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US20090317411A1 - Compositions for inducing immune responses specific to globo h and ssea3 and uses thereof in cancer treatment - Google Patents

Compositions for inducing immune responses specific to globo h and ssea3 and uses thereof in cancer treatment Download PDF

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US20090317411A1
US20090317411A1 US12/485,546 US48554609A US2009317411A1 US 20090317411 A1 US20090317411 A1 US 20090317411A1 US 48554609 A US48554609 A US 48554609A US 2009317411 A1 US2009317411 A1 US 2009317411A1
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cancer
globo
fut2
ssea3
fut1
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Chi-Huey Wong
Alice L. Yu
John. Yu
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Academia Sinica
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Academia Sinica
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Priority to US12/485,546 priority Critical patent/US20090317411A1/en
Priority to US12/537,129 priority patent/US8268969B2/en
Priority to EP09789075.0A priority patent/EP2310047B1/fr
Priority to KR1020117000382A priority patent/KR101677279B1/ko
Priority to NZ590140A priority patent/NZ590140A/en
Priority to AU2009269127A priority patent/AU2009269127B2/en
Priority to MX2014004316A priority patent/MX350230B/es
Priority to ES09789075T priority patent/ES2570630T3/es
Priority to CN201610100376.9A priority patent/CN105535955B/zh
Priority to CN200980122743.3A priority patent/CN102215862B/zh
Priority to JP2011514633A priority patent/JP5628158B2/ja
Priority to MX2010013932A priority patent/MX2010013932A/es
Priority to CA2728341A priority patent/CA2728341C/fr
Priority to PCT/US2009/004519 priority patent/WO2010005598A1/fr
Priority to TW102105871A priority patent/TWI583393B/zh
Priority to TW98127948A priority patent/TWI392502B/zh
Assigned to ACADEMIA SINICA reassignment ACADEMIA SINICA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WONG, CHI-HUEY, YU, ALICE L., YU, JOHN
Publication of US20090317411A1 publication Critical patent/US20090317411A1/en
Priority to US13/568,510 priority patent/US9028836B2/en
Priority to JP2014035431A priority patent/JP5795655B2/ja
Priority to US14/675,838 priority patent/US9603913B2/en
Priority to JP2015159196A priority patent/JP6151319B2/ja
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001169—Tumor associated carbohydrates
    • A61K39/001173—Globo-H
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/00118—Cancer antigens from embryonic or fetal origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • A61K2039/627—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier characterised by the linker
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • Globo H is a cancer antigen overly expressed in various epithelial cancers. It has been suggested that this antigen can serve as a target in cancer immunotherapy. While vaccines have been developed to elicit antibody responses against Globo H, their anti-cancer efficacies are unsatisfactory due to low antigenicity of Globo H. There is a need for a new vaccine capable of eliciting high levels of immune responses targeting Globo H.
  • the present invention is based on an unexpected discoveries that (1) SSEA3, the immediate precursor of Globo H, is expressed at a high level in breast cancer stem cells and therefore can serve as a suitable target for breast cancer treatment, and (2) ⁇ -galactosyl-ceramide ( ⁇ -GalCer) is an effective adjuvant that promotes production of anti-Globo H and anti-SSEA3 antibodies.
  • one aspect of this invention features an immune composition containing Globo H or its fragment (e.g., SSEA3) and an adjuvant (e.g., ⁇ -GalCer).
  • Globo H or its fragment can be conjugated with Keyhole Limpet Hemocyanin (KLH).
  • KLH Keyhole Limpet Hemocyanin
  • this immune composition elicits immune responses (e.g., antibody production) targeting Globo H or its fragment and, therefore, is effective in treating cancer (e.g., breast cancer, prostate cancer, ovarian cancer, and lung cancer).
  • cancer e.g., breast cancer, prostate cancer, ovarian cancer, and lung cancer.
  • Another aspect of this invention relates to a method of producing antibody specific to Globo H or its fragment by administering to a non-human mammal (e.g., mouse, rabbit, goat, sheep, or horse) the immune composition described above and isolating from the mammal antibody that binds to Globo H or its fragment.
