unencapsulated BSA compared to BSA-encapsulated PLGA nanoparticles.
- the dissolution of 100% powder (100 ⁇ g/ml) was tested using a USP dissolution bath in 10 mM PBS (pH 7.4) at a paddle speed of 6 rpm.
- FIGS. 4A-4D show orally delivered FS30D coated PLGA nanoparticle vaccine induces antigen- specific T cells in the large intestine, while LlOO- 55/PLG A/vaccine induces the T cells in the small intestine.
- FIG. 4A is a set of dot plots of flow cytometric data showing the activation of dendritic cells (DC) after incubation with supernatants from FS30D coated PLGA containing PCLUS3- 18IIIB+TLRL (FS30D/PLGA/PeptAg+TLRL), antigen peptide without TLRL (FS30D/PLGA/PeptAg), or only vaccine (PeptAg+TLRL) dissolved in PBS at pH 7.4 for 16 hours.
- DC dendritic cells
- Intracellular IL- 12 was measured by flow cytometry, p ⁇ 0.01 between FS30D/PLGA/PeptAg+TLRL and
- FIGS. 4B-4D are density plots of flow cytometric data and a bar graph showing induction of T cell responses after oral delivery of FS30D/ or L100-55/PLGA/PeptAg+TLRL.
- Oral administration to BALB/c mice was conducted twice with a 2-week interval. Tetramer positive cells in the colorectum (FIGS. 4B and 4C) or upper part of the small intestine (FIG. 4D) were measured three weeks after the second immunization. The i.c.r.
- FIG. 4C is representative of two independent studies and FIG. 4B is a representative flow pattern from FIG. 4C.
- FIG. 4D ap value less ⁇ 0.001 for L100-55 was observed as compared to the other groups.
- FIGS. 5A and 5B are bar graphs showing orally delivered FS30D coated PLGA nanoparticle peptide vaccine confers T-cell mediated resistance to virus infection in the rectal (FIG. 5A) or vaginal (FIG. 5B) tract.
- FS30D/ or LlOO- 55/PLG A/Pep tAg+TLRL was given orally to mice twice with a two-week interval, followed by i.c.r. (FIG. 5A) or i.vag. (FIG. 5B) challenge with 2xlO 7 or IxIO 7 PFU of vPE16, respectively, three weeks after the last immunization.
- FIGS. 6A and 6B illustrate orally delivered FS30D coated PLGA nanoparticle protein vaccine confers antibody-mediated resistance to virus infection in the rectal or vaginal tract.
- FS30D coated PLGA containing antigen proteins A33 and Ll and TLR ligands (ProtAg+TLRL) were administered orally with a two-week interval.
- FIG 6A is a set of bar graphs illustrating serum and local IgA ⁇ top) and IgG ⁇ bottom) antibodies against both A33 and Ll (together) measured at two weeks after the last immunization.
- Both FS30D/PLGA/ProtAg+TLRL p.o. and
- FIG. 6B is a set of graphs illustrating the disease course of the mice after challenge with WR by the i.c.r. (4xlO 7 PFU) or i.vag. (IxIO 7 PFU) route three weeks after the last immunization. ** p ⁇ 0.02, *** p ⁇ 0.001 indicate the differences between the FS30D/PLGA/ProtAg+TLRL and unimmunized groups in weight loss. ⁇ , 75% mortality; % 50% mortality.
- FIG. 7A is a set of dot plots of flow cytometric data showing colorectal mucosal uptake of PLGA nanoparticles administered i.c.r.
- Two days after administration of PLGA/FITC-BSA nanoparticles cells were isolated from the lamina basement and gated for all cells ⁇ each left panel) or FITC + cells ⁇ each right panel) from untreated mice ⁇ left group) or mice receiving particles ⁇ right group) after staining for CDlIb, CDlIc, and B220. Numbers for each region are the percentage of all cells (including FITC + and FITC " ).
- FIG. 7B is a transmission electron microscopy (TEM) image of intracellular
- PLGA nanoparticles after i.c.r. delivery of PLGA nanoparticles (left, 2,80Ox; right, 6,40Ox).
- ER endoplasmic reticulum; N, nucleus; n, nucleolus; NM, nucleus membrane; PM, plasma membrane.
- FIGS. 8A-8C illustrate uptake of PLGA nanoparticles by mouse bone marrow derived dendritic cells and colorectal mucosal cells.
- FIG. 8A is a set of histograms of flow cytometry measuring fluorescence expression. Bone marrow derived dendritic cells (DCs) were incubated with PLGA/FITC-BSA at different doses for 24 hours before the assay.
- FIG. 8B is a set of digital images of light microscopy (2Ox) to locate cells ⁇ left) and fluorescent microscopy to visualize FTIC- containing particles ⁇ right, photo enhanced).
- FIG. 8Ox light microscopy
- FIGS. 9A and 9B illustrate EUDRAGIT® FS30D size distribution and dissolution.
- FIG 9A is a tracing illustrating particle size before (top) and after 1 hour (bottom) incubation with PBS at pH 7.4.
- FIG. 9B is a TEM image of FS30D released PLGA. FS30D/PLGA were incubated for 1.5 hours in PBS at pH 7.4 (4,60Ox), and supernatants were concentrated for TEM (left). The particle diameter was measured using ImageJ. The geometric mean and size range are shown in the bar graph (right).
- FIGS. 1OA and 1OB illustrate FS30D microparticles release PLGA nanoparticles at a high pH.
- FIG. 1OA is a graph illustrating PLGA/FITC-BSA nanoparticle release from FS30D microparticles determined by UV absorption at 494 nm.
- FIG. 1OB is a fluorescence image of PLGA/FITC-BSA released from FS30D after 2 hours in PBS at pH 7.4 (150x).
- FIGS. HA and HB illustrate a combination of TLR ligands synergistically activate B cells and effectively induces antibody responses.
- FIG. HA is a bar graph showing expression of CD69 by B cells after 20 hours of stimulation with bone marrow-derived DCs pretreated with TLR ligands in combination (MALP- 2+poly(I:C)+CpG).
- FIG. HB is a bar graph illustrating induction of serum IgG responses against vaccinia proteins A33 and Ll after i.c.r. immunization twice (two- week interval) with recombinant A33 +Ll together and the triple TLR ligands formulated in DOTAP.
- Sera were collected two weeks after the last immunization and measured for antigen-specific IgG by an ELISA assay. ** p ⁇ 0.01 and *** p ⁇ 0.001 indicate difference from each of the other groups.
- SEQ ID NO: 1 is the amino acid sequence of PCLUS3-18IIIB peptide.
- SEQ ID NO: 2 is the amino acid sequence of MALP-2S peptide.
- SEQ ID NO: 3 is the amino acid sequence of P18-I10 peptide.
- SEQ ID NO: 4 is the amino acid sequence of OVA 2 57- 2 6 4 peptide. DETAILED DESCRIPTION OF SEVERAL EMBODIMENTS
- Adjuvant A vehicle used to enhance antigenicity; such as a suspension of minerals (alum, aluminum hydroxide, aluminum phosphate) on which antigen is adsorbed; or water-in-oil emulsion in which antigen solution is emulsified in oil (MF-59, Freund's incomplete adjuvant), sometimes with the inclusion of killed mycobacteria (Freund's complete adjuvant) to further enhance antigenicity (inhibits degradation of antigen and/or causes influx of macrophages).
- Adjuvants also include immunostimulatory molecules, such as cytokines, costimulatory molecules, and for example, immunostimulatory DNA or RNA molecules.
- Administration The introduction of a composition into a subject by a chosen route.
- the chosen route is oral delivery
- the composition is administered by introducing the composition into the mouth of the subject.
- the delivery can be anywhere from the duodenum, for example orally, intraesophageal, gastric (for example through a gastric tube) or even duodenally (for example through a duodenal feeding tube).
- Antibody A polypeptide substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof, which specifically binds and recognizes an analyte (antigen) such as an HIV envelope polypeptide or an antigenic fragment of an HIV envelope polypeptide.
- Immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
- Antibodies exist, for example as intact immunoglobulins and as a number of well characterized fragments produced by digestion with various peptidases. For instance, Fabs, Fvs, and single-chain Fvs (SCFvs) that bind to an HIV envelope polypeptide or fragments of an HIV envelope polypeptide would be HIV- specific binding agents.
- a scFv protein is a fusion protein in which a light chain variable region of an immunoglobulins and as a number of well characterized fragments produced by digestion with various peptidases.
- Fabs, Fvs, and single-chain Fvs (SCFvs) that bind to an HIV envelope polypeptide or fragments of an HIV envelope polypeptide would be HIV
- immunoglobulin and a heavy chain variable region of an immunoglobulin are bound by a linker, while in dsFvs, the chains have been mutated to introduce a disulfide bond to stabilize the association of the chains.
- the term also includes genetically engineered forms such as chimeric antibodies (such as humanized murine antibodies), heteroconjugate antibodies such as bispecific antibodies). See also, Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, IL); Kuby, J., Immunology, 3 rd Ed., W.H. Freeman & Co., New York, 1997.
- a naturally occurring immunoglobulin has heavy (H) chains and light (L) chains interconnected by disulfide bonds.
- H heavy chain
- L light chain
- ⁇ lambda
- K kappa
- IgM immunoglobulin heavy chain classes
- Each heavy and light chain contains a constant region and a variable region
- Light and heavy chain variable regions contain a "framework" region interrupted by three hypervariable regions, also called “complementarity-determining regions” or "CDRs.”
- CDRs complementarity-determining regions
- the extent of the framework region and CDRs have been defined (see, Kabat et al. , Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991, which is hereby incorporated by reference).
- the Kabat database is now maintained online.
- the sequences of the framework regions of different light or heavy chains are relatively conserved within a species.
- the framework region of an antibody that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three-dimensional space.
- Antigen A compound, composition, or substance that can stimulate the production of antibodies or a T cell response in an animal, including compositions that are injected or absorbed into an animal. Examples include, but are not limited to, peptides, lipids, polysaccharides, and nucleic acids containing antigenic determinants, such as those recognized by an immune cell. In some examples, antigens include tumor antigens which are antigens expressed on a specific type of tumor cells.
- antigens include peptides derived from a pathogen of interest.
- pathogens include bacteria, fungi, viruses and parasites.
- An antigen reacts with the products of specific humoral or cellular immunity, including those induced by heterologous immunogens.
- the term is used interchangeably with the term "immunogen.”
- the term "antigen" includes all related antigenic epitopes.
- an “antigenic polypeptide” is a polypeptide to which an immune response, such as a T cell response or an antibody response, can be stimulated.
- An “antigenic polypeptide” includes a polypeptide, such as a polypeptide to an HIV envelope protein (e.g. , gpl20 or gp41) or a portion thereof that is capable of provoking an immune response in a mammal, such as a mammal with or without a disease, such as an HIV infection.
- Administration of an antigenic polypeptide that provokes an immune response preferably leads to protective immunity, such as protective immunity against a disease or condition (e.g., protective immunity against HIV).
- Epitopes refers to a site on an antigen to which B and/or T cells respond.
- T cells respond to the epitope when the epitope is presented in conjunction with an MHC molecule.
- Epitopes can be formed both from contiguous amino acids (linear) or noncontiguous amino acids juxtaposed by tertiary folding of an antigenic polypeptide (conformational). Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents.
- a B-cell epitope will include at least about 5 amino acids but can be as small as 3-4 amino acids.
- a T-cell epitope such as a CTL epitope, will include at least about 7-9 amino acids, and a helper T-cell epitope at least about 12-20 amino acids. Normally, an epitope will include between about 5 and 15 amino acids, such as, 9, 10, 12 or 15 amino acids. The amino acids are in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and multi-dimensional nuclear magnetic resonance spectroscopy.
- antigen denotes both subunit antigens, (for example, antigens which are separate and discrete from a whole organism with which the antigen is associated in nature), as well as killed, attenuated or inactivated bacteria, viruses, fungi, parasites or other microbes.
- Antibodies such as anti-idiotype antibodies, or fragments thereof, and synthetic peptide mimotopes, which can mimic an antigen or antigenic determinant, are also captured under the definition of antigen as used herein.
- an oligonucleotide or polynucleotide which expresses an antigen or antigenic determinant in vivo, such as in gene therapy and DNA immunization applications, is also included in the definition of antigen herein.
- an "antigen,” when referring to a protein or fragment of a protein, includes a protein with modifications, such as deletions, additions and substitutions (generally conservative in nature) to the native sequence, so long as the protein maintains the ability to elicit an immunological response, as defined herein. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the antigens.
- Bacterial pathogen A bacteria that causes disease (pathogenic bacteria).
- pathogenic bacteria for which infections that can be treated in accordance with the disclosed methods and compositions include without limitation any one or more of (or any combination of) Acinetobacter baumanii, Actinobacillus sp., Actinomycetes, Actinomyces sp. (such as Actinomyces israelii and Actinomyces naeslundii), Aeromonas sp. (such as Aeromonas hydrophila, Aeromonas veronii biovar sobria (Aeromonas sobria), and Aeromonas caviae), Anaplasma
- Bacillus sp. such as Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Bacillus thuringiensis, and Bacillus ste ar other mophilus
- Bacteroides sp. such as Bacteroides fragilis
- Bartonella sp. such as Bartonella bacilliformis and Bartonella henselae
- Bordetella sp. such as Bordetella pertussis, Bordetella parapertussis, and Bordetella bronchiseptica
- Borrelia sp. such as Borrelia recurrentis, and Borrelia burgdorferi
- Brucella sp. such as Brucella abortus, Brucella canis, Brucella melintensis and Brucella suis
- Burkholderia sp. such as Burkholderia pseudomallei and Burkholderia cepacia
- Campylobacter sp. such as Campylobacter jejuni, Campylobacter coli,
- Cardiobacterium hominis Chlamydia trachomatis, Chlamydophila pneumoniae , Chlamydophila psittaci, Citrobacter sp. Coxiella burnetii, Corynebacterium sp. (such as, Corynebacterium diphtheriae, Corynebacterium jeikeum and
- Clostridium sp. such as Clostridium perfringens, Clostridium difficile, Clostridium botulinum and Clostridium tetan ⁇
- Eikenella corrodens Enterobacter sp.
- Enterobacter aerogenes Enterobacter agglomerans
- Enterobacter cloacae and Escherichia coli including opportunistic Escherichia coli, such as enterotoxigenic E. coli, enteroinvasive E. coli, enteropathogenic E. coli, enter ohemorrhagic E. coli, enteroaggregative E. coli and uropathogenic E. coli) Enterococcus sp. (such as Enterococcus faecalis and Enterococcus faecium) Ehrlichia sp.
- opportunistic Escherichia coli such as enterotoxigenic E. coli, enteroinvasive E. coli, enteropathogenic E. coli, enter ohemorrhagic E. coli, enteroaggregative E. coli and uropathogenic E. coli
- Haemophilus influenzae Haemophilus ducreyi
- Haemophilus aegyptius Haemophilus aegyptius
- Haemophilus parainfluenzae Haemophilus haemolyticus and Haemophilus parahaemolyticus
- Helicobacter sp. such as Helicobacter pylori, Helicobacter cinaedi and Helicobacter fennelliae
- Kingella kingii Klebsiella sp.
- Klebsiella pneumoniae Klebsiella granulomatis and Klebsiella oxytoca
- Lactobacillus sp. Listeria monocytogenes, Leptospira interrogans, Legionella pneumophila, Leptospira interrogans, Peptostreptococcus sp., Moraxella catarrhalis, Morganella sp. , Mobiluncus sp. , Micrococcus sp. , Mycobacterium sp. (such as Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium intracellular, Mycobacterium avium, Mycobacterium bovis, and Mycobacterium marinum), Mycoplasm sp.
- Nocardia sp. such as Nocardia asteroides, Nocardia cyriacigeorgica and Nocardia brasiliensis
- Neisseria sp. such as Neisseria gonorrhoeae and Neisseria meningitidis
- Pasteurella multocida Plesiomonas shigelloides.
- Prevotella sp. Porphyromonas sp., Prevotella melaninogenica, Proteus sp. (such as Proteus vulgaris and Proteus mirabilis), Providencia sp.
