WO2011036560A2 - Compositions de glycoconjugués et méthodes pour le traitement du vih - Google Patents

Compositions de glycoconjugués et méthodes pour le traitement du vih Download PDF

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WO2011036560A2
WO2011036560A2 PCT/IB2010/002541 IB2010002541W WO2011036560A2 WO 2011036560 A2 WO2011036560 A2 WO 2011036560A2 IB 2010002541 W IB2010002541 W IB 2010002541W WO 2011036560 A2 WO2011036560 A2 WO 2011036560A2
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glycoconjugate
composition according
hiv
composition
carrier
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PCT/IB2010/002541
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WO2011036560A3 (fr
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Paolo Costantino
Anna Kabanova
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/595—Polyamides, e.g. nylon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • HIV human immunodeficiency virus
  • Env HIV-1 envelope protein
  • the broadly neutralizing monoclonal antibody 2G12 binds a cluster of high-mannose-type oligosaccharides on the gp120 subunit of Env, revealing a conserved epitope on the glycan shield [2].
  • the sugar multivalency was demonstrated to be the key to higher 2G12 affinity [3].
  • Dendrimers are polymers of spherical or other three-dimensional shapes that have precisely defined compositions and that possess a precisely defined molecular weight. Dendrimers can be synthesized as water-soluble macromolecules through appropriate selection of internal and external moieties, See, U.S. Pat. Nos. 4,507,466 and 4, 568,737, incorporated by reference herein. The first well-defined, symmetrical, dendrimer family were the polyamidoamine (PAMAM) dendrimers, which are manufactured by the Dow Chemical Company.
  • PAMAM polyamidoamine
  • Figure 1 illustrates total IgG antibody titres specific against an9 in ELISA assay performed on microplates coated with human serum albumine (HSA) conjugate of Man9. Each dot represents single rabbit sera. Horizontal bars indicate GMT meaning of group.
  • HSA human serum albumine
  • Figure 2 illustrates inhibition of anti-Man9PAMAM4-CRM sera in ELISA assay with Man4-PAMAM4-CRM plate coating.
  • a composition having a glycoconjugate of at least 2 sugar moieties bound to a multivalent support and wherein said composition binds neutralizing antibodies greater than monovalent oligosaccharides.
  • Such glycoconjugates can be further bound to carriers.
  • the glycoconjugates are useful in vaccines and as antigens which bind to antibodies.
  • the present invention relates to glycoconjugates having sugar moieties bound to a multivalent support for the treatment of HIV.
  • glycoconjugates are provided which comprise oligosaccharides composed of synthetic high mannose sugars bound to dendrimer scaffolds, such as flexible polyamidoamine (PAMAM).
  • PAMAM flexible polyamidoamine
  • the invention also encompasses, glycoconjugates or oligosaccharides bound directly to carriers. The invention thus provides glyconconjugates as vaccine antigens which bind to neutralizing antibodies.
  • Oletaccharides refer to a saccharide polymer containing a number, for example two or more, of component sugars.
  • Man4, Man6, Man9, Man(X) refer to a polymer of mannose sugars linked together by the number of sugars, i.e., 4, 6, or 9 manrioses respectively. (X) refers to the number of sugars in the polymer.
  • “Sugar” or “sugar moiety” or “saccharide” refer to simple sugars, saccharide, saccharide residues, or derivatives thereof.
  • Cluster refers to a linear or branched polymers of sugars.
  • Glycoconjugate refers to a oligosaccharide or oligosaccharide cluster linked to or associated with carrier protein.
  • Oligosaccharides included in the present invention are selected from the group monosaccharide, disaccharide, trisaccharide, and polymers of sugar moieties including 4, 6, 8, 9, 10 units.
  • Suitable sugar moieties include at least one hexose residue, such as allose, altrose, glucose, mannose, gulose, idose, galactose, talose and combinations thereof.
  • a saccharide residue is a pentose, tetrose or triose.
  • a sugar moeity may contain a combination of hexose, pentose, tetrose and triose residues.