  • a non-human mammal e.g., mouse, rabbit, goat, sheep, or horse
  • this invention features a method of treating cancer with a first agent that inhibits the activity of 2-fucosyltransferase 1 (FUT1) or 2-fucosyltransferase 2 (FUT2). Both FUT1 and FUT2 are involved in Globo H biosynthesis.
  • This agent can be an antibody that blocks the interaction between FUT1/FUT2 and its substrate or an interfering RNA (e.g., siFUT1 or siFUT2) that suppresses expression of FUT1 or FUT2.
  • the first agent, targeting FUT1 can be combined with a second agent that inhibits the activity of FUT2.
  • the first agent is siFUT1 and the second agent is siFUT2.
  • the immune composition or the first and 10 second agents in treating cancer and in manufacturing a medicament for the treatment of cancer.
  • FIG. 1 is a diagram depicting the structures of the hexasaccharide epitope in Globo H (GH) and fragments of this epitope.
  • Panel A the structure of the hexasaccharide epitope.
  • Panel B the structures of the hexasaccharide epitopes and its seven fragments.
  • FIG. 2 is a chart showing the levels of anti-Globo H and anti-SSEA3 antibodies in mice immunized with KLH-conjugated Globo H alone and with KLH-conjugated Globo H together with ⁇ -GalCer.
  • FIG. 3 is a diagram showing the effects of siFUT1 and siFUT2 on FUT1 and FUT2 expression in breast cancer cells.
  • Panel A suppression of FUT1 expression by siFUT1 in MB157 cells.
  • Panel B suppression of FUT1 and FUT2 expression by siFUT1 and siFUT2, respectively, in T-47D cells.
  • FIG. 4 is a diagram showing the effects of siFUT1 and siFUT2 on inhibiting growth of breast cancer xenografts.
  • Panel a a chart showing that siFUT1 and siFUT2 inhibited breast tumor growth.
  • Panel b a chart showing that siFUT1 and siFUT2 reduced weights of tumor mass.
  • Globo H and its immediate precursor SSEA3 both can serve as targets in cancer treatment.
  • one embodiment of this invention is a method of treating cancer by administering to a subject in need thereof an effective amount of an immune composition containing either Globo H or a fragment thereof (e.g., SSEA3, also known as Gb5) and an adjuvant.
  • an immune composition containing either Globo H or a fragment thereof (e.g., SSEA3, also known as Gb5) and an adjuvant.
  • target cancer include, but are not limited to, breast cancer (including stages 1-4), lung cancer (e.g., small cell lung cancer), liver cancer (e.g., hepatocellular carcinoma and cohlagiocarcinoma), oral cancer, stomach cancer (including T1-T4), colon cancer, nasopharynx cancer, skin cancer, kidney cancer, brain tumor (e.g., astrocytoma, glioblastoma multiforme, and meningioma), prostate cancer, ovarian cancer, cervical cancer, bladder cancer, and endometrium, rhabdomyosarcoma, osteosarcoma, leiomyosarcoma, and gastrointestinal stromal tumor.
  • breast cancer including stages 1-4
  • lung cancer e.g., small cell lung cancer
  • liver cancer e.g., hepatocellular carcinoma and cohlagiocarcinoma
  • oral cancer e.g., hepatocellular carcinoma and cohlagiocarcinoma
  • stomach cancer including T1
  • treating refers to the application or administration of a composition including one or more active agents to a subject, who has cancer, a symptom of cancer, or a predisposition toward cancer, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the cancer, the symptoms of the cancer, or the predisposition toward the cancer.
  • An effective amount refers to the amount of C each active agent required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents. Effective amounts vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and co-usage with other active agents.
  • the immune composition used in the above-described method can contain a glycan (i.e., a molecule containing a sugar moiety) that is Globo H or a fragment thereof and an adjuvant.
  • Globo H is a glycan containing the hexasaccharide epitope shown in FIG. 1 , Panel A, and optionally, a non-sugar moiety.