- Rhodococcus sp. (such as Providencia alcalifaciens, Providencia rettgeri and Providencia stuartii), Pseudomonas aeruginosa, Propionibacterium acnes, Rhodococcus equi, Rickettsia sp. (such as Rickettsia rickettsii, Rickettsia akari and Rickettsia prowazekii, Orientia tsutsugamushi (formerly: Rickettsia tsutsugamushi) and Rickettsia typhi), Rhodococcus sp. , Serratia marcescens, Stenotrophomonas maltophilia, Salmonella sp. (such as Salmonella enterica, Salmonella typhi, Salmonella paratyphi,
- Salmonella enteritidis Salmonella cholerasuis and Salmonella typhimurium
- Serratia sp. such as Serratia marcesans and Serratia liquifaciens
- Shigella sp. such as Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonne ⁇
- Staphylococcus sp. such as Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hemolyticus, Staphylococcus saprophyticus
- Streptococcus sp. such as Streptococcus pneumoniae (for example chloramphenicol-resistant serotype 4 Streptococcus pneumoniae , spectinomycin-resistant serotype 6B
- Streptococcus pneumoniae streptomycin-resistant serotype 9V Streptococcus pneumoniae, erythromycin-resistant serotype 14 Streptococcus pneumoniae, optochin-resistant serotype 14 Streptococcus pneumoniae , rifampicin-resistant serotype 18C Streptococcus pneumoniae , tetracycline-resistant serotype 19F Streptococcus pneumoniae, penicillin-resistant serotype 19F Streptococcus pneumoniae, and trimethoprim-resistant serotype 23F Streptococcus pneumoniae, chloramphenicol-resistant serotype 4 Streptococcus pneumoniae , spectinomycin- resistant serotype 6B Streptococcus pneumoniae , streptomycin-resistant serotype 9V Streptococcus pneumoniae , optochin-resistant serotype 14 Streptococcus pneumoniae, rifampicin-resistant serotype 18C Streptococcus pneumoniae
- Streptococcus pyogenes Group B streptococci, Streptococcus agalactiae, Group C streptococci, Streptococcus anginosus, Streptococcus equismilis, Group D streptococci, Streptococcus bovis, Group F streptococci, and Streptococcus anginosus Group G streptococci), Spirillum minus, Streptobacillus moniliformi, Treponema sp.
- Vibrio vulnificus Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio alginolyticus, Vibrio mimicus, Vibrio hollisae, Vibrio fluvialis, Vibrio metchnikovii, Vibrio damsela and Vibrio fur nisi ⁇ ), Yersinia sp. (such asYersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis) and Xanthomonas maltophilia among others.
- Yersinia sp. such asYersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis
- Xanthomonas maltophilia among others.
- Biodegradable polymer Polymers that degrade fully (e.g., down to monomelic species) under physiological or endosomal conditions.
- the polymers and polymer biodegradation byproducts are biocompatible.
- Biodegradable polymers are not necessarily hydrolytically degradable and may require enzymatic action to fully degrade.
- the mode of polymerization for these biodegradable polymers can be any, including random, block or
- Possible biodegradable polymers include aliphatic polyesters, such as, homopolymers or copolymers synthesized from one or more kinds of ⁇ - hydroxycarboxylic acids (such as, glycolic acid, lactic acid, 2-hydroxybutyric acid, and like compounds), hydroxydicarboxylic acids (such as, malic acid and like compounds), and hydroxytricarboxylic acids (e.g., citric acid and like compounds), or mixtures thereof.
- exemplary aliphatic polyesters include copolymers synthesized from two or more kinds of the ⁇ -hydroxycarboxylic acids. Such copolymers can be used as mixtures with, for example, polyethylene glycols (PEGs).
- the ⁇ -hydroxycarboxylic acids are chiral compounds, they can D-, L- and D-, or L-configuration.
- the ratio of the D-/L-configuration (mol %) is in the range of about 75/25 to about 25/75.
- a hydroxycarboxylic acid includes a D-/L-configuration (mol %) ratio in the range of about 60/40 to about 30/70, including about 50/50 to about 40/60.
- An example of the above mentioned ⁇ -hydroxycarboxylic acid polymer is a lactic acid polymer (hereinafter sometimes referred to as "polylactic acid").
- the ⁇ - hydroxycarboxylic acid copolymer includes copolymers of glycolic acid with the other ⁇ -hydroxycarboxylic acids such as lactic acid and 2-hydroxybutyric acid.
- Exemplary ⁇ -hydroxycarboxylic acid copolymers included lactic acid-glycolic acid copolymer and 2-hydroxybutyric acid-glycolic acid copolymer.
- Another ⁇ - hydroxycarboxylic acid copolymer is a lactic acid-glycolic acid copolymer.
- the polylactic acid has a weight average molecular weight of about 1,000 to about 100,000, such as a polylactic acid having the weight average molecular weight of about 2,000 to about 80,000. Particularly suitable is a polylactic acid having the weight average molecular weight of about 3,000 to about 60,000.
- the dispersity (weight average molecular weight/number average molecular weight) of polylactic acid is in the range of about 0.2 to about 4.0, and such as in the range of about 0.5 to about 3.5.
- Cancer A class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood).
- the "pathology" of cancer includes, without limitation, abnormal or uncontrollable cell growth, metastasis, interference with the normal functioning of neighboring cells, release of cytokines or other secretory products at abnormal levels, suppression or aggravation of inflammatory or immunological response, neoplasia, premalignancy, malignancy, invasion of surrounding or distant tissues or organs, such as lymph nodes, etc.
- Methodastatic disease refers to cancer cells that have left the original tumor site and migrate to other parts of the body, for example via the bloodstream or lymph system.
- “Mucosal cancer” refers to cancer cells that are present within a mucosal surface, examples include, but are not limited to, colonic or cervical cancer.
- Chemotherapy; chemotherapeutic agents any chemical agent with therapeutic usefulness in the treatment of diseases characterized by abnormal cell growth. Such diseases include tumors, neoplasms, and cancer as well as diseases characterized by hyperplastic growth such as psoriasis.
- a chemotherapeutic agent is an agent of use in treating neoplasms such as solid tumors.
- a chemotherapeutic agent is radioactive molecule.
- chemotherapeutic agent of use e.g., see Slapak and Kufe, Principles of Cancer Therapy, Chapter 86 in
- CD4 Cluster of Differentiation 4
- the known sequence of the CD4 precursor has a hydrophobic signal peptide, an extracellular region of approximately 370 amino acids, a highly hydrophobic stretch with significant identity to the membrane-spanning domain of the class II
- CD4 includes polypeptide molecules that are derived from CD4 include fragments of CD4, generated either by chemical (for example enzymatic) digestion or genetic engineering means. Such a fragment may be one or more entire CD4 protein domains.
- the extracellular domain of CD4 consists of four contiguous immunoglobulin- like regions (Dl, D2, D3, and D4, see Sakihama et al., Proc. Natl. Acad. ScL 92:6444, 1995; U.S. Patent No. 6,117,655), and amino acids 1 to 183 have been shown to be involved in gpl20 binding.
- a binding molecule or binding domain derived from CD4 would comprise a sufficient portion of the CD4 protein to mediate specific and functional interaction between the binding fragment and a native or viral binding site of CD4.
- One such binding fragment includes both the Dl and D2 extracellular domains of CD4 (D1D2 is also a fragment of soluble CD4 or sCD4 which is comprised of Dl D2 D3 and D4), although smaller fragments may also provide specific and functional CD4-like binding.
- the gpl20- binding site has been mapped to Dl of CD4.
- CD4 polypeptides also include "CD4-derived molecules" which
- analogs non-protein organic molecules
- derivatives chemically functionalized protein molecules obtained starting with the disclosed protein sequences
- mimetics three-dimensionally similar chemicals
- CD8 A transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR). Like the TCR, CD8 binds to a major histocompatibility complex (MHC) molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene. In humans, both genes are located on chromosome 2 in position 2pl2.
- MHC major histocompatibility complex
- the CD8 co-receptor is predominantly expressed on the surface of cytotoxic T cells, but can also be found on natural killer cells.
- a CD8+ T cells is a cytotoxic T lymphocytes.
- a CD8 cell is a suppressor T cell.
- CD8 forms a dimer, consisting of a pair of CD8 chains.
- the extracellular IgV-like domain of CD8- ⁇ interacts with to the 01 3 portion of the Class I MHC molecule. This affinity keeps the T cell receptor of the cytotoxic T cell and the target cell bound closely together during antigen- specific activation.
- Coating As used herein "coating”, “coatings”, “coated” and “coat” are forms of the same term defining material and process for making a material where a first substance or substrate surface is at least partially covered or associated with a second substance. Both the first and second substance are not required to be different. Thus, a composition composed of a first substance may be "coated” with a second substance via a linking agent that is a third substance. As used herein, the “coating” need not be complete or cover the entire surface of the first substance to be “coated.” The “coating” may be complete as well (e.g., approximately covering the entire first substance). There can be multiple coatings and multiple substances within each coating. The coating may vary in thickness or the coating thickness may be substantially uniform.
- compositions of coated particles are disclosed in U.S. Patent No. 6,406,745 (Talton, 2000) which is hereby incorporated by reference in its entirety.
- Coatings contemplated in accordance with the present disclosure include, but are not limited to, medicated coatings, drug-eluting coatings, drugs or other compounds, pharmaceutically acceptable carriers and combinations thereof, or any other organic, inorganic or organic/inorganic hybrid materials.
- a coating is an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid, such as EUDRAGIT® (e.g., EUDRAGIT® FS 30 D or
- a coating is a copolymer that is insoluble in acidic media, but dissolves by salt formation above pH 6.5, such as above pH 7.0.
- a coating is a hydrophilic or hydrophobic polymer, such as those containing carboxylic groups, including polyacrylic acid.
- a coating includes one or more polyanhydride, polyhydroxy acid, or polyesters, such as polylactides,
- a coating includes one or more bioerodible polyhydroxy acids and copolymers thereof, such as polylactic acid, polyglycolic acid, polyhydroxy-butyric acid, polyhydroxy valeric acid, polycaprolactone, polylactide-co-caprolactone, and polylactide-co-glycolide.
- a coating is a polymer containing labile bonds, such as polyanhydrides and polyorthoesters.
- a coating is one or more natural polymers, synthetic polymers or combinations thereof.
- Representative natural polymers include proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and polysaccharides such as dextrans, polyhyaluronic acid and alginic acid.
- Representative synthetic polymers include polyphosphazenes, polyamides, polycarbonates, polyacrylamides, polysiloxanes, polyurethanes and copolymers thereof. Celluloses also can be used. As defined herein the term "celluloses" includes naturally occurring and synthetic celluloses, such as alkyl celluloses, cellulose ethers, cellulose esters, hydroxyalkyl celluloses and nitrocelluloses.
- Exemplary celluloses include ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate and cellulose sulfate sodium salt.
- a coating is one or more polymers of acrylic and methacrylic acids or esters and/or copolymers thereof.
- Acrylic and methacrylic acids or esters include polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate, and
- a coating is one or more polyalkylenes, such as polyethylene and polypropylene; polyarylalkylenes, such as polystyrene;
- a coating is one or more polyvinyl polymers, including polyvinyl alcohols, polyvinyl ethers, polyvinyl esters and polyvinyl halides.
- a coating includes one or more polyvinyl polymers including polyvinyl acetate, polyvinyl phenol, polyvinylpyrrolidone or a
- a coating is one or more water soluble or water insoluble polymers.
- suitable water soluble polymers include polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyethylene glycol, copolymers of acrylic and methacrylic acid esters, and mixtures thereof.
- Suitable water insoluble polymers include ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or -higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate,
- a water insoluble polymer and a water-soluble polymer are used together, such as in a mixture.
- Such mixtures are useful in controlled drug release formulations, wherein the release rate can be controlled by varying the ratio of water-soluble polymer to water insoluble polymer.
- Polymers that alter viscosity as a function of temperature or shear or other physical forces can also be used as a coating.
- Polyoxyalkylene polymers and copolymers such as polyethylene oxide -polypropylene oxide (PEO-PPO), known also as Poloxamer, or polyethylene oxide)-poly(butylene oxide) (PEO-PBO) copolymers, and copolymers and blends of these polymers with polymers such as polyalpha-hydroxy acids, including but not limited to lactic, glycolic and hydroxybutyic acids, polycaprolactones, and polyvalerolactones, can be synthesized or commercially obtained (e.g., polyoxyalkylene copolymers are commercially available from BASF Wyandotte Corporation (Wyandotte, MI)).
- these materials are applied as viscous solutions at room temperature or lower which solidify at the higher body temperature.
- Other materials with similar properties known to one of ordinary skill in the art, including, but not limited to hydroxypropyl cellulose, purified xanthum and guar gums can also be used as coatings.
- EUDRAGIT ® polymers sold by Rohm America, Inc.
- EUDRAGIT ® polymers can be selected having various permeability and water solubility, which properties can be pH dependent or pH independent.
- EUDRAGIT ® RL and EUDRAGIT ® RS are acrylic resins including copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, which are present as salts and give rise to the permeability of the lacquer films; EUDRAGIT ® RL is freely permeable and EUDRAGIT RS is slightly permeable, independent of pH.
- EUDRAGIT ® L is pH dependent.
- EUDRAGIT ® L is an anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester. It is insoluble in acids and pure water, but becomes increasingly soluble in a neutral to weakly alkaline solution by forming salts with alkalis.
- a coating is a matrix, such that particles (for example nanoparticles) are encapsulated by the matrix.
- Colon cancer Colorectal cancer, also called large bowel cancer, includes cancerous growths in the colon, rectum and appendix. With 655,000 deaths worldwide per year, it is the third most common form of cancer and the second leading cause of cancer-related death in the Western world.
- the first symptoms of colon cancer are usually vague, such as bleeding, weight loss, and fatigue (tiredness).
- Local (bowel) symptoms are rare until the tumor has grown to a large size. Generally, the nearer the tumor is to the anus, the more bowel symptoms there will be.
- Degenerate variant and conservative variant A polynucleotide encoding a polypeptide or an antibody that includes a sequence that is degenerate as a result of the genetic code.
- examples include a polynucleotide encoding an HIV envelope polypeptide or an antibody that binds an HIV envelope polypeptide, such as gp41 or gpl20, which includes a sequence that is degenerate as a result of the genetic code.
- nucleotide sequences are included as long as the amino acid sequence of the specific polypeptide (such as a gp41 or gpl20 polypeptide) or antibody that binds the specific polypeptide encoded by the nucleotide sequence is unchanged.
- the codons CGU, CGC, CGA, CGG, AGA, and AGG all encode the amino acid arginine.
- the codon can be altered to any of the corresponding codons described without altering the encoded protein.
- Such nucleic acid variations are "silent variations," which are one species of conservative variations. Each nucleic acid sequence herein that encodes a polypeptide also describes every possible silent variation.
- each codon in a nucleic acid can be modified to yield a functionally identical molecule by standard techniques. Accordingly, each "silent variation" of a nucleic acid which encodes a polypeptide is implicit in each described sequence.
- substitutions, deletions or additions which alter, add or delete a single amino acid or a small percentage of amino acids (for instance less than 5%, in some embodiments less than 1%) in an encoded sequence are conservative variations where the alterations result in the substitution of an amino acid with a chemically similar amino acid.
- Epitope An antigenic determinant. These are particular chemical groups or peptide sequences on a molecule that are antigenic, such that they elicit a specific immune response.
- An antibody binds a particular antigenic epitope, such as an epitope of an HIV polypeptide, such as a gp41 polypeptide or a gpl20 polypeptide.
- Proteins may be expressed and remain intracellular, become a component of the cell surface membrane, or be secreted into the extracellular matrix or medium.
- Expression Control Sequences Nucleic acid sequences that regulate the expression of a heterologous nucleic acid sequence to which it is operatively linked. Expression control sequences are operatively linked to a nucleic acid sequence when the expression control sequences control and regulate the transcription and, as appropriate, translation of the nucleic acid sequence.
- expression control sequences can include appropriate promoters, enhancers, transcription terminators, a start codon (ATG) in front of a protein-encoding gene, splicing signal for introns, maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons.
- control sequences is intended to include, at a minimum, components whose presence can influence expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences. Expression control sequences can include a promoter.
