WO2006121656A2 - Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease - Google Patents
Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease Download PDFInfo
- Publication number
- WO2006121656A2 WO2006121656A2 PCT/US2006/016481 US2006016481W WO2006121656A2 WO 2006121656 A2 WO2006121656 A2 WO 2006121656A2 US 2006016481 W US2006016481 W US 2006016481W WO 2006121656 A2 WO2006121656 A2 WO 2006121656A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- peptide
- ompc
- immunogenic fragment
- conjugate
- adjuvant
- Prior art date
Links
Classifications
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
- A61K39/0007—Nervous system antigens; Prions
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61K2039/6068—Other bacterial proteins, e.g. OMP
-
- 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
- A61K2039/6087—Polysaccharides; Lipopolysaccharides [LPS]
-
- 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
- A61K2039/6093—Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
-
- 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
- A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
Definitions
- the present invention relates to compositions and methods for the prevention and treatment of amyloidogenic diseases and, in particular, Alzheimer's disease.
- Alzheimer's disease is characterized by progressive memory impairment and cognitive decline. Its hallmark pathological lesions are amyloid deposits (senile plaques), neurofibrillary tangles and neuronal loss in specific brain regions.
- the amyloid deposits are composed of amyloid beta peptides (A ⁇ ) of 40 to 43 amino acid residues, which are the proteolytic products of the amyloid precursor protein (APP).
- Neurofibrillary tangles are the intracellular filamentous aggregates of hyperphosphorylated tau proteins (Selkoe, Science, 275: 630-631, 1997).
- AD Alzheimer's disease
- a ⁇ is believed to play a pivotal role in the disease process, also know as the amyloid cascade hypothesis (Golde, Brain Pathol., 15: 84-87, 1995).
- a ⁇ is prone to form various forms of aggregates, ranging from small oligomers to large, elongated profibrile structures.
- These aggregates are neurotoxic and are responsible for the synaptic pathology associated with the memory loss and cognition decline in the early stage of the disease (Klein et al, Neurobiol. Aging, 25: 569-580, 2004).
- Betabloc showed regional clearance of senile plaques (Nicoll et al., Nature Med., 9: 448-452, 2003; Ferrer et al, Brain Pathol.. 14: 11-20, 2004; Masliah et al, Neurology, 64: 129-131, 2005).
- This data collectively indicates that vaccines that effectively elicit antibody responses to A ⁇ antigens are efficacious against the pathological senile plaques found in AD.
- the mechanism of vaccine or antibody efficacy remains to be defined.
- peripheral sink refers to a change in the equilibrium of brain and plasma A ⁇ stores resulting in a net efflux of central A ⁇ to the periphery (see, for example, Deane et al., J. Neurosci., 25: 11495-11503, 2005; DeMattos et al, Pro. Natl. Acad. Sci. USA. 98: 8931-8932, 2001).
- mice expressing the wild-type human A ⁇ sequence plus the Swedish mutation responded to active immunization with both increases in plasma A ⁇ and subsequent decreases in central A ⁇ (Cribbs et al., 7th International Conference on AD/PD, Sorrento, Italy, 2005). Accordingly, it is expected that any active vaccine immunogen capable of generating an immune response that results in the elevation of plasma A ⁇ levels will be useful for the treatment of Alzheimer's disease and related disorders characterized by elevated brain A ⁇ levels.
- Applicants herein have surprisingly found that an antigen which eliminated T-cell epitopes, to avoid a self T-cell response, is immunogenic and elevates plasma A ⁇ levels. This represents a potential means to produce a safe and effective AD vaccine. Applicants herein provide such an antigen and a formulation for use as an AD vaccine.
- the invention provides a pharmaceutical composition comprising an immunogenic fragment of A ⁇ , lacking a T-cell epitope, capable of inducing an immune response in the form of antibodies to A ⁇ .
- this composition comprises linear 8 amino acid peptides (8- mers) of A ⁇ .
- this composition comprises multivalent linear 8-mers interspersed with at least one spacer or a multivalent branched multiple antigenic peptide (MAP).
- MAP multivalent branched multiple antigenic peptide
- the pharmaceutical composition can be used as a vaccine for AD and related amyloid diseases.