  • Its fragment is a glycan containing a fragment of the hexasaccharide epitope and, if applicable, the non-sugar moiety. Fragments of the hexasaccharide epitope are shown in FIG. 1 , Panel B.
  • These oligosaccharides can be prepared by routine methods. See, e.g., Huang et al., Proc. Natl. Acad. Sci. USA 103:15-20 (2006). If desired, they can be linked to a non-sugar moiety.
  • any of the glycans described above can be conjugated to a protein carrier, such as KLH. They can then be mixed with an adjuvant and optionally a pharmaceutically acceptable carrier (e.g., a phosphate buffered saline, or a bicarbonate solution) to form an immune composition (e.g., a vaccine) via conventional methods.
  • a pharmaceutically acceptable carrier e.g., a phosphate buffered saline, or a bicarbonate solution
  • an immune composition e.g., a vaccine
  • the composition may be prepared as injectables, as liquid solutions, or emulsions and the carrier is selected on the basis of the mode and route of administration, as well as on the basis of standard pharmaceutical practice.
  • the immune composition preferably contains ⁇ -GalCer as an adjuvant.
  • adjuvant include, but are not limited to, a cholera toxin, Escherichia coli heat-labile enterotoxin (LT), liposome, immune-stimulating complex (ISCOM), or immunostimulatory sequences oligodeoxynucleotides (ISS-ODN).
  • the composition can also include a polymer that facilitates in vivo delivery. See Audran R. et al. Vaccine 21:1250-5, 2003; and Denis-Mize et al.
  • auxiliary substances such as wetting or emulsifying agents, or pH buffering agents to enhance the ability of the composition to elicit immune responses against the sugar moiety in Globo H or its fragment.
  • the immune composition described herein can be administered parenterally (e.g., intravenous injection, subcutaneous injection or intramuscular injection).
  • parenterally e.g., intravenous injection, subcutaneous injection or intramuscular injection.
  • binders and carriers may include, for example, polyalkylene glycols or triglycerides.
  • Oral formulations may include normally employed incipients such as, for example, pharmaceutical grades of saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10-95% of the immune composition described herein.
  • the immune composition is administered in a manner compatible with the dosage formulation, and in an amount that is therapeutically effective, protective and immunogenic.
  • the quantity to be administered depends on the subject to be treated, including, for example, the capacity of the individual's immune system to synthesize antibodies, and if needed, to produce a cell-mediated immune response. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner. However, suitable dosage ranges are readily determinable by one skilled in the art. Suitable regimes for initial administration and booster doses are also variable, but may include an initial administration followed by subsequent administrations.
  • the dosage of the vaccine may also depend on the route of administration and varies according to the size of the host.
  • the immune composition of this invention can also be used to generate antibodies in animals for production of antibodies, which can be used in both cancer treatment and diagnosis.
  • Methods of making monoclonal and polyclonal antibodies and fragments thereof in animals are well known in the art. See, for example, Harlow and Lane, (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York.
  • the term “antibody” includes intact immunoglobulin molecules as well as fragments thereof, such as Fab, F(ab′) 2 , Fv, scFv (single chain antibody), and dAb (domain antibody; Ward, et. al. (1989) Nature, 341, 544).
  • Another embodiment of this invention is a method of treating cancer by inhibiting the activity of FUT1 and/or FUT2, both being responsible for Globo H biosynthesis.
  • FUT1 and C FUT2 are well-known 2-fucosyltransferases that transfer a fucose unit to the reducing end of an oligosaccharide substrate via an ⁇ 1,2 linkage. See, e.g., NCBI Gene ID:2523 and NCBI Gene ID:2524.
  • the just-described method is performed by administering to a subject in need thereof an effective amount of an antibody that interferes with the interaction between FUT1/FUT2 and their substrate, i.e., an antibody specific to FUT1/FUT2 or their substrate.
  • an antibody that interferes with the interaction between FUT1/FUT2 and their substrate, i.e., an antibody specific to FUT1/FUT2 or their substrate.