- a promoter is a minimal sequence sufficient to direct transcription. Also included are those promoter elements which are sufficient to render promoter- dependent gene expression controllable for cell-type specific, tissue-specific, or inducible by external signals or agents; such elements may be located in the 5' or 3' regions of the gene. Both constitutive and inducible promoters are included (see for example, Bitter et al, Methods in Enzymology 153:516-544, 1987). For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage lambda, plac, ptrp, ptac (ptrp-lac hybrid promoter) and the like may be used.
- promoters derived from the genome of mammalian cells such as metallothionein promoter or from mammalian viruses (such as the retrovirus long terminal repeat; the adenovirus late promoter; the vaccinia virus 7.5 K promoter) can be used.
- mammalian viruses such as the retrovirus long terminal repeat; the adenovirus late promoter; the vaccinia virus 7.5 K promoter
- Promoters produced by recombinant DNA or synthetic techniques may also be used to provide for transcription of the nucleic acid sequences.
- a polynucleotide can be inserted into an expression vector that contains a promoter sequence which facilitates the efficient transcription of the inserted genetic sequence of the host.
- the expression vector typically contains an origin of replication, a promoter, as well as specific nucleic acid sequences that allow phenotypic selection of the transformed cells.
- Fungal pathogen A fungus that causes disease.
- fungal pathogens for which infections that can be treated in accordance with the disclosed methods and compositions include without limitation any one or more of (or any combination of) Trichophyton rubrum, T. mentagrophytes, Epidermophyton floccosum, Microsporum canis, Pityrosporum orbiculare (Malassezia furfur), Candida sp. (such as Candida albicans), Aspergillus sp. (such as Aspergillus fumigatus, Aspergillus flavus and Aspergillus clavatus), Cryptococcus sp. (such as Cryptococcus neoformans, Cryptococcus gattii, Cryptococcus laurentii and
- Cryptococcus albidus Histoplasma sp. (such as Histoplasma capsulatum), Pneumocystis sp. (such as Pneumocystis jirov ecu), and Stachybotrys (such as Stachybotrys chartarum).
- Histoplasma sp. such as Histoplasma capsulatum
- Pneumocystis sp. such as Pneumocystis jirov ecu
- Stachybotrys such as Stachybotrys chartarum.
- Glycoprotein 41 An HIV-I envelope glycoprotein that mediates receptor binding and HIV entry into a cell.
- Gp41 includes a MPR and a
- Gp41 is immunogenic and induces a variety of neutralizing antibodies, such as neutralizing antibodies directed to 2F5, 4E10 and Z13. These three gp41 neutralizing antibodies recognize the MPR of the HIV-I gp41 glycoprotein.
- Glycoprotein 120 (gpl20): An envelope protein from Human
- the envelope protein is initially synthesized as a longer precursor protein of 845-870 amino acids in size, designated gpl60.
- Gpl60 forms a homotrimer and undergoes glycosylation within the Golgi apparatus. It is then cleaved by a cellular protease into gpl20 and gp41.
- Gp41 contains a transmembrane domain and remains in a trimeric configuration; it interacts with gpl20 in a non-covalent manner.
- Gpl20 contains most of the external, surface- exposed, domains of the envelope glycoprotein complex, and it is gpl20 which binds both to the cellular CD4 receptor and to the cellular chemokine receptors (such as CCR5).
- the mature gpl20 wildtype polypeptides have about 500 amino acids in the primary sequence. Gp 120 is heavily N-glycosylated giving rise to an apparent molecular weight of 120 kD.
- the polypeptide is comprised of five conserved regions (C1-C5) and five regions of high variability (V1-V5).
- Exemplary sequence of wt gpl60 polypeptides are shown on GENBANK, for example accession numbers AAB05604 and AAD 12142
- the gpl20 core has a unique molecular structure, which comprises two domains: an "inner” domain (which faces gp41) and an “outer” domain (which is mostly exposed on the surface of the oligomeric envelope glycoprotein complex).
- the two gpl20 domains are separated by a "bridging sheet” that is not part of either domain.
- the gpl20 core comprises 25 beta strands, 5 alpha helices, and 10 defined loop segments.
- Gpl20 polypeptides also include "gpl20-derived molecules” which encompasses analogs (non-protein organic molecules), derivatives (chemically functionalized protein molecules obtained starting with the disclosed protein sequences) or mimetics (three-dimensionally similar chemicals) of the native gpl20 structure, as well as proteins sequence variants (such as mutants), genetic alleles, fusions proteins of gpl20, or combinations thereof.
- gpl20-derived molecules encompasses analogs (non-protein organic molecules), derivatives (chemically functionalized protein molecules obtained starting with the disclosed protein sequences) or mimetics (three-dimensionally similar chemicals) of the native gpl20 structure, as well as proteins sequence variants (such as mutants), genetic alleles, fusions proteins of gpl20, or combinations thereof.
- the numbering used in gpl20 polypeptides disclosed herein is relative to the HXB2 numbering scheme as set forth in Numbering Positions in HIV Relative to HXB2CG Bette Korber et al, Human Retroviruses and AIDS 1998: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Korber B, Kuiken CL, Foley B, Hahn B, McCutchan F, Mellors JW, and Sodroski J, Eds. Theoretical
- Host cells Cells in which a vector can be propagated and its DNA expressed.
- the cell may be prokaryotic or eukaryotic.
- the term also includes any progeny of the subject host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. However, such progeny are included when the term "host cell" is used.
- Immune response A response of a cell of the immune system, such as a B cell, T cell, or monocyte, to a stimulus.
- the response is specific for a particular antigen (an "antigen-specific response").
- an immune response is a T cell response, such as a CD4+ response or a CD8+ response.
- the response is a B cell response, and results in the production of specific antibodies.
- Immunogen An agent (such as an antigen) capable of stimulating a specific immune response against a target, such as a pathogen or tumor.
- Immunogenic peptide A peptide which comprises an allele- specific motif or other sequence such that the peptide will bind an MHC molecule and induce a cytotoxic T lymphocyte ("CTL”) response, or a B cell response (for example antibody production) against the antigen from which the immunogenic peptide is derived.
- CTL cytotoxic T lymphocyte
- B cell response for example antibody production
- immunogenic peptides are identified using sequence motifs or other methods, such as neural net or polynomial determinations known in the art.
- algorithms are used to determine the "binding threshold" of peptides to select those with scores that give them a high probability of binding at a certain affinity and will be immunogenic.
- the algorithms are based either on the effects on MHC binding of a particular amino acid at a particular position, the effects on antibody binding of a particular amino acid at a particular position, or the effects on binding of a particular substitution in a motif-containing peptide.
- a "conserved residue” is one which appears in a significantly higher frequency than would be expected by random distribution at a particular position in a peptide.
- a conserved residue is one where the MHC structure may provide a contact point with the immunogenic peptide.
- an immunogenic polypeptide includes a region of gpl20, or a fragment thereof.
- Immunogenic composition A composition comprising an immunogenic peptide that induces a measurable CTL or other T cell response against virus expressing the immunogenic peptide, or induces a measurable B cell response (such as production of antibodies) against the immunogenic peptide.
- an "immunogenic composition” is composition comprising an HIV envelope polypeptide that induces a measurable CTL response against a virus expressing an HIV envelope protein, or induces a measurable B cell response (such as production of antibodies) against an HIV envelope polypeptide. It further refers to isolated nucleic acids encoding an immunogenic peptide, such as a nucleic acid that can be used to express the HIV envelope polypeptide (and thus be used to elicit an immune response against this polypeptide).
- an immunogenic composition may consist of the isolated protein, peptide epitope, or nucleic acid encoding the protein, or peptide epitope.
- the immunogenic composition will typically comprise the protein or immunogenic peptide in pharmaceutically acceptable carriers, and/or other agents. Any particular peptide, such as an HIV envelope polypeptide, or nucleic acid encoding the polypeptide, can be readily tested for its ability to induce a T cell or B cell response by art-recognized assays. Immunogenic compositions can include adjuvants, which are well known to one of skill in the art.
- Immunologically reactive conditions Includes reference to conditions which allow an antibody raised against a particular epitope to bind to that epitope to a detectably greater degree than, and/or to the substantial exclusion of, binding to substantially all other epitopes. Immunologically reactive conditions are dependent upon the format of the antibody binding reaction and typically are those utilized in immunoassay protocols or those conditions encountered in vivo.
- immunologically reactive conditions employed in the methods are "physiological conditions" which include reference to conditions (such as temperature, osmolality, pH) that are typical inside a living mammal or a mammalian cell. While it is recognized that some organs are subject to extreme conditions, the intra-organismal and intracellular environment is normally about pH 7 (such as from pH 6.0 to pH 8.0, more typically pH 6.5 to 7.5), contains water as the predominant solvent, and exists at a temperature above 0 0 C and below 50 0 C. Osmolality is within the range that is supportive of cell viability and proliferation.
- Immunostimulatory agent An adjunct agent different from an immunogen that is administered with an immunogen to enhance an immune response against the immunogen.
- examples include one or more TLR ligands, cytokines or a combination thereof.
- one or more TLR ligands include TLR ligands provided in Table 1 (e.g., MALP2, poly(I:C), CpG 2343 or combination thereof).
- Exemplary cytokines include, but are not limited to, IL- 15, IL- 12 or GM- CSF.
- Immunotherapy A method of evoking an immune response against a virus or cancer based on their production of target antigens.
- Immunotherapy based on cell-mediated immune responses involves generating a cell-mediated response to cells that produce particular antigenic determinants, while immunotherapy based on humoral immune responses involves generating specific antibodies to virus that produce particular antigenic determinants.
- Immunostimulatory CpG motifs Immunostimulatory nucleic acid sequences that trigger macrophages, monocytes and lymphocytes to produce a variety of pro-inflammatory cytokines and chemokines. CpG motifs represent a type of Toll like receptor TLR ligand. Examples of immunostimulatory
- oligonucleotides that include CpG motifs are found for example in U.S. Patent No. 6,194,388; U.S. Patent No. 6,207,646; U.S. Patent No. 6,214,806; U.S. Patent No. 6,218,371; U.S. Patent No. 6,239,116; U.S. Patent No. 6,339,068; U.S. Patent No. 6,406,705; and U.S. Patent No. 6,429,199.
- Inhibiting or treating a disease Inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease such as an STD including acquired immune deficiency syndrome (AIDS), an AIDS related conditions, an HIV-I infection, or combinations thereof.
- Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop.
- the term "ameliorating,” with reference to a disease or pathological condition refers to any observable beneficial effect of the treatment.
- the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of metastases, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
- a "prophylactic" treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology.
- Isolated An "isolated" biological component (such as a nucleic acid, peptide or protein) has been substantially separated, produced apart from, or purified away from other biological components in the cell of the organism in which the component naturally occurs, such as, other chromosomal and extrachromosomal DNA and RNA, and proteins.
- Nucleic acids, peptides and proteins which have been “isolated” thus include nucleic acids and proteins purified by standard purification methods.
- the term also embraces nucleic acids, peptides, and proteins prepared by recombinant expression in a host cell as well as chemically synthesized nucleic acids.
- MALP-2 Macrophage-activating lipopeptide-2
- MALP-2 is a Toll-like receptor (TLR) agonist and is beleived to bind the complex of TLR 2 and TLR 6.
- TLR Toll-like receptor
- MALP-2S or S-[2,3-bispalmitoyloxy-(2#)- propyl] -cysteinyl-GNNDESNISFKEK (SEQ ID NO: 2) is the synthetic analogue of MALP-2.
- MALP-2 refers to the natural product isolated from Mycoplasma fermentans as well as synthetic analogues, such as MALP-2S.
- Nanoparticle A microscopic particle whose size is measured in nanometers
- Nanoparticles are effectively a bridge between bulk materials and atomic or molecular structures.
- a bulk material should have constant physical properties regardless of its size, but at the nano-scale this is often not the case. Size-dependent properties are observed such as quantum confinement in semiconductor particles, surface plasmon resonance in some metal particles and superparamagnetism in magnetic materials.
- Semi-solid and soft nanoparticles have been manufactured. A prototype nanoparticle of semi-solid nature is the liposome.
- nanoparticles are often referred to as clusters.
- Metal, dielectric, and semiconductor nanoparticles have been formed, as well as hybrid structures (e.g., core-shell nanoparticles).
- Nanospheres, nanorods, and nanocups are just a few of the shapes that have been grown.
- Semiconductor quantum dots and nanocrystals are types of nanoparticles. Such nanoscale particles are used in biomedical applications as drug carriers or imaging agents.
- Nanoparticle characterization is necessary to establish understanding and control of nanoparticle synthesis and applications. Characterization is done by using a variety of different techniques, mainly drawn from materials science. Common techniques are electron microscopy [transmission or scanning, abbreviated TEM or SEM respectively], atomic force microscopy [AFM], dynamic light scattering [DLS], x-ray photoelectron spectroscopy [XPS], powder x-ray diffractometry
- Naturally Occurring Amino Acids L-isomers of the naturally occurring amino acids.
- the naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, gamma. -carboxy glutamic acid, arginine, ornithine and lysine. Unless specifically indicated, all amino acids referred to in this application are in the L- form. "Synthetic amino acids" refers to amino acids that are not naturally found in proteins.
- Examples of synthetic amino acids used herein include racemic mixtures of selenocysteine and selenomethionine.
- unnatural amino acids include the D or L forms of nor-leucine, para-nitrophenylalanine, homophenylalanine, para- fluorophenylalanine, 3-amino-2-benzylpropionic acid, homoarginine, and D- phenylalanine.
- the term "positively charged amino acid” refers to any naturally occurring or synthetic amino acid having a positively charged side chain under normal physiological conditions. Examples of positively charged naturally occurring amino acids are arginine, lysine and histidine.
- negatively charged amino acid refers to any naturally occurring or synthetic amino acid having a negatively charged side chain under normal physiological conditions. Examples of negatively charged naturally occurring amino acids are aspartic acid and glutamic acid.
- hydrophobic amino acid refers to any amino acid having an uncharged, nonpolar side chain that is relatively insoluble in water. Examples of naturally occurring hydrophobic amino acids are alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine.
- hydrophilic amino acid refers to any amino acid having an uncharged, polar side chain that is relatively soluble in water. Examples of naturally occurring hydrophilic amino acids are serine, threonine, tyrosine, asparagine, glutamine, and cysteine.
- Nucleic acid A polymer composed of nucleotide units (ribonucleotides, deoxyribonucleotides, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof) linked via phosphodiester bonds, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof.
- nucleotide polymers in which the nucleotides and the linkages between them include non-naturally occurring synthetic analogs, such as, for example and without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like.
- Such polynucleotides can be synthesized, for example, using an automated DNA synthesizer.
- oligonucleotide typically refers to short polynucleotides, generally no greater than about 50 nucleotides. It will be understood that when a nucleotide sequence is represented by a DNA sequence (i.e., A, T, G, C), this also includes an RNA sequence (i.e., A, U, G, C) in which "U” replaces "T.”
- Nucleotide includes, but is not limited to, a monomer that includes a base linked to a sugar, such as a pyrimidine, purine or synthetic analogs thereof, or a base linked to an amino acid, as in a peptide nucleic acid (PNA).
- a nucleotide is one monomer in a polynucleotide.
- a nucleotide sequence refers to the sequence of bases in a polynucleotide.
- An HIV envelope polynucleotide is a nucleic acid encoding an HIV envelope polypeptide.
- nucleotide sequences the left-hand end of a single-stranded nucleotide sequence is the 5'-end; the left-hand direction of a double-stranded nucleotide sequence is referred to as the 5'-direction.
- the direction of 5' to 3' addition of nucleotides to nascent RNA transcripts is referred to as the transcription direction.
- the DNA strand having the same sequence as an mRNA is referred to as the "coding strand;" sequences on the DNA strand having the same sequence as an mRNA transcribed from that DNA and which are located 5' to the 5'-end of the RNA transcript are referred to as "upstream sequences;” sequences on the DNA strand having the same sequence as the RNA and which are 3' to the 3' end of the coding RNA transcript are referred to as "downstream sequences.”
- cDNA refers to a DNA that is complementary or identical to an mRNA, in either single stranded or double stranded form.
- Encoding refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (for example, rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
- a gene encodes a protein if transcription and translation of mRNA produced by that gene produces the protein in a cell or other biological system.
- coding strand the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings
- non-coding strand used as the template for transcription
- a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns.