  • a sugar moiety may contain a 7-, 8-, 9, 10-, 11-, 12- or more carbon sugar, such as sialic acid.
  • a sugar moiety also encompasses steroisomers or anomer forms, combinations thereof, acid derivatives thereof, and glycosyl residues thereof.
  • the present invention relates to a glycoconjugate comprising oligosaccharides linked to or associated with a multivalent scaffold.
  • the number of sugar moieties which may be linked or associated with a multivalent scaffold is limited only by scaffold valency, the amount of active groups desired or presented and cross-reactivity to 2G12.
  • Preferably the number of sugar moieties that form a cluster most closely resembles glycosylation patterns on envelope regions of HIV.
  • a preferred glycoconjugate comprises a cluster of 4, 6, 8, 9, 10 or more sugar moieties conjugated to a multivalent support.
  • Preferred glycoconjugate includes Man6, Man9, Man4PA AM4, Man4PAMAM8, Man9PAMAM4, Man9PAMAM8.
  • a multivalent support may also be protein-based, including single amino acid polymers such as polylysine, polyarginine and polyhistidine, gelatin, collagen, complex natural ' protein carriers such as albumins and globulins; and including recombinant versions and combinations of these.
  • a multivalent support may also be carbohydrate- based, including for instance polymers such as carrageen, alginates, pectins and celluloses.
  • a multivalent support includes those that are lipid-based, such as cationic lipids of various compositions, liposome compositions of various types as described for instance in R. R. C. New, Liposomes: A Practical Approach, Oxford University Press.
  • a preferred multivalent support includes a dendrimer upon which monosaccharides and oligosaccharides are bound or associated.
  • Dendrimer creation is generally characterized by multistage synthesis of generational products having an organized branched structure. Preparation and synthesis of dendrimers is well known and is described by way of example in 4507466, 4558120, 4568737 and 4587329. Briefly, a dendrimer is synthesized from monomers added in stepwise fashion, such that each synthetic step produces a generation which is added to in a subsequent step. Each generation of dendrimers has an increasing number of terminals available for conjugation to a functional group.
  • a first generation dendrimer may have 4 sites available for functional group conjugation, a second generation 8, etc.
  • the number of functional groups conjugated to the sites available for attachment on the dendrimer may be equal to or less than the maximum number of sites available on the dendrimer.
  • Various types of dendrimers are known in the art including polyamidoamine (PAMAM) and poly (propylene imine) dendrimers.
  • Additional dendrimer compositions may be used as a multivalent support in an inventive composition include L-lysine and N,N'-bis(acrylamido)acetic acid dendrimers.
  • Dendrimer compositions, in the context of the present invention are advantageous due to their structural stability and ability to mimic the glycosylated regions of antigenic epitopes on HIV.
  • Preferred glycoconjugates include Man4PAMAM4, an4PAMAM8, Man9PAMAM4, Man9PAMAM8.
  • the glycoconjugates of the invention have a relative binding efficiency to 2G12 and HIV gp120 proteins similar to 2G12, as well as a 10 to 20- fold enhancement of capacity to inhibit gp120-2G 2 interaction in in vitro assays compared to monovalent sugars.
  • Man4 and an9 glycoconjugates showed cross-reactivity with 2G12 in ELISA assay.
  • the glycoconjugates of the invention induce antibodies having dissociation constant values of 10 "6 , W 7 , 10 10 "9 ,10 - 10 , 10 "11 , 10 2 , 10 "13 , 10 “14 , less than 10 "6 , preferably less than 10 "8 , preferably less than 10 "10 .
  • Conjugation of sugar to functional groups on multivalent supports utilizes techniques known in the art.
  • an amino group of synthetic oligosaccharide or of a linker bound to a synthetic oligosaccharide, activated with N-disuccinimidyl adipate is linked to an amine on a scaffold or carrier protein.
  • An exemplary method for conjugation is described in the Examples herein.
  • other conjugation chemistries can be used.
  • a free amino group on sugar or on a linker bound to a sugar it can be activated with squarate linker or other linker with ester groups. Further this activated amino group may be conjugated to an amino group on a protein or scaffold.