  • FUT1/FUT2 a fragment thereof, or a substrate thereof can be coupled to a carrier protein (e.g., KLH), if necessary, mixed with an adjuvant, and then injected into a host animal.
  • Antibodies produced in the animal can then be purified by conventional methods, e.g., affinity chromatography.
  • Commonly employed host animals include rabbits, mice, guinea pigs, and rats.
  • adjuvants that can be used to increase the immunological response depend on the host species and include Freund's adjuvant (complete and incomplete), mineral gels such as aluminum hydroxide, CpG, surface-active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol.
  • Useful human adjuvants include BCG (bacille Calmette-Guerin) and Corynebacterium parvum.
  • Monoclonal antibodies, homogeneous populations of antibodies to FUT1/FUT2 or their substrate can be prepared using standard hybridoma technology (see, for example, Kohler et al. (1975) Nature 256, 495; Kohler et al. (1976) Eur. J. Immunol. 6, 511; Kohler et al. (1976) Eur J Immunol 6, 292; and Hammerling et al. (1981) Monoclonal Antibodies and T Cell Hybridomas, Elsevier, N.Y.).
  • monoclonal antibodies can be obtained by any technique that provides for the production of antibody molecules by continuous cell lines in culture such as described in Kohler et al. (1975) Nature 256, 495 and U.S. Pat. No. 4,376,110; the human B-cell hybridoma technique (Kosbor et al. (1983) Immunol Today 4, 72; Cole et al. (1983) Proc. Natl. Acad. Sci. USA 80, 2026, and the EBV-hybridoma technique (Cole et al. (1983) Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96).
  • Such antibodies can be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD, and any subclass thereof.
  • the hybridoma producing the monoclonal antibodies of the invention may be cultivated in vitro or in vivo. The ability to produce high titers of monoclonal antibodies in vivo makes it a particularly useful method of production.
  • techniques developed for the production of “chimeric antibodies” can be used. See, e.g., Morrison et al. (1984) Proc. Natl. Acad. Sci. USA 81, 6851; Neuberger et al. (1984) Nature 312, 604; and Takeda et al. (1984) Nature 314:452.
  • a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.
  • techniques described for the production of single chain antibodies can be adapted to produce a phage library of single chain Fv antibodies.
  • Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge.
  • antibody fragments can be generated by known techniques.
  • such fragments include, but are not limited to, F(ab′) 2 fragments that can be produced by pepsin digestion of an antibody molecule, and Fab fragments that can be generated by reducing the disulfide bridges of F(ab′) 2 fragments.
  • Antibodies can also be humanized by methods known in the art. For example, monoclonal antibodies with a desired binding specificity can be commercially humanized (Scotgene, Scotland; and Oxford Molecular, Palo Alto, Calif.). Fully human antibodies, such as those expressed in transgenic animals are also features of the invention. See, e.g., Green et al. (1994) Nature Genetics 7, 13; and U.S. Pat. Nos. 5,545,806 and 5,569,825.
  • RNA interference is a process in which a dsRNA directs homologous sequence-specific degradation of messenger RNA.
  • RNAi can be triggered by 21-nucleotide duplexes of small interfering RNA (siRNA) without activating the host interferon response.
  • a dsRNA can be synthesized by methods known in the art. See, e.g., Caruthers et al., 1992, Methods in Enzymology 211, 3-19, Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997, Methods Mol. Bio. 74, 59, Brennan et al., 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, U.S. Pat. No. 6,001,311. It can also be transcribed from an expression vector and isolated using standard techniques.
  • the dsRNA or vector as described above can be delivered to cancer cells by methods, such as that described in Akhtar et al., 1992, Trends Cell Bio. 2, 139.
  • it can be introduced into cells using liposomes, hydrogels, cyclodextrins, biodegradable nanocapsules, or bioadhesive microspheres.
  • the dsRNA or vector can be locally delivered by direct injection or by use of an infusion pump.