- Recombinant nucleic acid refers to a nucleic acid having nucleotide sequences that are not naturally joined together. This includes nucleic acid vectors comprising an amplified or assembled nucleic acid which can be used to transform a suitable host cell. A host cell that comprises the recombinant nucleic acid is referred to as a "recombinant host cell.” The gene is then expressed in the recombinant host cell to produce, such as a "recombinant polypeptide.”
- a recombinant nucleic acid may serve a non-coding function (such as a promoter, origin of replication, ribosome-binding site, etc.) as well.
- a first sequence is an "antisense" with respect to a second sequence if a polynucleotide whose sequence is the first sequence specifically hybridizes with a polynucleotide whose sequence is the second sequence.
- sequence relationships between two or more nucleotide sequences or amino acid sequences include “reference sequence,” “selected from,” “comparison window,” “identical,” “percentage of sequence identity,” “substantially identical,” “complementary,” and “substantially complementary.”
- sequence comparison For sequence comparison of nucleic acid sequences and amino acids sequences, typically one sequence acts as a reference sequence, to which test sequences are compared.
- test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters are used.
- Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482, 1981, by the homology alignment algorithm of Needleman & Wunsch, /. MoI. Biol. 48:443, 1970, by the search for similarity method of Pearson & Lipman, Proc.
- PILEUP uses a
- PILEUP can be obtained from the GCG sequence analysis software package, such as version 7.0 (Devereaux et al., NMC. Acids Res. 12:387-395, 1984.
- BLAST Altschul et al, J. MoI. Biol. 215:403-410, 1990 and Altschul et al., Nucleic Acids Res. 25:3389-3402, 1977.
- Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information on the worldwide web at ncbi.nlm.nih.gov.
- the BLASTP program (for amino acid sequences) uses as defaults a word length (W) of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. ScL USA 89:10915, 1989).
- W word length
- E expectation
- BLOSUM62 scoring matrix See Henikoff & Henikoff, Proc. Natl. Acad. ScL USA 89:10915, 1989.
- Another indicia of sequence similarity between two nucleic acids is the ability to hybridize. The more similar are the sequences of the two nucleic acids, the more stringent the conditions at which they will hybridize.
- the stringency of hybridization conditions are sequence-dependent and are different under different environmental parameters. Thus, hybridization conditions resulting in particular degrees of stringency will vary depending upon the nature of the hybridization method of choice and the composition and length of the hybridizing nucleic acid sequences.
- the temperature of hybridization and the ionic strength (especially the Na + and/or Mg ++ concentration) of the hybridization buffer will determine the stringency of hybridization, though wash times also influence stringency.
- stringent conditions are selected to be about 5°C to 20 0 C lower than the thermal melting point (T m ) for the specific sequence at a defined ionic strength and pH.
- T m is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe.
- “Stringent conditions” encompass conditions under which hybridization will only occur if there is less than 25% mismatch between the hybridization molecule and the target sequence. “Stringent conditions” may be broken down into particular levels of stringency for more precise definition. Thus, as used herein, “moderate stringency” conditions are those under which molecules with more than 25% sequence mismatch will not hybridize; conditions of “medium stringency” are those under which molecules with more than 15% mismatch will not hybridize, and conditions of “high stringency” are those under which sequences with more than 10% mismatch will not hybridize. Conditions of "very high stringency” are those under which sequences with more than 6% mismatch will not hybridize. In contrast nucleic acids that hybridize under “low stringency conditions include those with much less sequence identity, or with sequence identity over only short subsequences of the nucleic acid. For example, a nucleic acid construct can include a
- polynucleotide sequence that hybridizes under high stringency or very high stringency, or even higher stringency conditions to a polynucleotide sequence that encodes SEQ ID NO: 1.
- Parasite An organism that lives inside humans or other organisms acting as hosts (for the parasite). Parasites are dependent on their hosts for at least part of their life cycle. Parasites are harmful to humans because they consume needed food, eat away body tissues and cells, and eliminate toxic waste, which makes people sick.
- Exemplary parasites that can be treated with the compositions and methods disclosed herein include Malaria ⁇ Plasmodium falciparum, P. vivax, P. malariae), Schistosomes, Trypanosomes, Leishmania, Filarial nematodes, Trichomoniasis, Sarcosporidiasis, Taenia (T. saginata, T. solium), Leishmania, Toxoplasma gondii, Trichinelosis (Trichinella spiralis) or Coccidiosis (Eimeria species).
- Peptide Any compound composed of amino acids, amino acid analogs, chemically bound together.
- Peptide as used herein includes oligomers of amino acids, amino acid analog, or small and large peptides, including polypeptides or proteins encompasses any chain of amino acids, regardless of length or post- translational modification (such as glycosylation or phosphorylation).
- “Peptide” applies to amino acid polymers to naturally occurring amino acid polymers and non- naturally occurring amino acid polymer as well as in which one or more amino acid residue is a non-natural amino acid, for example a artificial chemical mimetic of a corresponding naturally occurring amino acid.
- a “residue” refers to an amino acid or amino acid mimetic incorporated in a polypeptide by an amide bond or amide bond mimetic.
- a peptide has an amino terminal (N-terminal) end and a carboxy terminal (C-terminal) end.
- “Peptide” is used interchangeably with polypeptide or protein, and is used interchangeably herein to refer to a polymer of amino acid residues.
- Amino acids generally are chemically bound together via amide linkages (CONH). Additionally, amino acids may be bound together by other chemical bonds.
- Peptides may be modified by a variety of chemical techniques to produce derivatives having essentially the same activity as the unmodified proteins, and optionally having other desirable properties.
- carboxylic acid groups of the protein may be provided in the form of a salt of a pharmaceutically-acceptable cation or esterified to form a Ci-Ci 6 ester, or converted to an amide of formula NR 1 R 2 wherein Ri and R 2 are each independently H or C 1 -C 16 alkyl, or combined to form a heterocyclic ring, such as a 5- or 6- membered ring.
- Amino groups of the protein may be in the form of a pharmaceutically-acceptable acid addition salt, such as the HCl, HBr, acetic, benzoic, toluene sulfonic, maleic, tartaric and other organic salts, or may be modified to Ci-Ci 6 alkyl or dialkyl amino or further converted to an amide.
- a pharmaceutically-acceptable acid addition salt such as the HCl, HBr, acetic, benzoic, toluene sulfonic, maleic, tartaric and other organic salts
- Hydroxyl groups of the protein side chains may be converted to Ci-Ci 6 alkoxy or to a Ci-Ci 6 ester using well-recognized techniques.
- Phenyl and phenolic rings of the protein side chains may be substituted with one or more halogen atoms, such as fluorine, chlorine, bromine or iodine, or with Ci-Ci 6 alkyl, Ci-Ci 6 alkoxy, carboxylic acids and esters thereof, or amides of such carboxylic acids.
- Methylene groups of the protein side chains can be extended to homologous C 2 -C 4 alkylenes. Thiols can be protected with any one of a number of well-recognized protecting groups, such as acetamide groups.
- the polypeptide is an HIV envelope protein, such as a gp41 or gpl20 polypeptide.
- a "residue” refers to an amino acid or amino acid mimetic incorporated in a polypeptide by an amide bond or amide bond mimetic.
- a polypeptide has an amino terminal (N-terminal) end and a carboxy terminal (C- terminal) end.
- Pharmaceutical agent A chemical compound or composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject or a cell.
- An "anti- viral agent” or “anti- viral drug” is an agent that specifically inhibits a virus from replicating or infecting cells.
- an “anti- retroviral agent” is an agent that specifically inhibits a retrovirus from replicating or infecting cells.
- non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
- pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
- Poly (lactic-c ⁇ -glycolic acid) or PLGA A biodegradable copolymer.
- PLGA is synthesized by means of random ring-opening co-polymerization of two different monomers, the cyclic dimers (l,4-dioxane-2,5-diones) of glycolic acid and lactic acid.
- Common catalysts used in the preparation of this polymer include tin(II) 2-ethylhexanoate, tin(II) alkoxides, or aluminum isopropoxide.
- PLGA polyglycolide which show poor solubilities
- PLGA can be dissolved by a wide range of common solvents, including chlorinated solvents, tetrahydrofuran, acetone or ethyl acetate.
- the compositional ratio (lactic acid/glycolic acid, mol %) in the lactic acid-glycolic acid copolymer is about 100/0 (homopolymer) to about 0/100, such as about 90/10 to about 85/15, about 75/25 to 25/75, or about 60/40 to about 40/60.
- the weight average molecular weight of the lactic acid-glycolic acid copolymer is about 1,000 to about 20,000, such as about 4,000 to about 15,000.
- the dispersity (weight average molecular weight/number average molecular weight) of the lactic acid-glycolic acid copolymer is about 0.2 to about 4.0, such as about 0.5 to about 3.5.
- a mixture of a lactic acid-glycolic acid copolymer has a compositional ratio of lactic acid/glycolic acid (mol %) of about 50/50 and the weight average molecular weight of about 6,000.
- a lactic acid- glycolic acid copolymer has a compositional ratio of lactic acid/glycolic acid (mol %) of about 50/50 and the weight average molecular weight of about 4,000.
- the suitable weight ratio of the mixture is about 25/75 to about 75/25.
- PLGA degrades by hydrolysis of its ester linkages in the presence of water. It has been shown that the time required for degradation of PLGA is related to the monomers' ratio used in production: the higher the content of glycolide units, the lower the time required for degradation.
- a composition includes a target immunogen encapsulated by PLGA.
- Polyinosinicrpolycytidylic acid (Poly I:C): Is a Toll like receptor (TLR) agonist.
- Poly I: C is believed to interact with Toll-like receptor (TLR) 3, which is expressed in the intracellular compartments of B-cells and dendritic cells.
- SID Sexually Transmitted Disease or Infection
- Donovanosis (Granuloma inguinale or Calymmatobacterium granulomatis), Gonorrhea (Neisseria gonorrhoeae), Lymphogranuloma venereum (LGV)
- Chlamydia trachomatis serotypes L 1 , L 2 , L 3 See Chlamydia), Non-gonococcal urethritis (NGU) (Ureaplasma urealyticum or Mycoplasma hominis),
- Staphylococcal infection Staphylococcus aureus, MRSA
- Syphilis Teponema pallidum
- fungal such as Trichophyton rubrum
- parasitic such as Phthirius pubis or Sarcoptes scabiei
- viral such as adenoviruses, Hepatitis (e.g., Hepatitis A, Hepatitis B, or Hepatitis E), Herpes simplex virus (1, T), HIV/ AIDS, human T- lymphotropic virus (HTLV 1 or T), human papilloma virus, molluscum contagiosum virus, cytomegalovirus, Epstein-Barr virus, SARS, or Kaposi's sarcoma-associated herpes virus).
- Hepatitis e.g., Hepatitis A, Hepatitis B, or Hepatitis E
- Herpes simplex virus (1, T)
- HIV/ AIDS Herpes simplex virus
- HTLV 1 or T human T- lymph
- Subject Living multi-cellular vertebrate organisms, a category that includes both human and veterinary subjects, including human and non-human mammals.
- T Cell A white blood cell critical to the immune response.
- T cells include, but are not limited to, CD4 + T cells and CD8 + T cells.
- Therapeutic agent Used in a generic sense, it includes treating agents, prophylactic agents, and replacement agents.
- Therapeutically effective amount An amount of a composition that alone, or together with an additional therapeutic agent(s) induces the desired response (e.g., inhibition of HIV infection or replication).
- a therapeutically effective amount of a composition including the active agent can be administered in a single dose, or in several doses, for example daily, during a course of treatment.
- the therapeutically effective amount can depend on the subject being treated, the severity and type of the condition being treated, and the manner of administration.
- a therapeutically effective amount of such agent can vary from about 1 mg to 1 gram per 70 kg body weight if administered orally.
- Toll-like receptors (TLR) A class of proteins that play a role in the innate immune system. They are single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs which activates immune cell responses.
- TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). TLRs together with the Interleukin- 1 receptors form a receptor superfamily, known as the "Interleukin- 1 Receptor/Toll-Like Receptor
- TIR ToIl-IL- 1 receptor
- TIR domains Three subgroups of TIR domains exist. Proteins with subgroup 1 TIR domains are receptors for interleukins that are produced by macrophages, monocytes and dendritic cells and all have extracellular Immunoglobulin (Ig) domains.
- Ig Immunoglobulin
- Proteins with subgroup 2 TIR domains are classical TLRs, and bind directly or indirectly to molecules of microbial origin.
- a third subgroup of proteins containing TIR domains consists of adaptor proteins that are exclusively cytosolic and mediate signaling from proteins of subgroups 1 and 2.
- TLRs are believed to function as dimers. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLRl or TLR6, each dimer having a different ligand specificity. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4's recognition of LPS, which requires MD-2. CD 14 and LPS Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.
- LBP LPS Binding Protein
- TLRs When activated, TLRs recruit adapter molecules within the cytoplasm of cells in order to propagate a signal.
- adapter molecules Four adapter molecules are known to be involved in signaling. These proteins are known as MyD88, Tirap (also called MaI), Trif, and Tram.
- the adapters activate other molecules within the cell, including certain protein kinases (IRAKI, IRAK4, TBKl, and IKKi) that amplify the signal, and ultimately lead to the induction or suppression of genes that orchestrate the inflammatory response.
- IRAKI protein kinases
- IRAK4 RBK4
- TLRs constitutes one of the most pleiotropic yet tightly regulated gateways for gene modulation.
- Toll-like receptors recognize molecules that are constantly associated with threats (e.g., pathogen or cell stress) and are highly specific to these threats (e.g., cannot be mistaken for self molecules). These molecules are known as TLR ligands. Exemplary TLR ligands are provided in the Table 1 below.
- Immune cells can produce signaling factors called cytokines which trigger inflammation.
- cytokines In the case of a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells.
- the infected cell In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons.
- a TLR ligand is a molecule that activates a TLR located on the mucosal surface of the lower gastrointestinal tract, for example a TLR expressed on a dendritic cell.
- a TLR ligand is a molecule that activates a TLR expressed on a dendritic cell resulting in augmentation of immunity by enhancing the T cell quality (especially avidity).
- a Toll-like receptor (TLR) ligand is MALP-2 or an analogue of MALP-2, such as MALP-2S.
- a Toll-like receptor (TLR) ligand is poly I:C.
- a Toll-like receptor (TLR) ligand is an immunostimulatory oligonucleotide (such as those including a CpG motif).
- TLR Toll-like receptor
- Some combinations that are identified here as synergistic ally active as vaccine adjuvants include MALP-2 and Poly I:C, Poly LC and CpG, or a triple combination of all three, MALP2, Poly LC and CpG (Zhu et ah, J. Clin. Invest. 120(2): 607-616, 2010, which is hereby incorporated by reference in its entirety).
- Some combinations that are not synergistic or even additive include MALP-2 and CpG (Zhu et al, Proc. Natl. Acad. ScL USA 105(42): 16620-16265, 2008, which is hereby incorporated by reference in its entirety).
- Tumor antigen is an antigen produced by tumor cells that can stimulate tumor-specific T-cell immune responses.
- exemplary tumor antigens include, but are not limited to, RAGE-I, tyrosinase, MAGE-I, MAGE-2, NY-ESO- 1, Melan-A/MART-1, glycoprotein (gp) 75, gplOO, beta-catenin, preferentially expressed antigen of melanoma (PRAME), MUM-I, Wilms tumor (WT)-I, carcinoembryonic antigen (CEA), and PR-I.
- Additional tumor antigens are known in the art (for example see Novellino et ah, Cancer Immunol. Immunother.
- Tumor antigens are also referred to as "cancer antigens.”
- Neoplasia, malignancy, cancer and tumor are often used interchangeably and refer to abnormal growth of a tissue or cells that results from excessive cell division.
- Hematological cancers are cancers of the blood or bone marrow.
- hematological tumors include leukemias, including acute leukemias (such as acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia and myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia), chronic leukemias (such as chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (indolent and high grade forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia and myelodysplasia.
- acute leukemias such as acute lymphocytic leukemia, acute myelocytic leukemia, acute mye
- Solid tumors are abnormal masses of tissue that usually do not contain cysts or liquid areas and are named for the type of cells that form them.