  • a carboxylic ester is present on a synthetic oligosaccharide or on a linker bound to it
  • treatment with a diamine can generate a free amino group which can be activated as described above.
  • activation can be performed by EDAC-NHS or any other chemistry capable of activating carboxylic groups.
  • the ratio of sugar or oligosaccharide to carrier protein (w/w) in a glycoconjugate may be determined calculating the ratio of carbohydrate to protein concentration or directly by mass analysis (ESI, MALDI).
  • the amount of protein is determined using a BCA or Lowry assay (for example Lowry et al (1951) J. Biol. Chem. 193, 265-275 or Peterson et al Analytical Biochemistry 100, 201-220 (1979)), and the amount of saccharide is determined using HPAEC-PAD analysis.
  • the conjugation method may also rely on activation of the saccharide with 1- cyano-4-dimethylamino pyridinium tetrafluoroborate (CDAP) to form a cyanate ester.
  • CDAP 1- cyano-4-dimethylamino pyridinium tetrafluoroborate
  • the activated saccharide may thus be coupled directly or via a spacer (linker) group to an amino group on the carrier protein.
  • the spacer could be cystamine or cysteamine to give a thiolated polysaccharide which could be coupled to the carrier via a thioether linkage obtained after reaction with a maleimide-activated carrier protein (for example using GMBS) or a holoacetylated carrier protein (for example using iodoacetimide or N-succinimidyl bromoacetatebromoacetate).
  • a maleimide-activated carrier protein for example using GMBS
  • a holoacetylated carrier protein for example using iodoacetimide or N-succinimidyl bromoacetatebromoacetate.
  • the cyanate ester obtained by CDAP chemistry
  • the amino-derivatised saccharide is conjugated to the carrier protein using carbodiimide (e.g. EDAC) chemistry via a carboxyl group on the protein carrier.
  • carbodiimide e.g. EDAC
  • the glycoconjugates of the inventions are bound to a carrier molecule.
  • the oligosaccharides may or may not be proximately associated (such as by conjugation) to the carrier molecule.
  • glyconconjugates are composed of oligosaccharides associated with multivalent structures which are further bound to carriers.
  • oligosaccharides are associated with or linked to carriers directly.
  • Preferred glycoconjugates of the invention comprise oligosaccharides bound to PAMAM and further conjugated to CRM197.
  • monovalent sugars are bound to a carrier having a glycosylation degree with a medium value of 41.5% carbohydrate/protein wt/wt %.
  • the inventors have found enhanced antigenic properties in glycoconjugates of the invention to inhibit gp120 and 2G12 interaction or reactivity with gp120 in comparison to monovalent sugars.
  • Carriers are known in the art. Plotkin, Vaccines 3rd Ed. Philadelphia, WB Saunders Co. (1999).
  • Bacterial carriers i.e., carriers derived from bacteria
  • Bacterial carriers include, but are not limited to, cholera toxin B subunit (CTB); diphtheria toxin mutant (CRM197); diphtheria toxoid; group B streptococcus alpha C protein; meningococcal outer membrane protein (OMPC); tetanus toxoid; outer membrane protein of nontypeable Haemophilus influenza (such as P6); recombinant class 3 porin (rPorB) of group B meningococci; heat-killed Brucella abortus; heat-killed Listeria monocytogenes; and Pseudomonas aeruginosa recombinant exoprotein A; N19 recombinant protein.
  • Another carrier is keyhole limpet hemo
  • carriers also encompass virus-like particles produced recombinantly in a eukaryotic cell line.
  • Virus-like particles could be of any viral nature providing sufficient immunogenicity to said glycoconjugate.
  • Virus-like particles encompassed by the invention include recombinant alphavirus, adenovirus, poxvirus, canaryvirus.
  • Alphavirus particles, methods of making and using are described in detail in 5843723, 5789245, 6342372, 5814482, 6015694, 63762366451592 and 753 180.
  • Methods for determining if glycoconjugates encompassed by the present invention can be performed by common assays for evaluating HIV antibodies and further provided below.