- the pharmaceutical composition is an A ⁇ plasma elevating agent comprising an immunogenic fragment of A ⁇ , lacking a T-cell epitope, capable of inducing an immune response in the form of antibodies to A ⁇ that elevate plasma A ⁇ levels.
- the pharmaceutical composition can be used as a vaccine for AD and related amyloid diseases characterized by elevated brain A ⁇ levels.
- the pharmaceutical composition is linked to a carrier molecule to form a conjugate, wherein the carrier helps to elicit an immune response comprising antibodies to the A ⁇ fragment.
- the carrier is the outer membrane protein complex of Neisseria meningitides (OMPC).
- the pharmaceutical composition is administered with a pharmaceutically acceptable adjuvant.
- the adjuvant is an
- the invention provides methods for preventing or treating a disease associated with amyloid deposits of A ⁇ in the brain of a patient.
- diseases include Alzheimer's disease, Down's syndrome, cognitive impairment or other forms of senile dementia.
- the method comprises administering an immunogenic fragment of A ⁇ , lacking a T-cell epitope, selected from the group consisting of linear 8 amino acid peptides (8-mers), a multivalent linear peptides interspersed with at least one spacer and a multivalent branched multiple antigenic peptide (MAP).
- the immunogenic fragment comprises a multivalent linear peptide with a polyethylene glycol (PEG) spacer.
- the immunogenic fragment comprises a multivalent branched MAP, A ⁇ (3-10)/(21-28) conjugate, Construct No. 12, Figure 6A, conjugated to OMPC.
- Such methods entail the administration of an effective dose of an immunogenic fragment of A ⁇ , lacking a T-cell epitope, to patients in need of such treatment that will induce an immune response in the form of antibodies to A ⁇ . Said antibody response is capable of elevating plasma A ⁇ levels.
- the immunogenic fragment to be administered is linked to a carrier molecule.
- the immunogenic fragment is administered with an adjuvant.
- Figure 1 represents synthetic 8-amino acid peptides (8-mers) (SEQ ID NOS: 2-36) derived from A ⁇ (1-42) (SEQ ID NO: 1) from which peptides were selected to conduct a linear peptide scan to identify the epitopes of A ⁇ .
- Figure 2 represents the 8-mers selected for conjugation to KLH ( Figure 2A) and OMPC ( Figure 2B).
- Figure 3 represents the immunogenicity of selected A ⁇ conjugates, described in Figure 2, after the first (PDl), second (PD2) and third dose (PD3).
- Figure 4 represents the cross-reactivity of sera extracted from a guinea pig previously immunized with an A ⁇ (3-1O)-KLH conjugate (SEQ ID NO: 40) on human AD brain tissue.
- Figure 4A shows immunoreactivity of the anti-A ⁇ monoclonal antibody 6F3D (which recognizes amino acids 8-17 of A ⁇ ). The staining pattern reveals extensive amyloid pathology in this human brain.
- Figure 4B demonstrates a lack of immunoreactivity of this same brain to the pre-immune sera from the immunized guinea pig prior to immunization.
- Figure 4C shows the immunoreactivity of the sera from an immunized guinea pig following immunization
- Figure 5 shows representative multivalent linear 8-mer peptides, which were selected based on the immunogenicity of the separate 8-mers in guinea pig studies (Example 3). These conjugates were synthesized as described and conjugated to OMPC (Example IJ and 1.K).
- Figure 6 shows representative multivalent branched MAP conjugates, which were selected based on the immunogenicity of the separate 8-mers in guinea pig studies (Example 3).
- Figure 6A shows representative divalent MAPs and
- Figure 6B shows representative bromoacetyl-cysteine MAPs. These conjugates were synthesized as described and conjugated to OMPC (Example 2).
- Figure 7 represents the anti-A ⁇ 4o titer from sera collected from rhesus monkeys following 1 (PDl) or 2 (PD2) injections with an A ⁇ (1-18) peptide conjugated to OMPC formulated in Merck alum alone or Merck alum plus MX (ISCOMATRIX , CSL, Ltd., Parkville, Australia) as an adjuvant.
- Figure 8 represents the increase in plasma A ⁇ levels following administration of a A ⁇ conjugate.