- solid tumors such as sarcomas and carcinomas
- solid tumors include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma,
- Vaccine A pharmaceutical composition that elicits a prophylactic or therapeutic immune response in a subject.
- the immune response is a protective immune response.
- a vaccine elicits an antigen-specific immune response to an antigen of a pathogen, for example, a bacterial or viral pathogen, or to a cellular constituent correlated with a pathological condition, such as cancer.
- a vaccine may include a polynucleotide, a peptide or polypeptide, a virus, a bacterium, a cell or one or more cellular constituents.
- the virus, bacteria or cell may be inactivated or attenuated to prevent or reduce the likelihood of infection, while maintaining the immunogenicity of the vaccine constituent.
- the immunogenic material may include live- attenuated or killed microorganisms (such as bacteria or viruses), or antigenic proteins, peptides or DNA derived from them.
- the vaccine is a subunit vaccine, which is an immunizing agent that has been treated to remove traces of nucleic acid (such as viral nucleic acid) so that only protein subunits remain. The subunits have less risk of causing adverse reactions.
- the vaccine can also be a live vaccine, which is a vaccine prepared from living attenuated organisms or from viruses that have been attenuated but can still replicate in the cells of the host organism.
- the immunogenic material for a cancer vaccine may include, for example, a protein or peptide expressed by a tumor or cancer cell.
- Vaccines may elicit both prophylactic (preventative) and therapeutic responses.
- a vaccine vector is a virus, bacterium, or other microbe, or a nucleic acid, used to deliver an antigen or a gene for an antigen, as part of a vaccine.
- a nucleic acid vector is a nucleic acid molecule as introduced into a host cell, thereby producing a transformed host cell.
- Recombinant DNA vectors are vectors having recombinant DNA.
- a vector can include nucleic acid sequences that permit it to replicate in a host cell, such as an origin of replication.
- a vector can also include one or more selectable marker genes and other genetic elements known in the art.
- Viral vectors are recombinant DNA vectors having at least some nucleic acid sequences derived from one or more viruses.
- Virus A microscopic infectious organism that reproduces inside living cells.
- a virus consists essentially of a core of nucleic acid surrounded by a protein coat, and has the ability to replicate only inside a living cell. "Viral replication" is the production of additional virus by the occurrence of at least one viral life cycle.
- a virus may subvert the host cells' normal functions, causing the cell to behave in a manner determined by the virus. For example, a viral infection may result in a cell producing a cytokine, or responding to a cytokine, when the uninfected cell does not normally do so.
- a virus is a pathogen.
- RNA viruses wherein the viral genome is RNA.
- the genomic RNA is reverse transcribed into a DNA intermediate which is integrated very efficiently into the chromosomal DNA of infected cells.
- the integrated DNA intermediate is referred to as a provirus.
- the term "lentivirus” is used in its conventional sense to describe a genus of viruses containing reverse transcriptase.
- the lentiviruses include the "immunodeficiency viruses” which include human immunodeficiency virus (HIV) type 1 and type 2 (HIV-I and HIV-II), simian immunodeficiency virus (SIV), and feline
- FMV immunodeficiency virus
- HIV-I is a retrovirus that causes immunosuppression in humans (HIV disease), and leads to a disease complex known as AIDS.
- HIV disease refers to a well-recognized constellation of signs and symptoms (including the development of opportunistic infections) in persons who are infected by an HIV virus, as determined by antibody or western blot studies. Laboratory findings associated with this disease are a progressive decline in T cells.
- viral pathogens for which an infection can be treated in accordance with the disclosed methods include, without limitation; Arenaviruses (such as Guanarito virus, Lassa virus, Junin virus, Machupo virus and Sabia), Arteriviruses, Roniviruses, Astroviruses, Bunyaviruses (such as Crimean-Congo hemorrhagic fever virus and Hantavirus), Barnaviruses, Birnaviruses, Bornaviruses (such as Borna disease virus), Bromoviruses, Caliciviruses, Chry so viruses, Coronaviruses (such as Coronavirus and SARS), Cystoviruses, Closteroviruses, Comoviruses, Dicistroviruses, Flaviruses (such as Yellow fever virus, West Nile virus, Hepatitis C virus, and Dengue fever virus), Filoviruses (such as Ebola virus and Marburg virus), Flexiviruses, Hepeviruses (such as Hepatitis E virus), human
- human papillomavirus type 101 human papillomavirus type 103, human papillomavirus type 107, human papillomavirus type 16, human papillomavirus type 24, human papillomavirus type 26, human papillomavirus type 32, human papillomavirus type 34, human papillomavirus type 4, human papillomavirus type 41, human papillomavirus type 48, human papillomavirus type 49, human papillomavirus type 5, human papillomavirus type 50, human papillomavirus type 53, human papillomavirus type 60, human papillomavirus type 63, human papillomavirus type 6b, human papillomavirus type 7, human papillomavirus type 71, human papillomavirus type 9, human papillomavirus type 92, and human papillomavirus type 96), human
- Weight average molecular weight and number average molecular weight The polystyrene equivalent average molecular weight and number average molecular weight of a sample as determined by gel permeation chromatography (GPC) using 9 polystyrene standards having the weight average molecular weights of 120,000, 52,000, 22,000, 9,200, 5,050, 2,950, 1,050, 580 and 162. These determinations can be made using GPC Column Millenium Stryragel HE 4E (Waters), an HP 1047A refractive index detector (Hewlett Packard), and THF as the mobile phase.
- GPC gel permeation chromatography
- Immunization in the large intestine, by the intrarectal route, has been a preferred method for the protection against viral infections transmitted through the rectal mucosa.
- induction of gut immune responses by vaccination at the large intestine also confers vaginal protection against virus challenge. While this immunization route is believed superior to that induced at a distant site, such as a parenteral or intranasal route, intrarectal administration is considered impractical and invasive.
- oral vaccine delivery is desirable because it would increase compliance as more subjects would be willing to obtain treatment.
- FIG. IA provides a schematic illustration of an exemplary oral delivery system.
- an exemplary oral delivery system 100 includes a polymer core 120
- the particle 150 is a matrix composed of a mixture of polymer core 120 surrounding and suspending a therapeutically effective amount of target immunogen 130 and a therapeutically effective amount of one or more immunostimulatory agents 140.
- Target immunogens can include an immunogen that stimulates protective immunity against a target, such as multiple identical immunogens and multiple identical immunostimulatory agents contained within the surrounding polymer matrix 120.
- Multiple encapsulated particles 150 are in turn suspended within, coated by and encapsulated within a pH-sensitive matrix 160 to form an immunogenic composition capable of eliciting an immune response in the intestine.
- FIG. IB provides an illustration of an exemplary method of oral vaccine delivery to the large intestine.
- a micro/nanoparticle/vaccine complex system has been developed for oral delivery of immunogens and other immunogenic compositions to large intestine, with minimal perturbation in upper gastrointestinal regions.
- PLGA nanoparticles encapsulate vaccine components thereby forming particles in a size range at which efficient particle uptake by the gut can be attained once they are in the lumen and in contact with the intestinal mucosal surface.
- PLGA nanoparticles are pre-coated with an excipient that is pH sensitive (such as EUDRAGIT®) to form larger, micrometer- sized particles to prevent particles from degradation and uptake in the upper gastrointestinal segments.
- the exterior coating of a pH sensitive excipient, such as EUDRAGIT® is designed to dissolve and be able to release contents (e.g., PLGA nanoparticles) at high pH (>6.5, for example greater than 7.0), such as the relatively less acidic conditions measured in the large intestine.
- EUDRAGIT® pH sensitive excipient
- This method allows the transfer of antigens and adjuvants in the form of peptide or protein (or nucleic acid) while protected by excipients.
- the oral vaccination system also enhances the immune response induced by the vaccine by invoking combinatorial targeting of multiple TLRs to improve host defense.
- TLRs recognize viruses, bacteria, fungi, and protozoa by specific ligation to a certain range of components of these microbes.
- the mucosal surface of the lower gastrointestinal tract expresses various TLRs.
- These TLRs expressed in the lower gastrointestinal tract play a role in the induction of innate and adaptive immunity against these microorganisms.
- Dendritic cells are found to express almost all TLRs, and are able to produce inflammatory cytokines, such as IL-12, synergistically when encountering certain combinations of TLR ligands. As disclosed herein, selective combinations of TLR ligands can have substantial impacts on DCs and the downstream T-cell response.
- an oral delivery system that allows site-specific delivery of a vaccine to the large intestine as well as an enhanced immune response induced by the vaccine once delivered to the target site.
- the system includes immunogenic compositions with one or more particles, such as
- nanoparticles having a core including a bioactive agent (such as a target immunogen) and an immunostimulatory agent (such as a TLR ligand) encapsulated by a controlled-release polymer and a pH-sensitive copolymer matrix (also known as a coating) disposed about the encapsulated core, for example a pH-sensitive copolymer matrix that becomes soluble in high pH, for example pH greater than about pH 6.5, such as greater than about pH 6.6, greater than about pH 6.7, greater than about pH 6.8, greater than about pH 6.9, greater than about pH 7.0, greater than about pH 7.1, greater than about pH 7.2, greater than about pH 7.3, greater than about pH 7.4, or even greater than about pH 7.5.
- a bioactive agent such as a target immunogen
- an immunostimulatory agent such as a TLR ligand
- a pH-sensitive copolymer matrix also known as a coating
- Such compositions can be ingested by a subject, for example by oral administration
- nanoparticles having a size between about 10 and about 1000 nm, for example, between about 10 and about 100 nm, between 100 and about 500 nm, or between about 500 and about 1000 nm. Following coating, the nanoparticles are
- microparticles having a size between about 1 and about 100 micrometers, for example, between about 1 and about 10 micrometers, between about 10 and about 50 micrometers, or between about 50 and about 100
- sustained-release profiles of PLGA nanoparticles provide 6 to 12 hour release in vitro. In other examples, faster release occurs such as less than about 6 hours, for example less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours or even less than about 1 hour.
- the disclosed oral delivery system can be used to control STDs. It is also envisioned that this novel vaccine design can be useful in the development of vaccines against other emerging diseases, including infectious diseases as well as the prevention of cancer.
- Bioactive Agents such as Immunogens and
- the bioactive agent is an agent that effects the desired therapeutic effects, such as stimulation of an immune response (such as a specific immune response) against a target pathogen of interest (such as a viral or bacterial pathogen of interest that causes a disease in a host, such as a sexually transmitted disease, for example a disease that infects or is transmitted through the lower intestinal tract of the subject, for example a pathogen that infects the rectal mucosa).
- a target pathogen of interest such as a viral or bacterial pathogen of interest that causes a disease in a host, such as a sexually transmitted disease, for example a disease that infects or is transmitted through the lower intestinal tract of the subject, for example a pathogen that infects the rectal mucosa.
- the bioactive agent is an immunogen, such as an immunogen derived from the pathogenic organisms listed in the foregoing listing of terms, which provides a specific protective immune response against the pathogen of interest.
- bioactive agents that can be included in the disclosed immunogenic compositions include peptide, protein, polysaccharide, glycolipid, glycoprotein, or fragments thereof.
- the target immunogen can be a subunit, fragment or element of, or derived from, an antigen.
- the immunogen is an antigenic polypeptide of a pathogenic organism, such as a viral, fungal, parasitic or bacterial organism that produces undesirable symptoms in a subject following exposure.
- the immunogen may for example be an attenuated virus, bacteria, fungus and/or parasite. Mixtures thereof are also contemplated by the present disclosure.
- the immunogen includes only a part of a microorganism, such as viruses, bacteria and fungi.
- the bioactive agent includes one or more molecules, which have been derived from viruses, bacteria and fungi, such as for example polypeptides, polysaccharides, glycolipids, glycoproteins, or nucleic acid sequences.
- a bioactive agent includes molecules such as for example polypeptides, polysaccharides, glycolipids, glycoproteins, or nucleic acid sequences, which include only fragments of viral, bacterial, fungi and parasite derived polypeptides, polysaccharides, glycolipids, glycoproteins, or nucleic acid sequences. Such molecules can include more than one fragment.
- the bioactive agent e.g., immunogen
- the bioactive agent is an antigen derived from a pathogen.
- pathogens include viruses, bacteria, fungi or parasites.
- viruses, bacteria, fungi and parasites A non-limiting, and far from exhaustive list of viruses, bacteria, fungi and parasites from which antigen can be derived is provided in the listing of terms provided above.
- the bioactive agent e.g., immunogen
- a pathogen involved in a sexually transmitted disease such as Haemophilus ducreyi, Granuloma inguinale, Calymmatobacterium granulomatis, Neisseria gonorrhoeae, Lymphogranuloma venereum, Chlamydia trachomatis (serotypes L 1 , L 2 , L3, Ureaplasma urealyticum, Mycoplasma hominis,
- Hepatitis e.g., Hepatitis A, Hepatitis B, or Hepatitis E
- Herpes simplex virus (1, 2)
- HIV/AIDS Herpes simplex virus
- HTLV 1 or 2 human T-lymphotropic virus
- papilloma virus molluscum contagiosum virus
- cytomegalovirus Epstein-Barr virus, SARS, or Kaposi's sarcoma-associated herpes virus.
- a bioactive agent e.g., immunogen
- a bioactive agent is any antigen that is used as a vaccine for a single disease ("single antigen") or two or more diseases simultaneously (“mixed antigen").
- the mixed antigen may be a mixture of two or more antigens, or an antigen that has antigenicities for two or more diseases simultaneously, e.g., a. recombinant protein.
- an antigen there may be used an entire organism, e.g., a viral or bacterial whole cell, or a part of the organism, e.g., a certain protein having an antigenicity.
- a bioactive agent includes more than one different polypeptide and/or peptide, such as 2, for example 3, such as 4, for example 5, such as 6, for example 7, such as 8, for example 9, such as 10, for example more than 10 different polypeptides.
- the immunogen comprises or essentially consists of an organism, preferably a microorganism or part of an organism, preferably a microorganism and accordingly the antigen comprises a very large number of different polypeptides, such as more than 100, for example more than 500, such as more than 1000, for example more than 2500.
- the antigen may essentially consist of or consist of one or more polypeptides and/or peptides.
- a bioactive agent is at least one HIV envelope CTL polypeptide, such as a gp41 or gpl20 peptide.
- a bioactive agent is a PCLUS3-18IIIB peptide.
- the bioactive agent has an amino acid sequence as provided by SEQ ID NO: 1.
- the disclosed immunogenic compositions include an immunogen and an immunostimulatory agent, to enhance the immune response induced by the bioactive agent.
- immunostimulatory agents are known to those of skill in the art and include TLR ligands.
- one or more TLR ligands are included within the immunogenic composition, such as at least two, at least three, at least four, at least five TLR ligands, for example 2, 3, 4, 5, 6, 7, 8, 9 or 10 TLR ligands.
- Exemplary ligands are provided in Table 1.
- the composition includes TLR ligands, MALP2, poly(I:C) and CpG.
- a disclosed immunogenic composition includes an encapsulation material to encapsulate or surround the bioactive agent and/or immunostimulatory agent (such as a TLR ligand).
- the bioactive active agent e.g., immunogen
- immunostimulatory agent are encapsulated with one or more encapsulating pharmaceuticals to form particles in a size range at which efficient particle uptake can be reached in the lumen of the large intestine.
- Materials for use in encapsulating pharmaceuticals for use with the disclosure can be biodegradable or non-biodegradable. A variety of biodegradable polymers are well known to those skilled in the art.
- Exemplary synthetic polymers suitable for use with this disclosure include but are not limited to poly(arylates), poly(anhydrides), poly(hydroxy acids), polyesters, poly(ortho esters), polycarbonates, poly(propylene fumerates), poly(caprolactones), polyamides, polyphosphazenes, polyamino acids, polyethers, polyacetals, polylactides, polyhydroxyalkanoates, polyglycolides, polyketals, polyesteramides, poly(dioxanones), polyhydroxybutyrates,
- polyhydroxyvalyrates polycarbonates, polyorthocarbonates, polyvinyl
- Naturally-occurring polymers such as polysaccharides and proteins, may also be employed.
- Exemplary polysaccharides include alginate, starches, dextrans, celluloses, chitin, chitosan, hyaluronic acid and its derivatives;
- exemplary proteins include collagen, albumin, and gelatin.