  • the formation of an antibody-antigen complex can be assayed using a number of well-defined diagnostic assays including conventional immunoassay formats to detect and/or quantitate antigen-specific antibodies.
  • diagnostic assays include, for example, enzyme immunoassays, e.g., ELISA, cell-based assays, flow cytometry, radioimmunoassays, and immunohistochemical staining.
  • Numerous competitive and non-competitive protein binding assays are known in the art and many are commercially available.
  • Representative assays include, for example, various binding assays with chemokine receptors (CCR5 or CXCR4), gp41 , characterized domains of these polypeptides, and competitive binding assays with characterized HIV-1 binding antibodies.
  • the glycoconjugates of the invention can also be employed to generate antibodies that recognize antigenic oligosaccharides mimicking the glycosylation pattern of HIV envelope polypeptides.
  • the method comprises administering to a subject or nonhuman animal an immunogenic composition comprising the glycoconjugate described herein.
  • immunogenic compositions of the invention can be administered to the subject by any suitable route of administration. Accordingly, in one embodiment, an immunogenic composition is administered to a subject to generate antibodies that recognize the heterologous HIV-1 neutralizing epitope.
  • Such antibodies find use in HIV research.
  • the nonhuman subjects employed in this embodiment is one typically employed for antibody production. Mammals, such as, rodents, rabbits, goats, sheep, etc., are preferred.
  • the antibodies generated can be either polyclonal or monoclonal antibodies.
  • Polyclonal antibodies are raised by injecting (e.g. subcutaneous or intramuscular injection) antigenic polypeptides into a suitable animal (e.g., a mouse or a rabbit). The antibodies are then obtained from blood samples taken from the animal.
  • the techniques used to produce polyclonal antibodies are extensively described in the literature.
  • Polyclonal antibodies produced by the subjects can be further purified, for example, by binding to and elution from a matrix that is bound with the polypeptide against which the antibodies were raised.
  • Monoclonal antibodies can also be generated using techniques known in the art.
  • the present invention provides a method for prophylactic or therapeutic treatment of an HIV or other viral infection in a human or non-human animal, which comprises administering to said human or animal an effective amount of a glycoconjugate as broadly described above.
  • An "effective amount” is defined herein as an amount of a biologically active agent that produces an intended biological activity.
  • viral infections for which glycoconjugates of the invention are useful in effecting treatment include, for example infections by HIV1 and H I V2 and other enveloped viruses including flaviviruses such as Hepatitis B and Hepatitis C, Bovine Viral Diarrhoea Virus, Human Influenza Virus A and B, Rhinovirus, Human Parainfluenza Virus, Respiratory Syncytial Virus (RSV), Varicella Zoster Virus (VZV), Human Cytomegalovirus (GMV), Epstein Barr Virus (EBV), Human Papilloma Virus (HPV), Adenovirus-8, Herpes Simplex Virus (HSV) type 1 and 2, Measles Virus, and Vesicular Stomatitis Virus (VSV).
  • flaviviruses such as Hepatitis B and Hepatitis C, Bovine Viral Diarrhoea Virus, Human Influenza Virus A and B, Rhinovirus, Human Parainfluenza Virus, Respir
  • a method of antiviral treatment is including the step of administering an effective amount of a glycoconjugate to an individual human or non- human animal in need of a therapeutic or prophylactic anti-viral treatment.
  • a glycoconjugate is administered to an individual human or non-human animal at risk of retroviral infection or in need of treatment for retrovirus infection.
  • a glycoconjugate is administered to an individual human or non-human animal at risk of HIV infection or in need of treatment for HIV infection.
  • glycoconjungates of the present invention are administered in combination with another composition, such as a protease inhibitor, nucleoside analog, virucidal agent, adjuvant or antibody, anti-viral nucleic acid such as an anti-sense construct or SIRNA, immune modulator, zinc finger inhibitor, integrase inhibitor or TAT inhibitor.