- Figure 8A shows a greater than three-fold elevation following administration of a MAP construct comprising A ⁇ (3-10)/(21-28) (Construct No. 12, Figure 6A) conjugated to OMPC versus the monomeric constructs, A ⁇ (3-10) (SEQ ID NO: 69) and A ⁇ (21-28) (SEQ ID NO: 73) (o , Construct No. 12, Figure 6A; •, A ⁇ (3-10) (SEQ ID NO 69), A, A ⁇ (21-28) (SEQ ID NO: 73).
- Figure 8B shows that plasma A ⁇ levels are independent of titer levels ( ⁇ , Construct No. 12, Figure 6A; •, A ⁇ (3-10) (SEQ ID NO 69), ⁇ , A ⁇ (21-28) (SEQ ID NO: 73).
- 8-mer refers to an eight amino acid peptide which corresponds to a fragment of A ⁇ , an analog of a natural A ⁇ peptide or a peptide mimetic.
- One or more 8-mers may be combined with at least one spacer to form a multivalent linear peptide or to form a multivalent branched MAP.
- a ⁇ conjugate means an 8-mer or immunogenic fragment of A ⁇ that is chemically or biologically linked to a carrier, such as keyhole limpet hemocyanin or the outer membrane protein complex of Nesseria rneningitidies (OMPC).
- a carrier such as keyhole limpet hemocyanin or the outer membrane protein complex of Nesseria rneningitidies (OMPC).
- a ⁇ peptide means any of the A ⁇ peptides described herein, including, but not limited to, linear 8-mers, multivalent linear peptides with at least one spacer and multivalent branched multiple antigenic peptides (MAPs).
- MAPs multivalent branched multiple antigenic peptides
- epitope refers to a site on an antigen to which B and/or T cells respond.
- B- cell epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. 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.
- T-cell epitopes consist of peptides which are capable of forming complexes with host MHC molecules.
- T-cell epitopes for a human MHC class I molecules which are responsible for induction of CD8+ T-cell responses, generally comprise 9 to 11 amino acid residues
- epitopes for human MHC class II molecules which are responsible for CD4+ T-cell responses, typically comprise 12 or more amino acid residues
- B cells are capable of recognizing peptides as small as 4 amino acids in length. It is the T-cell epitope/MHC complexes that are recognized by T-cell receptors leading to T cell activation.
- T-cell response refers to an 8-mer or an A ⁇ fragment that is capable of inducing an immune response in the form of antibodies to A ⁇ , but which response does not include a T-cell response to the self antigen, A ⁇ .
- immunological or “immune” or “immunogenic” response refers to the development of a humoral (antibody mediated) and/or a cellular (mediated by antigen-specific T cells or their secretion products) response directed against an antigen in a vertebrate individual.
- a humoral antibody mediated
- a cellular mediated by antigen-specific T cells or their secretion products
- Such a response can be an active response induced by administration of an immunogen or a passive response induced by administration of an antibody.
- multivalent peptide refers to peptides having more than one antigenic determinant.
- pharmaceutical composition means a chemical or biological composition suitable for administration to a mammalian individual. As used herein, it refers to a composition comprising 8-mers, immunogenic fragments of A ⁇ and A ⁇ conjugates described herein to be administered optionally with or without an adjuvant.
- Applicants herein used the differing nature of T and B cell epitopes to design the peptides used for the invention.
- the vaccine constructs were designed, by restricting the linear peptide size to eight amino acids and, if necessary, removing any potential C-terminal T-cell epitope anchor residues.
- one aspect of the present invention was the identification of A ⁇ fragments that are immunogenic, but lack a T-cell epitope, for use as an AD vaccine.
- Those skilled in the art would appreciate that previous teachings in the field did not predict, for example, that an 8-mer would produce an immunogenic response and did not distinguish the usefulness of fragments from different regions of the A ⁇ peptide. See, for example, U.S. Pat. Nos. 6,808,712 and 6,787,144.
- An additional aspect of the invention herein includes the identification of A ⁇ plasma elevating agents comprising an immunogenic fragment of A ⁇ , lacking a T-cell epitope, that induce an immune response in the form of antibodies to A ⁇ and that elevate plasma A ⁇ levels.
- Such agents can be used as an AD vaccine and for related amyloid diseases characterized by elevated brain A ⁇ levels.
- Prior to Applicants' invention it was not known or predictable which immunogenic fragments of A ⁇ would result in elevated plasma A ⁇ levels.