  • Other approaches include employing various transport and carrier systems, for example through the use of conjugates and biodegradable polymers
  • the above-described dsRNA contains a first strand that is complementary to CGCGGACTTGAGATCCTTT, or the complement thereof (e.g., siFUT1 described in Example 2 below).
  • the dsRNA contains a first strand that is complementary to CTATGTCCATGTCATGCCAAA, or the complement thereof (e.g., siFUT2 described in Example 2 below).
  • conjugated means two entities are associated, preferably with sufficient affinity that the therapeutic benefit of the association between the two entities is realized. Conjugated includes covalent or noncovalent bonding as well as other forms of association, such as entrapment of one entity on or within the other, or of either or both entities on or within a third entity (e.g., a micelle).
  • the chaperone agent can be a naturally occurring substance, such as a protein (e.g., human serum albumin, low-density lipoprotein, or globulin), carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid), or lipid.
  • a protein e.g., human serum albumin, low-density lipoprotein, or globulin
  • carbohydrate e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid
  • lipid e.g., lipid-lipid
  • the chaperone agent is a micelle, liposome, nanoparticle, or microsphere, in which the dsRNA or the DNA plasmid is encapsulated.
  • a chaperone agent serves as a substrate for attachment of one or more of a fusogenic agent, a condensing agent, or a targeting agent.
  • a fusogenic agent is responsive to the local pH. For instance, upon encountering the pH within an endosome, it can cause a physical change in its immediate environment (e.g., a change in osmotic properties, which disrupts or increases the permeability of the endosome membrane), thereby facilitating release of a dsRNA or DNA plasmid into host cell's cytoplasm.
  • a preferred fusogenic agent changes charge, for example, becoming protonated at a pH lower than a physiological range (e.g., at pH 4.5-6.5). Fusogenic agents can be molecules containing an amino group capable of undergoing a change of charge (e.g., protonation) when exposed to a specific pH range.
  • Such fusogenic agents include polymers that contain polyamino chains (e.g., polyethyleneimine) and membrane disruptive agents (e.g., mellitin).
  • polymers that contain polyamino chains e.g., polyethyleneimine
  • membrane disruptive agents e.g., mellitin
  • Other examples include polyhistidine, polyimidazole, polypyridine, polypropyleneimine, mellitin, and a polyacetal substance (e.g., a cationic polyacetal).
  • a condensing agent interacts with (e.g., attracts, holds, or binds to) the dsRNA or the DNA plasmid and causes it to condense (e.g., reducing the size of the dsRNA/plasmid), thus protecting the dsRNA/plasmid against degradation.
  • the condensing agent includes a moiety (e.g., a charged moiety) that interacts with the dsRNA or the DNA plasmid via, e.g., ionic interactions.
  • condensing agent examples include a polylysine, spermine, spermidine, polyamine or quaternary salt thereof, pseudopeptide-polyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, and an alpha helical peptide.
  • Globo H-KLH was purchased from Optimer Pharmaceuticals. Three groups of 6-week-old female BALB/b mice (BioLASCO), two in each group, were injected (s.c.) with PBS (“control mice”), 0.6 ⁇ g KLH-Globo H (“Globo H mice”), and 0.6 ⁇ g KLH-Globo H in combination with 2 ⁇ g ⁇ -GalCer (“Globo H-GalCer mice”), respectively, once every week for three weeks. Sera were collected from the mice of each group 10 days after the last injection and antibodies specific to Globo H and SSEA3 were detected following the method described in Huang et al., Proc, Natl. Acad. Sci. USA 103:15-20 (2006).
  • the sera were diluted 1:25 with 3% BSA/PBS buffer and 50 ml of each diluted serum were incubated with a slide, to which Globo H and SSEA3 were attached, in a humidifying chamber for 1 hour.
  • the slide was washed three times with 0.05% PBS/Tween 20 (PBST) and subsequently incubated with 100 ⁇ l Cy5-conjugated goat anti-mouse IgG antibody(1:200) in the same chamber. After being air-dried, the slide was washed with PBST and water, each for three times, and then measured for the levels of fluorescence released thereby with a microarray scanner (GenePix 4000B. Molecular Devices). The results thus obtained were analyzed with the GenePix Pro software.