  • another composition such as a protease inhibitor, nucleoside analog, virucidal agent, adjuvant or antibody, anti-viral nucleic acid such as an anti-sense construct or SIRNA, immune modulator, zinc finger inhibitor, integrase inhibitor or TAT inhibitor.
  • the present invention provides a vaccine, wherein the host produces antibodies and/or CTL responses against the glycoconjugates of the invention, which responses then preferably serve to neutralize HIV viruses by, for example, inhibiting further HIV infection or generating neutralizing antibodies to glycoconjugates.
  • Administration of the glycoconjugates of the invention as a prophylactic vaccine would comprise administering to a subject a concentration of glycoconjugates effective in raising an immune response which is sufficient to elicit antibody and/or CTL responses to antigenic regions such as HIV Env, Gag, and Pol, and/or neutralize HIV, by, for example, inhibiting HIV ability to infect cells.
  • concentration will depend upon the specific compound to be administered, but may be determined by using standard techniques for assaying the development of an immune response which are well known to those of ordinary skill in the art.
  • the glyconconjugates of the invention may be formulated with a suitable adjuvant in order to enhance the immunological response.
  • suitable adjuvants may include, but are not limited to mineral gels such as aluminum hydroxide; surface active substances such as lysolecithin, pluronic polyols, polyanions; other peptides; oil emulsions; and potentially useful human adjuvants such as BCG and Corynebacterium parvum.
  • Adjuvants suitable for co-administration in accordance with the present invention should be those that are potentially safe, well tolerated and effective in people including QS-21 , Detox-PC, MPL-SE, MoGM-CSF, TiterMax-G, CRL-1005, GERBU, TERamide, PSC97B, Adjumer, PG-026, GSK-1 , GcMAF, B-alethine, MPC-026, Adjuvax, CpG ODN, Betafectin, Alum, and MF59 (see Kim et al., 2000, Vaccine, 18: 597 and references therein).
  • a variety of administration routes are available. The particular mode selected will depend, of course, upon the particular condition being treated and the dosage required for therapeutic efficacy.
  • the methods of this invention may be practised using any mode of administration that is medically acceptable, meaning any mode that produces therapeutic levels of the active component of the invention without causing clinically unacceptable adverse effects.
  • modes of administration include oral, rectal, topical, nasal, transdermal or parenteral (e.g. subcutaneous, intramuscular and intravenous) routes, such as by injection.
  • Formulations for oral administration include discrete units such as capsules, tablets, lozenges and the like.
  • Other routes include intrathecal administration directly into spinal fluid, direct introduction such as by various catheter and balloon angioplasty devices well known to those of ordinary skill in the art, and intraparenchymal injection into targeted areas.
  • a pharmaceutical composition according to the invention includes an inventive compound as described herein, and may further contain a pharmaceutically acceptable carrier or excipient formulation.
  • pharmaceutically acceptable is intended to mean a material that is not biologically or otherwise undesirable, which can be administered to an individual along with an inventive compound without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • a pharmaceutically acceptable carrier or excipient formulation may include sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile administrable solutions or dispersions.
  • aqueous and non-aqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example, water, alcohol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like
  • suitable mixtures thereof examples include vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • a pharmaceutical composition according to the invention may include other pharmaceutical agents.
  • the general content of a pharmaceutically acceptable carrier or excipient formulation will depend on the form in which the pharmaceutical composition containing an inventive compound is given.
  • a pharmaceutical composition containing an inventive compound is delivered in solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, or suspensions, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the glyconconjugate may be administered orally, parenterally (for example, intravenously), by intramuscular injection, by intraperitoneal injection, or transdermally.
  • fine powders or granules may contain diluting, dispersing, and/or surface active agents, and may be presented in water or in a syrup, in capsules or sachets in the dry state or in a nonaqueous solution or suspension wherein suspending agents may be included, in tablets wherein binders and lubricants may be included, or in a suspension in a liquid or gel. Tablets and granules are preferred oral administration forms, and these may be coated.
  • Parenteral administration is generally by injection. Injectables can be prepared in conventional forms, either liquid solutions or suspensions, solid forms suitable for solution or prior to injection, or as suspension in liquid prior to injection or as emulsions.