- Polysaccharides such as starches, dextrans, and celluloses may be unmodified or may be modified physically or chemically to affect one or more of their properties such as their characteristics in the hydrated state, their solubility, or their half- life in vivo.
- the polymer includes polyhydroxy acids such as polylactic acid (PLA), polyglycolic acid (PGA), their copolymers poly(lactic-co- glycolic acid) (PLGA), and mixtures of any of these.
- PLA polylactic acid
- PGA polyglycolic acid
- PLGA poly(lactic-co- glycolic acid)
- mixtures of any of these are among the synthetic polymers approved for human clinical use as surgical suture materials and in controlled release devices. They are degraded by hydrolysis to products that can be metabolized and excreted.
- copolymerization of PLA and PGA offers the advantage of a large spectrum of degradation rates from hours to several months, such as less than about 6 hours, for example less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours or even less than about 1 hour, by varying the copolymer ratio of glycolic acid to lactic acid, which is more hydrophobic and less crystalline than PGA and degrades at a slower rate.
- Non-biodegradable polymers may also be employed for use with the disclosure.
- Exemplary non-biodegradable, yet biocompatible polymers include polystyrene, polyesters, non-biodegradable polyurethanes, polyureas, poly(vinyl alcohol), poly amides, poly(tetrafluoroethylene), poly (ethylene vinyl acetate), polypropylene, polyacrylate, non-biodegradable polycyanoacrylates, nonbiodegradable polyurethanes, polymethacrylate, poly(methyl methacrylate), polyethylene, polypyrrole, polyanilines, polythiophene, and poly(ethylene oxide).
- any of the above polymers may be functionalized with a poly (alky lene glycol), for example, poly(ethylene glycol) (PEG) or poly (propyleneglycol) (PPG), or may have a particular terminal functional group, e.g., poly(lactic acid) modified to have a terminal carboxyl group.
- PEGylated polymers include but are not limited to PEGylated poly(lactic acid), PEGylated poly(lactic-co-glycolic acid), PEGylated poly(caprolactone), PEGylated poly(ortho esters), PEGylated polylysine, and PEGylated poly(ethylene imine).
- Poly (alky lene glycols) are known to increase the bioavailability of many pharmacologically useful compounds, partly by increasing the gastrointestinal stability of derivatized compounds.
- Poly(alkylene glycols) chains may be as short as about 100 Daltons or have a molecular weight of about 1000, about 3000, about 5000, about 7000 Daltons, or more.
- poly(alkylene glycol) chain may also be modified to have a charged endgroup or other group selected to engage in a particular interaction with the coating material.
- carboxylated PEG will engage in electrostatic interactions with positively charged coating materials such as chitosan.
- Co-polymers, mixtures, and adducts of any of the above modified and unmodified polymers may also be employed.
- amphiphilic block copolymers having hydrophobic regions and anionic or otherwise hydrophilic regions may be employed.
- Block co-polymers having regions that engage in different types of non-covalent or covalent interactions may also be employed.
- a block co-polymer may have one block that is optimized to interact with an active agent being encapsulated and another block optimized to interact with the bioadhesive coating.
- polymers may be chemically modified to have particular functional groups.
- polymers may be functionalized with hydroxyl, amine, carboxy, maleimide, thiol, N-hydroxy- succinimide (NHS) esters, or azide groups. These groups may be used to render the polymer hydrophilic or to achieve particular interactions with coating materials as described below.
- NHS N-hydroxy- succinimide
- the molecular weight and the degree of cross-linking may be adjusted to control the decomposition rate of the polymer and thus the release rate of the pharmaceutical.
- Methods of controlling molecular weight and cross-linking to adjust release rates are well known to those skilled in the art.
- particles in which active agents are encapsulated are well known to those skilled in the art.
- a double emulsion technique may be used to combine a polymer and active agent in particles.
- particles may be prepared by spray-drying.
- the disclosed immunogenic composition includes one or more carrier or coating materials to protect the disclosed immunogenic compositions from degradation prior to reaching the target site (e.g., the large intestine).
- Example compositions of particle carriers are available in U.S. Patent Nos. 6,406,745 (Talton, 2000) and U.S. Patent Application No. 20050175707, each of which is incorporated herein by reference in its entirety.
- Positively charged biocompatible materials are suitable for coating or protecting particles for use with this disclosure.
- chitosan, poly(L- lysine), and poly(ethylene imines) are suitable for coating particles for use with the disclosure.
- Lectins may also be used to coat particles. Lectins may particularly target M cells in Peyer's patches in the intestine, enhancing the affinity of the particles for the intestinal wall. Lectins are produced by a wide variety of plants; one skilled in the art will recognize that not all lectins are appropriate for use in pharmaceutical compositions. A wide variety of lectins are available from Sigma- Aldrich, which also provides information on the toxicity and mutagenicity of commercially available lectins. One skilled in the art will recognize that lectins that are found in commonly eaten foods are more likely to be suitable for use with embodiments of the disclosure.
- negatively charged materials are employed as
- bioadhesive materials include, without limitation, lecithin, polycarboxylic acids, poly(acrylic acids), polysaccharides, monosaccharides, oligosaccharides, oligopeptides, polypeptides, and co-polymers of two or more mucoadhesive materials.
- mucoadhesive or non-mucoadhesive polymers may be modified with mucoadhesive materials.
- sugars may be covalently linked to polyacrylates.
- Polymers having regions adapted to bind the coating to the core material and regions adapted to be mucoadhesive may also be employed.
- a block co-polymer of a polycation and a hydrogen bond donor can be used to coat a core containing a polymer that acts as a hydrogen bond receptor.
- Additional bioadhesive molecules that may be used with the disclosure include but are not limited to hydrophilic and amphiphilic polymers, hydrogels, and the polymers disclosed in U.S. Pat. Nos. 6,217,908, 6,297,337; 6,514,535; and 6,284,235.
- the particles are provided with a double coating.
- the particles may include a targeting agent that helps direct the particles to a specific tissue once they enter the blood stream.
- exemplary targeting agents include nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, p-glycoprotein receptors, and cell binding sequences such as RGD.
- Nucleic acid aptamers selective for a particular target may be known from the literature or may be identified using any method known to those skilled in the art, for example, the methods disclosed in U.S. Pat. Nos. 5,270,163, 5,475,096, and 6,114,120.
- Aptamers for certain tissues may also be obtained commercially, for example, from Archemix Corp. These targeting agents may be attached to the surface of the particle or may be attached to the polymer itself before the particles are formed.
- the particles are then encapsulated with a negatively charged material, e.g. , a negatively charged polymer.
- a negatively charged material e.g. , a negatively charged polymer.
- Exemplary polymers include carboxymethylcellulose, polyacrylic acid, polymethacrylic acid, polystyrenesulfonate, and polymers including carboxylate, sulfonate, sulfate, phosphate, or nitrate groups.
- a positively charged carrier/coating material is then coated over the negatively charged material, such as a copolymer based on methyl aery late, methyl methacrylate and methacrylic acid, including EUDR AGIT® (Evonik Industries, Darmstadt, Germany).
- the particles produced using the techniques described herein may be sufficiently small to traverse the intestinal mucosa or the alveolar wall. Enhanced uptake may be achieved for larger particles by the use of mucosal coatings, as described herein. The size of the particle may be optimized for stability and increased uptake.
- the environmental pH increases from about 2-3 to about 7.4.
- the pKa of the negative coating it may become neutrally charged, reducing its affinity for the positively charged mucoadhesive coating.
- the mucoadhesive coating becomes dislodged from the particle.
- the negatively charged carrier material or coating may also be biodegradable, for example, through hydrolysis or enzymatic mechanisms.
- the pKa of the negatively charged carrier material or coating is such that it will become neutrally charged after entering the bloodstream, the degradation of the material/coating will dislodge the outer mucoadhesive material/coating from the particle.
- the two coatings protect both the agent being delivered and the targeting agent from degradation in the digestive system while allowing the targeting agent to be exposed at the surface of the particles after they enter the bloodstream.
- a pH sensitive microparticle carrier is used to protect the disclosed PLGA nanoparticles disclosed herein from degradation prior to reaching the target site (e.g., the large intestine).
- the carrier is an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid, such as EUDRAGIT® (Evonik Industries, Darmstadt, Germany).
- EUDRAGIT® EUDRAGIT®
- a carrier/coating is a copolymer that is insoluble in acidic media, but dissolves by salt formation above about pH 6.5, such as about pH 6.6, about pH 6.7, about pH 6.8, about pH 6.9, about pH 7.0, about pH 7.1, about pH 7.2, about pH 7.3, about pH 7.4, or about pH 7.5.
- a carrier/coating is a copolymer that is insoluble in acidic media, but dissolves by salt formation above pH 7.0.
- a carrier/coating is EUDRAGIT® FS 30 D or EUDRAGIT® RS 100 (Evonik Industries, Darmstadt, Germany).
- EUDRAGIT® coats the PLGA nanoparticles to protect PLGA from degradation prior to reaching the target site (e.g., the large intestine).
- Carriers/Coatings may be immobilized on the particles using a variety of chemical interactions. For example, positively charged carriers/coatings such as chitosan will form electrostatic bonds with negatively charged PLA or PLGA. This interaction prevents the carrier/coating from being stripped off the particle as it passes into the bloodstream. Likewise, negatively charged carriers/coatings may be employed with positively charged cores.
- positively charged carriers/coatings such as chitosan will form electrostatic bonds with negatively charged PLA or PLGA. This interaction prevents the carrier/coating from being stripped off the particle as it passes into the bloodstream.
- negatively charged carriers/coatings may be employed with positively charged cores.
- the electrostatic interaction allows for easy fabrication of the particles and facilitates release of the active agent.
- Layer-by-layer deposition techniques may be used to coat the particles. For example, particles may be suspended in a solution containing the coating material, which then simply adsorbs onto the surface of the particles. The coating is not a thick or tight layer but rather allows the active agent to diffuse from the polymer core into the bloodstream.
- the carrier/coating allows enzymes to diffuse from the blood into the particle. Even though the carrier/coating can remain intact as the active agent is released, it is itself susceptible to decomposition, and the particle can be fully metabolized.
- non-covalent interactions include but are not limited to the following:
- biotin may be attached to the surface of the controlled release polymer core and streptavidin may be attached to the carrier/coating material; or conversely, biotin may be attached to the carrier/coating material and the streptavidin may be attached to the surface of the controlled release polymer core.
- the biotin group and streptavidin are typically attached to the controlled release polymer system or to the coating via a linker, such as an alkylene linker or a polyether linker. Biotin and streptavidin bind via affinity interactions, thereby retaining the carrier/coating on the controlled release polymer core.
- a polyhistidine may be attached to or included within the carrier/coating material, and a nitrilotriacetic acid can be attached to the surface of the controlled release polymer core.
- a metal such as Ni +2 , will chelate the polyhistidine and the nitrilotriacetic acid, thereby binding the carrier/coating to the controlled release polymer core.
- a hydrophobic tail such as
- polymethacrylate or an alkyl group having at least about 10 carbons may be attached to the carrier/coating material.
- the hydrophobic tail will adsorb onto the surface of a hydrophobic controlled release polymer, such as a polyorthoester, polysebacic anhydride, unmodified poly(lactic acid), or polycaprolactone, thereby binding the carrier/coating to the controlled release polymer core.
- a macrocyclic host such as cucurbituril or cyclodextrin
- a guest group such as an alkyl group, a polyethylene glycol, or a diaminoalkyl group
- the host group may be attached to the carrier/coating material and the guest group may be included in the controlled release polymer core.
- the host and/or the guest molecule may be attached to the carrier/coating material or the controlled release polymer system via a linker, such as an alkylene linker or a polyether linker.
- an oligonucleotide having a particular sequence may be attached to the surface of the controlled release polymer core, and an essentially complementary sequence may be attached to the
- oligonucleotides are essentially complimentary if about 80% of the nucleic acid bases on one oligonucleotide form hydrogen bonds via an oligonucleotide base pairing system, such as Watson-Crick base pairing, reverse Watson-Crick base pairing, Hoogsten base pairing, etc., with a base on the second oligonucleotide.
- an oligonucleotide sequence attached to the controlled release polymer system may form at least about 6 complementary base pairs with a complementary oligonucleotide attached to the nucleic acid ligand.
- a poly(cytosine) tag may be attached to the controlled release polymer core and a poly(guanine) tag may be attached to the coating material.
- sugars may be used as a mucoadhesive coating. The hydroxyl groups on sugars such as glucose and galactose will hydrogen bond with polar moieties on polymers such as polyvinyl alcohol). Sugar dimers or oligomers may be used as well.
- the core and the carrier/coating may also be linked via covalent interactions.
- PLGA may be modified with a carboxylate group and employed as a core material. Chitosan or another aminated coating material can be coupled to the core using a coupling reagent such as EDC or DCC. Alternatively, PLGA may be modified to have an activated NHS ester which can then be reacted with an amine group on the coating material. Either carrier/coating or core materials may be modified to include reactive groups such as hydroxyl, amine, carboxyl, maleimide, thiol, NHS ester, azide, or alkyne. Standard coupling reactions may then be used to couple the modified material to a second material having a complementary group (e.g., a carboxyl modified core coupled to an aminated carrier/coating material).
- a complementary group e.g., a carboxyl modified core coupled to an aminated carrier/coating material.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the encapsulated particle is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and
- Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the
- the disclosed immunogenic compositions are N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- a subject in an immunologically effective dose in a suitable form to prevent and/or treat infectious diseases.
- the particular dosage depends upon the age, weight and: medical condition of the subject to be treated, as well as on the method of administration. Suitable doses can be readily determined by those of skill in the art.
- the exact dosage is chosen by the individual physician in view of the patient to be treated.
- dosage and administration are adjusted to provide an effective amount of the desired active agent to the subject being treated.
- the effective amount of bioactive agent may vary depending on such factors as the desired biological endpoint, the active agent and/or immunostimulatory agents to be delivered, the target tissue, the route of administration, etc. For example, the severity of the disease state; age, weight and gender of the patient being treated; diet, time and frequency of administration; drug combinations; reaction sensitivities; and tolerance/response to therapy.
- the disclosed immunogenic compositions are preferably compounded with a carrier in dosage unit form for ease of administration and uniformity of dosage.
- the expression "dosage unit form" as used herein refers to a physically discrete unit of conjugate appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compositions of the immunogenic compositions will be decided by the attending physician within the scope of sound medical judgment.
- the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually mice, rabbits, dogs, pigs, or non-human primates. The animal model is also used to achieve a desirable concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
- Therapeutic efficacy and toxicity of particle materials and the drugs delivered thereby can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose is therapeutically effective in 50% of the population) and LD 50 (the dose is 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, LD 50 /ED 50 .
- Pharmaceutical compositions which 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. Preliminary doses can be determined according to animal tests, and the scaling of dosages for human administration is performed according to art- accepted practices such as standard dosing trials.
- the therapeutically effective dose can be estimated initially from serum antibody level testing.
- the immunogenic compositions of this disclosure can offer various advantages over conventional vaccines, including enhanced immunogenicity of weakly immunogenic antigens, potential reduction in the amount of antigen used, less frequent booster immunizations, improved efficacy, preferential stimulation of immunity, or potential targeting of immune responses.
- the immunogenic compositions can be administered to a subject by a variety of routes, but preferably by oral administration.
- the immunogenic compositions are preferably sterile and contain either a therapeutically or prophylactically effective amount of the immunogenic compositions in a unit of weight or volume suitable for administration to a subject.
- the characteristics of the carrier depend on the route of administration.
- Physiologically and pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials which are well known in the art.
- a therapeutically effective amount of the immunogenic composition is administered to a subject.
- the “effective amount” means the total amount of therapeutic agent (e.g., conjugate) or other active component that is sufficient to show a meaningful benefit to the subject, such as, enhanced immune response, treatment, healing, prevention or amelioration of the relevant medical condition (disease, infection, or the like), or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
- therapeutic agent e.g., conjugate
- the term refers to that therapeutic agent alone.
- the term refers to combined amounts of the ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
- administering an effective amount of a therapeutic agent means that the subject is treated with said therapeutic agent(s) in an amount and for a time sufficient to induce an improvement, and preferably a sustained improvement, in at least one indicator that reflects the severity of the disease, infection, or disorder.
- An improvement is considered “sustained” if the patient exhibits the improvement on at least two occasions separated by a period of time.