  • the RT-PCR reaction was carried out under the following conditions: 50° C. for 2 min, 95° C. for 10 min, followed by 40 cycles of 95° C. for 10 sec and 60° C. for 1 min, using an ABI Prism 7000 Sequence Detection System and the results thus obtained were analyzed using the ABI Prism 7000 SDS software (Applied Biosystems) to obtain a threshold cycle number (Ct value) for the mRNA levels of FUT1 and FUT2 in each cell line.
  • the Ct value was normalized against the mRNA level of HPRT1 in the same cell line to obtain a ⁇ Ct value.
  • the ⁇ Ct value of FUT1 in MCF-7 was used to normalize the ⁇ Ct value of either FUT1 or FUT2 in each cell-line.
  • the fold-change of a mRNA level was calculated based on the following formula: 2 ⁇ [ ⁇ Ct(target gene) ⁇ Ct(FUT1 in MCF-7)] .
  • the mRNA levels of HPRT1 and GAGDH were used as internal controls.
  • FUT1 FUT2 mRNAs were barely detectable in MCF-7 and MB 157 cells, while in the T47D cells, the level of FUT2 mRNA was 6000-fold greater than that in the other two cell lines.
  • FUT1 or FUT2 were reduced via RNA interference as follows. Nucleotide sequences encoding siFUT1 (containing a sequence complementary to CGCGGACTTGAGAGATCCTTT) and siFUT2 (containing a sequence complementary to CTA TGTCCATGTCATGCCAAA) were cloned into a VSV-G-pseudotype lentiviral vector and introduced into 293T cells together with packaging plasmids pMD.G and pCMV ⁇ R8.91. Lentiviral particles thus produced were harvested at 48 and 72 hours after transfection and concentrated by ultracentrifugation (25,000 rpm, 90 minutes).
  • virus particles capable of expressing siFUT1 or siFUT2
  • ThT-47D or MB157 plated at 2 ⁇ 10 5 cells/well in 6-well plates
  • polybrene Sigma-Aldrich Corp.
  • the cells were harvested 96 hours later and the mRNA levels of FUT1 and FUT2 were determined by quantitative RT-PCR as described above.
  • siFUT1 successfully reduced the level of FUT1 mRNA in MB157 cells (see panel A).
  • siFUT1 and siFUT2 reduced the levels of FUT1 and FUT2 mRNAs, respectively, in T-47D cells. See FIG. 3 , panel B.
  • the levels of Globo H in both the MB157 and the T-47D cells were determined via flow cytometry using the AlexaFluor488-VK-9 antibody as follows. Aliquots of cells, each containing 1 ⁇ 10 5 cells, were incubated first with anti-GloboH-Alexa488 (Vk9; see Chang et al., Proc. Natl. Acad. Sci. USA 105:11667-11672 (2008) for 1 hour on ice, then with biotinylated-UEA1 (Vector Laboratories) for one hour on ice, and finally with FITC-conjugated streptavidin (Jackson ImmunoResearch) for 1 hour on ice.
  • MB157 and T-47D cells infected with virus particles expressing siFUT1 or siFUT2, were suspended in DMEM/F12 medium supplemented with 0.4% BSA, 20 ng/ml EGF, 20 ng/ml bFGF, 5 ug/ml insulin, 1 ⁇ M hydrocortisone, 4 ⁇ g/ml heparin, 1 ⁇ B27 supplement, and 1% methyl cellulose (Sigma-Aldrich) at a density of 1,000 cells/ml. The suspended cells were then seeded on ultra low attachment plates (Costar) and cultured under suitable conditions to allow mammosphere formation. The primary mammosphere thus formed were Cultures were fed weekly.
  • primary mammospheres were harvested, dispersed with trypsin (Gibco), pelleted, suspended in the culture medium described above at 1,000 cells/ml. The suspended cells were then cultured following the method described above to allow formation of secondary mammosphere.