  • an excipient formulation may include conventional nontoxic solid carriers or fillers include, for example, pharmaceutical grades of cellulose, glucose, lactose, magnesium carbonate, magnesium stearate, mannitol, sodium saccharine, silicic acid, starches, sucrose and talc.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving or dispersing the glycoconjugate compound with optional pharmaceutical adjuvants in an excipient or inert diluent to thereby form a solution or suspension.
  • Liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • a liquid dosage form may contain such excipients or inert diluents as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • solubilizing agents and emulsifiers as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
  • Suspensions in addition to the glycoconjugate compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • An excipient formulation may contain further inert customary ingredients, such as binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; humectants, as for example, glycerol; disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; solution retarders, as for example paraffin; absorption accelerators, as for example, quaternary ammonium compounds; wetting agents, as for example, cetyl alcohol, and glycerol monostearate; adsorbents, as for example, kaolin and bentonite; and lubricants illustratively including talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
  • binders as for example, carboxymethylcellulose, alignates
  • the excipient formulation can also include adjuvants, such as emulsifying agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as emulsifying agents, sweetening, flavoring, and perfuming agents.
  • time release preparations or intravenous preparations are exemplary effective dosage formulations.
  • release control components include: carbomer, alpha-starch, polyacrylamides, polysaccharides, polyvinylpyrrolidone; natural gums such as gum arabic; clays; lipophilic gelling agents; fatty acid metal salts such as aluminum stearates; hydrophobic silica; celluloses such as various hydroxyalkylcelluloses; polyethylene glycol; and combinations thereof.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as pH buffering agents, for example, sodium acetate, sodium citrate, dicalcium phosphate or triethanolamine oleate. Contamination by microorganisms can be prevented or inhibited by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see A.
  • pH buffering agents for example, sodium acetate, sodium citrate, dicalcium phosphate or triethanolamine oleate. Contamination by microorganisms can be prevented or inhibited by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include iso
  • the exact amount of the pharmaceutical composition required will vary from subject to subject, depending on the age, weight and general condition of the subject, the condition being treated, the particular compound used, its mode of administration, and the like.
  • ., Cancer Chemother. Rep., 50:219-244, (1966) can be used to determine the maximum tolerated dose of an inventive compound for a human subject.
  • An appropriate amount may be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein.
  • Synthetic high mannose oligosaccharides are available from Ancora Farmaceuticals (MA, USA).
  • CRMi 97 is internally produced in Novartis V&D, Siena, Italy (Research Disclosure 453077 Jan 2002).
  • the 2G12 antibody and HIV gp140 UG37 (clade A strain 92/UG/037, a.a. 32-662, NCBI protein database No. AAC97548, catalog no. ENV001) are purchased from Polymun Scientific (Vienna, Austria).
  • HIV gp 120 Bal (a.a.32- 518, Geneban No. M68893, catalog no. IT-001-002p), gp120 R2 (a.a.41-520, Geneban No.
  • AF128126, catalog no. IT-001-0029p), gp120 JRFL (a.a.34-518, Geneban No. U63632, catalog no. IT-001-0024p) are available from Immune Technology Corp. (New York, US). Polymun and Immune Technology recombinant proteins are expressed in CHO and 293T cells, correspondingly. Biotinylated Galantus nivalis lectin (GNL) is available from Vector Laboratories (CA, US).
  • Isocratic separations are performed using a 30-min 16 m NaOH followed by a 5-min 500 mM NaOH regeneration step and 15-min re-equilibration, set to a flow rate of 1.0 ml min "1 .
  • Monosaccharide peaks are detected directly by using quadruple-potential waveform pulsed amperometry on a gold working electrode and an Ag/AgCI reference electrode.
  • Raw data are elaborated on a Chromeleon 6.8 chromatography software (Dionex) with application of 0.5-10 g/ml mannose calibration curve. Rapid hexose quantification is achieved by Phenol-H 2 S04 method [24]. Protein concentration is determined by Micro BCA kit (Thermo Fisher Scientific).