- the degree of improvement can be determined based, for example, on immunological data, or on signs or symptoms of a disease, infection, or disorder.
- Various indicators that reflect the extent of the patient's illness can be assessed for determining whether the amount and time of the treatment is sufficient.
- the baseline value for the chosen indicator or indicators can established based on by examination of the patient prior to administration of the first dose of the therapeutic agent, or based on statistical values generated from a population of healthy patients. If the therapeutic agent is administered to treat acute symptoms, the first dose is administered as soon as practically possible. Improvement is induced by administering therapeutic agents until the subject manifests an improvement over baseline for the chosen indicator or indicators.
- this degree of improvement is obtained by repeatedly administering the therapeutic agents over a period time, e.g., for one, two, or three months or longer, or indefinitely.
- a single dose can be sufficient for treating or preventing certain conditions.
- Treatment can be continued indefinitely at the same level or at a reduced dose or frequency, regardless of the patient's condition, if desired. Once treatment has been reduced or discontinued, it later can be resumed at the original level if symptoms reappear.
- the amount of the immunogenic compositions that provides an efficacious dose or therapeutically effective dose for vaccination against infection from bacterial, viral, fungal or parasitic infection is from about 1 ⁇ g or less to about 100 mg or more, per kg body weight, such as about 1 ⁇ g, 2 ⁇ g, 5 ⁇ g, 10 ⁇ g 15 ⁇ g, 25 ⁇ g, 50 ⁇ g, 100 ⁇ g, 250 ⁇ g, 500 ⁇ g, 1 mg, 2 mg, 5 mg, 10 mg, 15, mg, 25, mg, 50 mg, or 100 mg per kg body weight.
- the immunogenic compositions can be administered as a single dose or in a series including one or more boosters.
- an infant or child can receive a single dose early in life, then be administered a booster dose up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years later.
- the booster dose generates antibodies from primed B- cells, for example, an anamnestic response. That is, the immunogenic compositions elicit a high primary functional antibody response in infants or children, and is capable of eliciting an anamnestic response following a booster administration, demonstrating that the protective immune response elicited by the immunogenic compositions is long-lived.
- the immunogenic compositions can be formulated into liquid preparations for oral administration. Suitable forms for such administration include suspensions, syrups, and elixirs. Suitable forms for such administration include sterile suspensions and emulsions.
- Such conjugate vaccines can be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, and the like.
- the conjugate vaccines can also be lyophilized.
- the disclosed compositions can contain auxiliary substances such as wetting or emulsifying agents, pH buffeting agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired.
- Such preparations can include complexing agents, metal ions, polymeric compounds such as polyacetic acid, polyglycolic acid, hydrogels, dextran, and the like, liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts or spheroblasts.
- suitable lipids for liposomal formulation include, without limitation,
- compositions can be administered in combination with various vaccines either currently being used or in development, whether intended for human or non- human subjects.
- vaccines for human subjects and directed to infectious; diseases include the combined diphtheria and tetanus toxoids vaccine; pertussis whole cell vaccine; the inactivated influenza vaccine; the 23-valent pneumococcal vaccine; the live measles vaccine; the live mumps vaccine; live rubella vaccine; Bacille Calmette- Guerin I (BCG) tuberculosis vaccine; hepatitis A vaccine; hepatitis B vaccine; hepatitis C vaccine; rabies vaccine (e.g., human diploid cell vaccine); inactivated polio vaccine; meningococcal polysaccharide vaccine; quadrivalent meningococcal conjugate vaccine; yellow fever live virus vaccine; typhoid killed whole cell vaccine; cholera vaccine; Japanese B encephalitis killed virus vaccine; adenovirus vaccine; cytomegalovirus vaccine; rota
- the immunogenic compositions disclosed herein can be provided to an administering physician or other health care professional in the form of a kit.
- the kit is a package which houses a container which contains the immunogenic composition including the vaccine and instructions for administering the composition to a subject.
- the kit can optionally also contain one or more other therapeutic agents and instructions for use.
- a vaccine cocktail containing two or more vaccines can be included, or separate pharmaceutical compositions containing different vaccines or therapeutic agents.
- the kit can also contain separate doses of the composition for serial or sequential administration.
- the kit can optionally contain instructions for storage, reconstitution (if applicable), and administration of any or all therapeutic agents included.
- the kits can include a plurality of containers reflecting the number of administrations to be given to a subject. If the kit contains a first and second container, then a plurality of these can be present.
- This example provides the materials and methods used to perform the studies discussed in Examples 2-6 below.
- Female BALB/c (6-8 weeks) were purchased from the Frederick Cancer Research Center (Frederick, MD) or Taconic (Hudson, NY) and housed in pathogen-free conditions in the National Cancer Institute Animal Facility.
- RGPGRAFVTI and OVA 257 - 2 6 4 (SEQ ID NO: 4 SIINFEKL) were synthesized by NeoMPS (San Diego, CA).
- MALP2 For in vitro stimulation of DCs, MALP2, poly(I:C) and CpG ODN dosed at 0.1 ⁇ g/ml, 25 ⁇ g/ml and 2 ⁇ g/ml, respectively, were added to culture.
- the vPE16 replicating vaccinia virus was a kind gift of P. Earl and B. Moss. Recombinant vaccinia proteins A33 and Ll were supplied by BEI resources (Manassas, VA) and Gary Cohen.
- PLGA and EUDRAGIT® were manufactured with the NanoDRY ® (NANODRY is a registered trademark of NANO-TEX, Inc., Oakland, CA) technology (U.S. Patent Application No. 20050175707).
- a 0.9 ml of chloroform solution containing 9 mg of PLGA was prepared, followed by addition of 0.1-0.2 mg of FITC-BSA, peptides, or proteins in 0.1 ml of water to form the primary emulsion.
- the PLGA mixture is emulsified with a Vortex mixer 30 seconds to form the water-in-oil (without) emulsion.
- the mixture emulsion was added dropwise into 9 ml of isopropanol in a small stainless steel bowl agitated at low frequency sonication (60 hertz, 60% max) with four MOJO beads (1 cm ceramic marbles). Nanoparticles were precipitated at 300 to 400 Torr for 15 minutes at 25°C. The suspension settled for 1 hour in the freezer and the precipitate was lyophilized in a 20-ml glass vial under vacuum overnight. A white powder was typically obtained containing nanoparticles with a diameter of 300 to 400 nm. BSA content/release was determined by BCA or Bradford protein analysis. FITC-BSA release was measured by UV absorbance at 455 nm. Particle size was determined using a Horiba LA-930 Particle Sizer.
- PLGA and FITC-BSA were purchased from Lakeshore Biomaterials (Birmingham, AL) and Sigma-Aldrich Co. (St. Louis, MO), respectively.
- FITC-BSA PLGA/FITC-BSA is composed of 1-2% of HTC-BSA and 10 mg of the particle was given i.c.r. to examine mucosal uptake.
- encapsulated vaccine is comprised of peptide antigen (PeptAg: 100 ⁇ g of PCLUS3- 18IIIB per 10 mg of PLGA nanoparticle; ProtAg: A33+L1 10 ⁇ g each) and TLR ligands (TLRL: 0.5 ⁇ g of MALP-2, 100 ⁇ g of poly(LC) and 10 ⁇ g of CpG ODN).
- PeptAg 100 ⁇ g of PCLUS3- 18IIIB per 10 mg of PLGA nanoparticle
- ProtAg A33+L1 10 ⁇ g each
- TLR ligands TLR ligands
- EUDRAGIT ® FS30D or L100-55 were used to coat PLGA, and 20 mg of microparticles containing 200 ug of PeptAg or 20 ⁇ g of A33+L1, 1 ⁇ g of MALP-2, 200 ⁇ g of poly(LC) and 20 ⁇ g of CpG ODN vaccine were used for each oral delivery.
- Reagent delivery and virus challenge For oral delivery, micro/nanoparticles suspended in 50 ⁇ l of PBS were given orally through an animal feeding needle.
- reagents were suspended in 100 ⁇ l of PBS and delivered with a polished pipette tip through the anal canal.
- Peptide and TLR ligands as vaccines were mixed with 20 ⁇ g of DOTAP liposomal transfection reagent (Roche)
- vPE16 was recovered from paired ovaries 6 days after challenge. Tissues were homogenized in PBS with a homogenizer (POLYTRON , Kinematica, Inc., Cincinnati, OH). Plaque-forming assays were performed on CV-I cells for 48 hours followed by counterstaining with 5% w/v crystal violet. Virus presence was expressed as total plaque-forming units (loglO PFUs)/o varies.
- 4xlO 7 or IxIO 7 PFU of the virus were given by either the i.c.r. or i.vag. route, respectively. After WR challenge, mice were weighed for two weeks and euthanized when their weight loss was over 25%.
- EUDRAGIT® coating FS30D/PLGA/Pept+TLR ligands dry particles were incubated with 1-2 ml PBS (pH 7.4) at 37°C for 1.5 hours, and then centrifuged at 2,000 rpm for 2 minutes. The supernatant was concentrated by centrifugation at 1-2 ml PBS (pH 7.4) at 37°C for 1.5 hours, and then centrifuged at 2,000 rpm for 2 minutes. The supernatant was concentrated by centrifugation at
- the nanoparticles were examined under a FEI CM 120 TEM (equipped with a Gatan GIFlOO image filer) operating at a beam energy of 120KeV. Images were acquired by using a Gatan Ik x Ik cooled CCD camera. Field Emission SEM image was acquired. DCs previously incubated with PLGA/FITC-BSA nanoparticles were placed on a glass cover slip and examined for fluorescence expression with a Nikon Eclipse TE-300 inverted fluorescence microscope.
- Bone marrow cells were cultured at 7x10 5 AnI for 6 days in the presence of 15 ng/ml GM-CSF (Peprotech, Rocky Hill, NJ) in RPMI 1640 medium supplemented with 10% heat-inactivated fetal calf serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin. Sera were collected two weeks after the last immunization. Vaginal washes were collected by pipetting 20 ⁇ l of PBS. To prepare homogenates, colon/rectum samples were removed and homogenized in PBS with a homogenizer (POLYTRON, Kinematica, Cincinnati, OH).
- spleens were removed from na ⁇ ve mice and separated by negative separation (to avoid perturbation) on an autoMACS Separator (Miltenyi Biotec Inc., Auburn, CA) using a cocktail of antibodies against CD43, CD4, and Ter-119.
- the purity of sorted cell populations was at least 97%.
- EUDRAGIT/PLGA/Pept+TLR ligands particles were incubated with PBS (pH 7.4) for 16 hours and centrifuged at 2,000 rpm to remove aggregates. The supernatants were added to DC cultures. After 20 hours of incubation, DCs were stained for intracellular IL- 12 with IL-12p70/40 antibodies. For identification of FITC-expressing cells, isolated mucosal cells or in vitro cultured DCs were examined by flow cytometry.
- ELISA was performed by serially diluting samples and incubated in plates precoated with WR proteins A33 and Ll (BEI resources, Manassas, VA). The plates were then incubated with HRP-conjugated anti-mouse IgA or IgG detection antibodies (Southern Biotechnology Associates, Birmingham, AL) and color was developed by incubating TMB (Biolegend, San Diego, CA) in darkness. The optical density was read at 450 nm. Antibody titers were derived from the inverse dilution at which the sample yielded an optical density twice that of the background of control specimens from unimmunized mice.
- PLGA nanoparticles enter the mucosa once placed in the large intestine lumen and can induce specific mucosal immune responses
- Uncoated PLGA/FITC-BSA nanoparticles ranging from 300-500 nm (418 nm ⁇ 88 SD) (FIGS. 3A and 3B), were delivered directly to the colon of mice by i.c.r. administration.
- cells isolated from the large intestinal epithelium were detected positive for fluorescence expression (FIG. 2A), indicating an uptake of the nanoparticles, primarily found in CDl lb + B220 int macrophages and secondarily in CDl Ic + CDlIb + dendritic cells (DCs) (FIG. 7A).
- Transmission electron microscopy (TEM) indicates PLGA nanoparticles in the cytoplasm (FIG. 7B).
- EUDRAGIT® microencapsulation enables site-specific uptake of PLGA in the large intestine mucosa
- This example demonstrates site-specific oral delivery of nanoparticle- releasing microparticle vaccines.
- the EUDRAGIT® served to make 10-50 ⁇ m particles and released contents significantly as early as 1 hour (FIGS. 9A and 9B), while maximal release occurred in 3-4 hours (FIG. 10A).
- FS30D containing PLGA/FITC-BSA nanoparticles (FIG. 10B)
- nanoparticle uptake was observed almost exclusively in the large intestine (FIGS. 2C and 2D).
- the cecum is the first part of the large intestine encountered, but in humans, where the cecum is relatively small, the balance between cecum and colon may be different.
- FS30D was also contrasted with L100-55 microparticles containing the same nanoparticles for lower pH release (pH > 5.5) in the small intestine.
- Oral administration of EUDRAGIT® L100-55 coated nanoparticles resulted in primary uptake in the small intestine (FIGS. 2C and 2D).
- FSSOD/PLGA/vaccine complex induces immune responses and protection against rectal or vaginal viral infection
- This example shows that oral delivery of FS30D-coated PLGA vaccine targeting the large intestine is effective for local vaccination against rectal or vaginal viral infection.
- mice were challenged rectally with a replication-competent vaccinia virus vPE-16, which expresses the HIV Env epitope P18-I10 used in the peptide vaccine.
- Mice immunized with the LlOO-55-coated vaccine were not protected from the virus challenge.
- the FS30D-coated vaccine reduced viral load almost equally as well as the peptide vaccine given i.c.r. (FIG. 5A). Therefore, oral delivery of FS30D-coated PLGA vaccine targeting the large intestine is effective for local colorectal vaccination against viral infection.
- mice were immunized orally with FS30D/PLGA/PCLUS3-18IIIB+TLR ligands twice with a two-week interval, followed by intravaginal (i.vag.) challenge with vPE-16.
- intravaginal i.vag.
- oral delivery of large-intestine targeted FS30D vaccine induced almost equal clearance of virus after vaginal challenge (FIG.
- This example shows induction of antibody-mediated immunity against rectal or vaginal viral infection.
- the humoral response also plays a role in the gut and genital mucosal immunity. Therefore, it was examined whether encapsulating whole viral proteins in the FS30D coated PLGA vaccine could induce antibody-mediated protective immunity at both mucosal sites after challenging mice with pathogenic vaccinia strain WR.
- Vaccinia A33 and Ll are immunogens of the extracellular enveloped virion and intracellular mature virion, respectively.
- Antibody responses induced by the combination of both types of viral antigens encoded by plasmid DNA or as recombinant proteins can protect animals from lethal challenge of WR.
- CTLs specific for the vaccinia protein A33 or Ll have not been reported in BALB/c mice.
- TLR ligands can activate B cells directly and contribute to antigen- specific antibody responses, including in the gut.
- the triple TLR ligands were evaluated to determine if they synergistically activate B cells (FIG. HA) as determined by CD69. i.c.r. immunization with the combination of recombinant A33 and Ll mixed with the triple TLR ligands in DOTAP induced strong antibody responses in the blood (FIG. 1 IB).
- FS30D coated PLGA containing A33+L1+TLRL vaccine nanoparticles were constructed and administered orally.
- Vaccinia-specific IgA and IgG antibody responses were significantly induced in both the large intestine (evaluated in tissue homogenates) and vaginal tracts (evaluated in vaginal washes) (FIG. 6A). Further, immunized mice resisted the WR virus challenge by either the rectal or vaginal route (FIG. 6B) as determined by weight loss and by 0 versus 75% or 50% mortality, respectively. Therefore, these studies demonstrate that the FS30D coated PLGA vaccine system can also be used to induce antibody-mediated mucosal protection at both transmission sites. Although the B cell response is still required for the protective immunity even in the presence of CD4 + T cells, the possibility that protein- specific CD4 + T cells could provide help for B cell differentiation and maturation is not to be excluded. The present examples demonstrate that the disclosed two-part
- EUDRAGIT®/PLGA nanoparticle -releasing microparticle system can deliver orally administered vaccines highly specifically into the large intestinal mucosa and induce almost equal protective immunity not only in the rectal but also vaginal mucosa.