  • the numbers of mammospheres formed by both MB157 and T-47D cells expressing siFUT1 were only 50% of that of the mammospheres formed by non-infected cells, indicating that siFUT1 significantly reduced the mammosphere formation capacity of the cancer cells.
  • the number of the mammospheres formed by the T-47D cells expressing siFUT2 was only 17% of that of the mammospheres formed by non-infected cells. This result shows that, like siFUT1, siFUT2 also significantly reduced the mammosphere formation capacity of cancer cells.
  • balb/c nude mice and NOD/SCID mice were injected with 17- ⁇ -estradiol (1.7 mg/ml) subcutaneously at the lateral side of each mouse.
  • 8-week-old, female balb/c nude mice were injected at their mammary fat pad with (i) MB157 cells (1 ⁇ 10 7 ) stably expressing siFUT, (ii) vehicle control MB157 cells (1 ⁇ 10 7 ), (iii) T-47D cells (5 ⁇ 10 6 ) stably expressing siFUT1, (iv) T-7D cells (5 ⁇ 10 6 ) stably expressing siFUT2, and (v) vehicle control T-47D cells (5 ⁇ 10 6 ), all suspended in 0.1 ml of 50% Matrigel (BD Biosciences) and 50% supplemented RPMI-1640 medium.
  • T-47D cells expressing both siFUT1 and siFUT2 were small, round-shaped cells forming dense clusters. Similar morphology changes were observed in MB-157 cells expressing siFUT1.
  • ACEA's 96 microtiter plates were coated with fibronectin (25 ug/ml, Sigma), type IV collagen (2 ug/ml, BD biosciences), or laminin (5 ug/ml, Sigma), all being diluted at appropriate folds in PBS, at 37° C. for 1 hr and then blocked with 1% BSA for 1 h at 37° C.
  • MB157 and T-47D cells were seeded at 2.5 ⁇ 10 4 per 100 ⁇ l of culture medium in the coated ACEA's 96 microtiter plates.
  • the migration capacity of cells expressing siFUT1 or siFUT2 was first examined in a wound healing assay as follows.
  • MB157 and T-47D cells were plated in a 12-well plate in a serum-containing medium until they reached 60% confluence.
  • the cells were then infected with the virus particles described in Example 1 above or introduced with a control plasmid. These cells reached 100% confluence in a 2-day culture period.
  • the cells were then starved overnight and confluent monolayers of the cells were wounded with a 20 ul plastic pipette tip sharply.
  • Phase-contrast images of the cells were acquired every 4 h for 3 days or every 2 h for 1 day.
  • the rate of cell migration was determined using Metamorphic software that measures the distance that the cells have traveled during a desired time period.
  • Results indicate C that siFUT1 suppressed migration of T-47D cells and MB158 cells by 2.81 and 2.13, respectively, as compared with the cells transfected with the control plasmid.
  • Exogenous addition of Globo H-ceramide rescued the reduced migration capacity of cells expressing siFUT1 or siFUT2. This data indicates that the observed migration reduction was caused by the decreased level of Globo H resulting from suppression of FUT1 and FUT2 expression via RNA interference.

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MX2010013932A MX2010013932A (es) 2008-06-16 2009-08-06 Vacunas anticancer de globo h y relacionadas con adyuvantes de glucolipido novedosos.
KR1020117000382A KR101677279B1 (ko) 2009-06-16 2009-08-06 신규한 당지질 애주번트를 갖는 ｇｌｏｂｏ ｈ 및 관련 항암 백신
NZ590140A NZ590140A (en) 2008-06-16 2009-08-06 GLOBO H AND STAGE SPECIFIC EMBRYONIC ANTIGENS AND Bb4 AND RELATED ANTI-CANCER VACCINES WITH NOVEL GLYCOLIPID ADJUVANTS
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US8268969B2 (en) 2012-09-18
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CA2728341A1 (fr) 2010-01-14
US9028836B2 (en) 2015-05-12
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