  • PAMAM4 cluster formation is analyzed by direct sample injection in Micromass Q- Tof Micro system (Waters MS Technologies, UK).
  • PAMAM8 cluster formation is analyzed on Q-tof Micro system paired to UPLC system (ACQUITY UPLC System, Waters, UK).
  • the samples are diluted 1 :200 or less in 0.1 % formic acid, 1 :1 vol acetonitrile:water.
  • Chromatographic separations are performed on 2.1 mm i d. x 50 mm ACQUITY BEH C18 1.7 im column (Waters Corp., USA).
  • TOF MS analysis is performed operating in positive ion mode (ESI).
  • the nebulization gas is set to 800 LJh at a temperature of 250°C, the cone gas set to 50 L/h and the source temperature set to 100°C.
  • the capillary and cone voltages are 3500 V and 30 V, respectively.
  • the Q-Tof Micro is operated with a collision energy of 5 V.
  • the data acquisition rate is set to 0.1 s with a 0.1 s inter-scan delay.
  • the raw data are analyzed by the Micromass Marker-Lynx applications manager Version 1.0 (Waters, UK).
  • Oligosaccharide pellet is vaccum dried and weighed (9-10 mg, 90-100%). Oligosaccharide is coupled to PAMAM with stoichiometry of 8:1 mol CHO:PAMAM4 and 20:1 mol CHO:PAMAM8. Reaction in DMSO with 20 ⁇ /ml thiethylamine ias stirred overnight at RT. Cluster formation is monitored by ESI Q-TOF MS analysis. No signal of unreacted PAMAM is observed in any of the final reaction mixtures.
  • Reaction sample is lyophilized overnight and then dissolved in water. Excess of unreacted oligosaccharide is removed by hydrophobic interaction C4 column (0.5 ml resin, Bioselect, Grace Vydac) in a stepwise gradient of methanol (0-80% in water). Column is activated with methanol and then preconditioned with water. Fractions are analyzed by TLC and TOF-MS. Target fractions are dried to eliminate methanol. Carbohydrate yields for cluster formation and purification are 36.3% for Man4PAMAM4; 16.2% for Man9PAMAM4; 18% for Man4PAMAM8; 14.7% for Man9PAMAM8.
  • 2 Mg/ml 2G12 is preincubated with appropriate inhibitor for 15 minutes at 37°C before the start of analysis.
  • Analyte is injected at 10 ⁇ /min for 4 min, followed by 6 min dissociation and 30 sec of regeneration with 10 mM glycine, 3M NaCI pH 2.0. Similar conditions are used for analysis with 2G12 chips that had 490 RU and 4400 RU of immobilization.
  • oligosaccharides or oligosaccharide clusters are activated with disuccinimidyl adipate and purified according to the procedure mentioned above. Before activation Boc group of cluster is eliminated by stirring in 20% TFA for two hours. Conjugation stoichiometry of 30:1 or 40:1 CHO/cluster : protein mol is applied. Conjugation is done in 10-20 mg/ml protein solution in 200 mM NaPi pH 7,0 cluster. The mixture is incubated overnight at 37°C, and reaction outcome is verified by SDS-PAGE analysis.
  • Conjugates are purified from excess of unconjugated carbohydrate using ultrafiltration spin columns with 30 kDa or 50 kDa cut-off (Vivaspin, Sartorius). Glycosylation degree is calculated on the basis of protein and carbohydrate concentration.
  • Man9 is conjugated to HSA following similar procedures.
  • ELISA - 96-well Maxisorp plates (Nunc, Thermo Fisher Scientific) are coated with 100 ⁇ /well of PBS-diluted glycoproteins with 2 pg/ml coating concentration. Plates are incubated overnight at +4°C, then washed three times with TPBS (PBS with 0,05% Tween 20, pH 7.4) and blocked with 100 ⁇ well of 2% BSA (Sigma-Aldrich) for 1 hour at 37°C. Subsequently each incubation step is followed by triple TPBS wash. 200 ⁇ of prediluted 2G12 or lectin are transferred into coated-blocked plates (200 ⁇ ) and serially two-fold diluted followed by 2h incubation at 37°C.