- PLGA is a Food and Drug Administration (FDA) approved copolymer for therapeutic purposes owing to its biocompatibility and biodegradability, and long safety record.
- EUDRAGIT® polymers are also FDA documented copolymers and nontoxic and safe for use. Combinatorial use of these two polymers ensured our orally delivered vaccine's exclusively targeting the large intestine.
- the disclosed targeted micro/nanoparticle system lends itself to practical large-scale clinical applications because of its 1) great stability in a dry-powder formulation; 2) easy shipment and storage without refrigeration, and long shelf life; and 3) economical large batch GMP processing. These features would be highly desired for effective industrial manufacturing and clinical management.
- a nanoparticle -releasing microparticle oral delivery system was developed and demonstrated to be an easy, non-invasive vaccination strategy effective against viral infection occurring through the rectal or vaginal mucosa.
- Such a vaccination strategy can be used to develop vaccines against mucosal infections and potentially mucosal cancers and to advanced study of immunobiological mechanisms involving mucosal compartmentalization.
- this system can be used to design vaccines for HIV, HPV, HSV, and infections by other infectious species as well as colon cancer, cervical cancer or other types of mucosal cancers.
- This example describes specific antigens that can be used as immunogens in the compositions and methods disclosed herein.
- Viral antigens suitable for use with the disclosed methods and compositions include inactivated (or killed) virus, attenuated virus, split virus formulations, purified subunit formulations, viral proteins which may be isolated, purified or derived from a virus, and Virus Like Particles (VLPs).
- Viral antigens preferably include epitopes which are exposed on the surface of the virus during at least one stage of its life cycle.
- Viral antigens include but are not limited to antigens derived from one or more of the viruses set forth below as well as the specific antigen examples identified below.
- Viral antigens may be from a Hepatitis C virus (HCV).
- HCV antigens may be selected from one or more of El, E2, E1/E2, NS345 polyprotein, NS 345-core polyprotein, core, and/or peptides from the nonstructural regions (Houghton et al. (1991) Hepatology 14:381-388, which is incorporated by reference).
- Viral antigens may be derived from a Human Herpes virus, such as Herpes Simplex Virus (HSV), Varicella-zoster virus (VZV), Epstein-Barr virus (EBV), or Cytomegalovirus (CMV).
- Human Herpes virus antigens may be selected from immediate early proteins, early proteins, and late proteins.
- HSV antigens may be derived from HSV-I or HSV-2 strains.
- HSV antigens may be selected from glycoproteins gB, gC, gD and gH, or immune escape proteins (gC, gE, or gl).
- VZV antigens may be selected from core, nucleocapsid, tegument, or envelope proteins.
- EBV antigens may be selected from early antigen (EA) proteins, viral capsid antigen (VCA), and glycoproteins of the membrane antigen (MA).
- CMV antigens may be selected from capsid proteins, envelope glycoproteins (such as gB and gH), and tegument proteins.
- EA early antigen
- VCA viral capsid antigen
- MA glycoproteins of the membrane antigen
- CMV antigens may be selected from capsid proteins, envelope glycoproteins (such as gB and gH), and tegument proteins.
- Exemplary herpes antigens include (GENBANKTM Accession No. in parentheses) those derived from human herpesvirus 1 (Herpes simplex virus type 1)
- NC_001806 human herpesvirus 2 (Herpes simplex virus type 2) (NC_001798), human herpesvirus 3 (Varicella zoster virus) (NC_001348), human herpesvirus 4 type 1 (Epstein-Barr virus type 1) (NC_007605), human herpesvirus 4 type 2 (Epstein-Barr virus type 2) (NC_009334), human herpesvirus 5 strain AD169 (NC_001347), human herpesvirus 5 strain Merlin Strain (NC_006273), human herpesvirus 6A (NC_001664), human herpesvirus 6B (NC_000898), human herpesvirus 7 (NC_001716), human herpesvirus 8 type M (NC_003409), and human herpesvirus 8 type P (NC_009333).
- HPV antigens Human Papilloma virus (HPV) antigens are known in the art and can be found for example in International Patent Publication No. WO96/19496,
- HPV Ll based antigens are disclosed in international Patent publication Nos. W094/00152, W094/20137, W093/02184 and W094/05792, all of which are incorporated by reference.
- Such an antigen can include the Ll antigen as a monomer, a capsomer or a virus like particle. Such particles may additionally comprise L2 proteins.
- Other HPV antigens are the early proteins, such as E7 or fusion proteins such as L2-E7.
- Exemplary HPV antigens include (GENBANKTM Accession No. in parentheses) those derived from human papillomavirus- 1
- NC_001356 human papillomavirus- 18
- NC_001357 human papillomavirus-2
- NC_001352 human papillomavirus-54
- NC_001676 human papillomavirus-61
- NC_001694 human papillomavirus-cand90
- NC_004104 human papillomavirus RTRX7 (NC_004761)
- NC_001576 human papillomavirus type 10
- NC_008189 human papillomavirus type 103
- NC_008188 human papillomavirus type 107 (NC_009239), human
- NC_001526 human papillomavirus type 16
- NC_001683 human papillomavirus type 24
- NC_001583 human papillomavirus type 26
- NC_001586 human papillomavirus type 34
- NC_001587 human papillomavirus type 4
- NC_001354 human papillomavirus type 48
- NC_001690 human papillomavirus type 49
- NC_001531 human papillomavirus type 5
- NC_001691 human papillomavirus type 53 (NC_001593), human papillomavirus type 60 (NC_001693), human papillomavirus type 63 (NC_001458), human papillomavirus type 6b (NC_001355), human papillomavirus type 7 (NC_001595), human papillomavirus type 71 (NC_002644), human papillomavirus type 9
- NC_001596 human papillomavirus type 92 (NC_004500), and human papillomavirus type 96 (NC_005134).
- Viral antigens may be derived from a Retrovirus, such as an Oncovirus, a Lentivirus or a Spumavirus.
- Oncovirus antigens may be derived from HTLV-I, HTLV-2 or HTLV-5.
- Lentivirus antigens may be derived from HIV-I or HIV- 2.
- Retrovirus antigens may be selected from gag, pol, env, tax, tat, rex, rev, nef, vif, vpu, and vpr.
- HIV antigens for HIV are known in the art, for example HIV antigens may be selected from gag (p24gag and p55gag), env (gpl60 and gp41), pol, tat, nef, rev vpu, miniproteins, (p55 gag and gpl40v). HIV antigens may be derived from one or more of the following strains: HlVmb, HIV; HIVLAV, HIVLAI, HIVM N, HIV-I CM235, HIV-I US4. Examples of HIV antigens can be found in International Patent Publication Nos. WO09/089568, WO09/080719, WO08/099284, and WO00/15255, and U.S. Patent No.
- HIV antigens include (GENB ANKTM Accession No. in parentheses) those derived from human immunodeficiency virus 1 (NC_001802), human immunodeficiency virus 2 (NC_001722).
- Bacterial antigens suitable for use in the disclosed methods and compositions include proteins, polysaccharides, lipopolysaccharides, and outer membrane vesicles which may be isolated, purified or derived from a bacterium.
- bacterial antigens include bacterial Iy sates and inactivated bacteria formulations.
- Bacteria antigens can be produced by recombinant expression.
- Bacterial antigens preferably include epitopes which are exposed on the surface of the bacteria during at least one stage of its life cycle.
- Bacterial antigens include but are not limited to antigens derived from one or more of the bacteria set forth below as well as the specific antigens examples identified below.
- Neiserria gonorrhoeae antigens include Por (or porin) protein, such as PorB (see, e.g., Zhu et al. (2004) Vaccine 22:660-669), a transferring binding protein, such as TbpA and TbpB (see, e.g., Price et al. (2004) Infect. Immun. 71(l):277-283), an opacity protein (such as Opa), a reduction-modifiable protein (Rmp), and outer membrane vesicle (OMV) preparations (see, e.g., Plante et al. (2000) J. Infect. Dis. 182:848-855); WO 99/24578; WO 99/36544; WO 99/57280; and WO 02/079243, all of which are incorporated by reference).
- PorB see, e.g., Zhu et al. (2004) Vaccine 22:660-669
- Chlamydia trachomatis antigens include antigens derived from serotypes A,
- Chlamydia trachomas antigens also include antigens identified in WO 00/37494; WO 03/049762; WO 03/068811; and WO 05/002619 (all of which are incorporated by reference), including PepA (CT045), LcrE (CT089), Art (CT381), DnaK (CT396), CT398, OmpH-like (CT242), L7/L12 (CT316), OmcA (CT444), AtosS (CT467), CT547, Eno (CT587), HrtA (CT823), MurG (CT761), CT396 and CT761, and specific combinations of these antigens.
- Treponemapallidum (Syphilis) antigens include TmpA antigen.
- compositions of the invention can include one or more antigens derived from a sexually transmitted disease (STD).
- STD sexually transmitted disease
- Such antigens can provide for prophylactis or therapy for STDs such as chlamydia, genital herpes, hepatitis (such as HCV), genital warts, gonorrhea, syphilis and/or chancroid (see WO 00/15255, which is incorporated by reference).
- Antigens may be derived from one or more viral or bacterial STDs.
- Viral STD antigens for use in the invention may be derived from, for example, HIV, herpes simplex virus (HSV-I and HSV-2), human papillomavirus (HPV), and hepatitis (HCV).
- Bacterial STD antigens for use in the invention may be derived from, for example, Neiserria gonorrhoeae, Chlamydia trachomatis, Treponemapallidum, Haemophilus ducreyi, E. coli, and Streptococcus agalactiae.
- This example describes a particular method that can be used to treat a mucosal tumor in humans by use of the disclosed oral vaccine system. Although particular methods, dosages, and modes of administrations are provided, one skilled in the art will appreciate that variations can be made without substantially affecting the treatment.
- a mucosal cancer such as colonic or cervical cancer
- a disclosed immunogenic composition comprising one or more tumor- associated antigens, such as mucosal cancer-associated antigens.
- the method can include screening subjects to determine if they have a tumor, such as a mucosal cancer (e.g. , cervical or colonic cancer). Subjects having a mucosal cancer are selected.
- a clinical trial would include half of the subjects following the established protocol for treatment of mucosal cancer (such as a normal chemotherapy/radiotherapy /surgery regimen). The other half would follow the established protocol for treatment of the tumor (such as a normal chemotherapy/radiotherapy/surgery regimen) in combination with administration of the immunogenic compositions described above.
- the tumor is surgically excised (in whole or part) prior to treatment with the immunogenic compositions.
- a clinical trial would include half of the subjects following the established protocol for treatment of mucosal cancer (such as a normal chemotherapy/radiotherapy/surgery regimen). The other half would follow the administration of the immunogenic compositions described above.
- the tumor is surgically excised (in whole or part) prior to treatment with the therapeutic compositions.
- the subject is first screened to determine if they have a mucosal cancer or are at risk of acquiring one.
- the subject is screened to determine if they have colonic or cervical cancer.
- methods that can be used to screening for a mucosal cancer include a combination of ultrasound, tissue biopsy, and serum blood levels. If blood or a fraction thereof (such as serum) is used, 1-100 ⁇ l of blood is collected. Serum can either be used directly or fractionated using filter cut-offs to remove high molecular weight proteins. If desired, the serum can be frozen and thawed before use. If a tissue biopsy sample is used, 1-100 ⁇ g of tissue is obtained, for example using a fine needle aspirate.
- the biological sample e.g., tissue biopsy or serum
- the biological sample is analyzed to determine if it expresses one or more molecules known to be associated with a particular type of mucosal cancer, such as colon or cervical cancer.
- Expression of one or more molecules associated with mucosal cancer is indicative that the subject is a candidate for receiving the therapeutic compositions disclosed herein. However, such pre-screening is not required prior to administration of the therapeutic compositions disclosed herein.
- the subject is treated prior to administration of a immunogenic composition for the treatment of a mucosal cancer.
- a immunogenic composition for the treatment of a mucosal cancer.
- the tumor can be surgically excised (in total or in part) prior to administration of one or more immunogenic compositions.
- the subject can be treated with an established protocol for treatment of the particular tumor present (such as a normal chemotherapy/radiotherapy regimen).
- a therapeutic effective dose of the immunogenic composition is administered to the subject.
- a therapeutic effective dose of an agent to one or more of the disclosed immunogenic compositions is orally administered to the subject to reduce or inhibit tumor growth and/or vascularization.
- the amount of the composition administered to prevent, reduce, inhibit, and/or treat a mucosal cancer or a condition associated with it depends on the subject being treated, the severity of the disorder, and the manner of administration of the therapeutic composition.
- a therapeutically effective amount of an agent is the amount sufficient to prevent, reduce, and/or inhibit, and/or treat the condition (e.g., mucosal cancer) in a subject without causing a substantial cytotoxic effect in the subject.
- An effective amount can be readily determined by one skilled in the art, for example using routine trials establishing dose response curves.
- particular exemplary dosages are provided above.
- the immunogenic compositions can be administered in a single dose delivery or in a repeated administration protocol (for example, by a, daily, weekly, or monthly repeated administration protocol).
- these compositions may be formulated with an inert diluent or with a pharmaceutically acceptable carrier.
- the bioactive agent is a tumor-associated antigen.
- Tumor antigens are proteins that are produced by tumor cells that elicit an immune response, particularly T-cell mediated immune responses.
- the tumor antigen can be any tumor-associated antigen, which are well known in the art and include, for example, carcinoembryonic antigen (CEA), ⁇ -human chorionic gonadotropin, alphafetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-I, MN-CA IX, human telomerase reverse transcriptase, RUl, RU2 (AS), intestinal carboxyl esterase, mut hsp70-2, macrophage colony stimulating factor, prostase, prostate- specific antigen (PSA), PAP, NY-ESO-I, LAGE-Ia, p53, prostein, PSMA,
- CEA carcinoembryonic antigen
- AFP alphafetoprotein
- lectin-reactive AFP lectin-reactive AFP
- IGF insulin growth factor
- a subject is administered an immunogenic composition including one or more tumor-associated antigens following diagnosis of the subject (e.g. a diagnosis of the cancer).
- the immunogenic composition can be administered in a single dose or in multiple doses over time.
- a subject having a mucosal cancer is administered an immunogenic composition orally daily for at least one week, at least one month or at least three months. Administration of the immunogenic compositions can be continued after chemotherapy and radiation therapy is stopped and can be taken long term (for example over a period of months or years).
- subjects having a tumor can be monitored for tumor treatment, such as regression or reduction in metastatic lesions, tumor growth or vascularization.
- subjects are analyzed one or more times, starting 7 days following treatment.
- Subjects can be monitored using any method known in the art.
- diagnostic imaging can be used (such as x-rays, CT scans, MRIs, ultrasound, fiber optic examination, and laparoscopic examination), as well as analysis of biological samples from the subject (for example analysis of blood, tissue biopsy, or other biological samples), such as analysis of the type of cells present, or analysis for a particular tumor marker.
- assessment can be made using ultrasound, MRI, or CAT scans, or analysis of the type of cells contained in a tissue biopsy. It is also contemplated that subjects can be monitored for the response of their tumor(s) to therapy during therapeutic treatment by at least the aforementioned methods.
- subjects are stable or have a minor, mixed or partial response to treatment, they can be re-treated after re-evaluation with the same schedule and preparation of agents that they previously received for the desired amount of time, such as up to a year of total therapy.
- a partial response is a reduction in size or growth of some tumors, but an increase in others.
Abstract
L'invention porte sur des compositions immunogènes formulées pour une distribution par voie orale. Ces compositions comprennent un cœur polymère encapsulant un immunogène cible et un ou plusieurs agents immunostimulatoires; et une matrice copolymère sensible au pH, disposée autour du cœur polymère. Dans certains exemples, l'immunogène cible est un antigène issu d'un pathogène viral, bactérien, fongique ou parasite. Dans certains exemples, le ou les différents agents immunostimulatoires est un ligand de récepteur de type Toll. L'invention porte également sur des procédés d'induction d'une réponse immunitaire mucosale dans le gros intestin d'un sujet, de tels procédés comprenant l'administration d'une quantité thérapeutiquement efficace des compositions immunogènes formulées pour une distribution par voie orale. L'invention porte également sur des méthodes de traitement ou d'inhibition d'une infection par une bactérie, un virus, un champignon ou un parasite pathogène.
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