  • TPBS PBS with 0,05% Tween 20, pH 7.4
  • BSA Sigma-Aldrich
  • Serum samples are initially diluted 1 :50-1 :1000 in 2 % BSA in TPBS. Then 100 ⁇ well of 1 :10000-1 :20000 diluted appropriate alkaline phosphatase-conjugated secondary antibody or streptavidin-alkaline phosphatase conjugate (Sigma-Aldrich) is added for 1 h at 37°C. 100 ⁇ /well of 1 mg/ml pNPP disodium hexahydrate (Sigma Aldrich) in 1 M diethanolamine (pH 9.8) is distributed onto plates to visualize the amount of bound alkaline phosphatase. After 30 minutes of development at RT plates are read with a microplate spectrophotometer at 405 nm. Antibody titres are those dilutions that give an optical density (OD) higher than triple average OD obtained for the mock-immunized rabbit sera.
  • OD optical density
  • One prime and two boosting doses of 20 pg carbohydrate antigen were administered i.m.
  • Control animals were immunized with MF-59 in PBS.

Abstract

L'invention concerne des composés qui sont des compositions de glycoconjugués présentant des oligosaccharides liés à des structures multivalentes destinés à être utilisés dans des vaccins et se liant aux anticorps.
PCT/IB2010/002541 2009-09-23 2010-09-21 Compositions de glycoconjugués et méthodes pour le traitement du vih WO2011036560A2 (fr)

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CN102807621A (zh) * 2011-06-01 2012-12-05 厦门大学 包含白喉毒素无毒突变体crm197或其片段的融合蛋白

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EP2709656A4 (fr) * 2011-05-18 2015-01-14 Matrivax Inc Compositions de vaccin à matrice de protéine incluant des polycations
AU2012255878B2 (en) * 2011-05-18 2016-05-12 Matrivax Research & Development Corporation Protein matrix vaccine compositions including polycations
EP3524265A1 (fr) * 2011-05-18 2019-08-14 Matrivax, Inc. Compositions de vaccin à matrice de protéine incluant des polycations
EP2709656A1 (fr) * 2011-05-18 2014-03-26 Matrivax, Inc. Compositions de vaccin à matrice de protéine incluant des polycations
KR20140045416A (ko) * 2011-05-18 2014-04-16 매트리백스 인코포레이티드 폴리양이온을 포함하는 단백질 매트릭스 백신 조성물
JP2014513726A (ja) * 2011-05-18 2014-06-05 マトリヴァックス，インコーポレーテッド ポリカチオンを含むタンパク質マトリックスワクチン組成物
US9724401B2 (en) 2011-05-18 2017-08-08 Matrivax, Inc. Protein matrix vaccine compositions including polycations
KR101670340B1 (ko) * 2011-05-18 2016-10-28 매트리백스 인코포레이티드 폴리양이온을 포함하는 단백질 매트릭스 백신 조성물
WO2012158701A1 (fr) 2011-05-18 2012-11-22 Matrivax Research & Development Corporation Compositions de vaccin à matrice de protéine incluant des polycations
WO2012156750A1 (fr) * 2011-05-19 2012-11-22 Isis Innovation Limited Vaccin contre le vih
CN102807621B (zh) * 2011-06-01 2016-04-13 厦门大学 包含白喉毒素无毒突变体crm197或其片段的融合蛋白
US9512185B2 (en) 2011-06-01 2016-12-06 Xiamen University Fusion protein comprising diphtheria toxin non-toxic mutant CRM197 or fragment thereof
US9757450B2 (en) 2011-06-01 2017-09-12 Xiamen University Fusion protein comprising diphtheria toxin non-toxic mutant CRM197 or fragment thereof
US9764028B2 (en) 2011-06-01 2017-09-19 Xiamen University Fusion protein comprising diphtheria toxin non-toxic mutant CRM197 or fragment thereof
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