- the A ⁇ plasma elevating agents described herein act to induce an immune response in the form of antibodies to A ⁇ that, according to the peripheral sink theory of A ⁇ clearance, produce elevated levels of plasma A ⁇ that leads to subsequent decreases in brain A ⁇ .
- the invention provides compositions and methods for prophylactic and therapeutic treatment of disease characterized by accumulation of amyloid deposits.
- Amyloid deposits comprise a peptide aggregated to an insoluble mass. The nature of the peptide varies in different disease but in most cases, the aggregate' has a ⁇ -pleated sheet structure and stains with Congo Red dye.
- Diseases characterized by amyloid deposits include Alzheimer's disease (AD), both late and early onset. In both diseases, the amyloid deposit comprises a peptide termed amyloid beta (A ⁇ ), which accumulates in the brain of affected individuals.
- AD Alzheimer's disease
- a ⁇ amyloid beta
- the term "amyloid disease” also refers to disease characterized by elevated brain A ⁇ levels.
- Therapeutic agents for use in the present invention induce an immune response in the form of antibodies to A ⁇ .
- Induction of an immune response can be active as when an immunogen is administered to induce antibodies or T cells reactive with A ⁇ in an individual or passive, as when an antibody is administered that itself binds to A ⁇ in the individual.
- the therapeutic agent to be used in preventing or treating amyloid diseases, such as AD include peptide fragments of A ⁇ , which can be any of the naturally occurring forms (i.e. A ⁇ 39, A ⁇ 40, A ⁇ 42, A ⁇ 42, or A ⁇ 43). These sequences are known in the art, see, for example, Hardy et al., TINS 20: 155-158, 1997.
- the therapeutic agent is, in a preferred embodiment, an immunogenic fragment, lacking a T-cell epitope, capable of inducing an immune response in the form of antibodies to A ⁇ .
- the immunogenic fragment of A ⁇ can be in the form of an 8-mer, a multivalent linear A ⁇ conjugate having at least one PEG spacer or a multivalent branched MAP A ⁇ conjugate.
- the therapeutic agent can be administered in the form of a pharmaceutical composition.
- the therapeutic agent is an A ⁇ plasma elevating agent capable of inducing an immune response in the form of antibodies to A ⁇ and that elevate plasma A ⁇ levels in an individual.
- Such agents can comprise a naturally occurring peptide fragment or may include one or more substitutions, additions or deletions, and may include synthetic or non-naturally occurring amino acids. Fragments and constructs can be screened for prophylactic and therapeutic efficacy in the assays described in the examples herein.
- the therapeutic agents comprise a peptide fragment of A ⁇
- such agents may also include peptides and other compounds that do not necessarily have a significant amino acid sequence similarity with A ⁇ , but that nevertheless can serve as mimetics of A ⁇ and induce a similar immune response.
- peptides and proteins forming ⁇ -pleated sheets can be screened for suitability for the invention herein.
- combinatorial libraries and other compounds can be screened for suitability for the invention herein.
- Such identified therapeutic agents can be linked either chemically or biologically to a carrier to facilitate their use as an immunogen.
- a carrier include serum albumins, keyhole limpet hemocyanin (KLH), immunoglobulin molecules, ovalbumin, tetanus toxoid protein, or a toxoid from other pathogenic bacteria, such as diphtheria, E. coli, cholera, or H. pylori, or an attenuated toxin derivative.
- the carrier is the outer membrane protein complex of Neisseria meningitides (OMPC).
- the invention herein also contemplates the use of such therapeutic agents in a pharmaceutical composition comprising an 8-mer or immunogenic fragment of A ⁇ , which may be linked to a carrier, to be administered optionally with an adjuvant.
- Suitable adjuvants include aluminum salts (alum), a lipid, such as 3 De-O-acylated monophosphoryl lipid A (MPL) or a saponin-based adjuvant.
- the adjuvant is an aluminum adjuvant (Merck alum adjuvant, MAA) or a saponin-based adjuvant (ISCOMATRK * , CSL Ltd, Parkville, Australia.
- Effective doses of the compositions of the invention herein for the prophylactic or therapeutic treatment of AD and other amyloid diseases will vary depending upon many factors including, but not limited to, means of administration, target site, physiological state of the patient, other medications administered and whether treatment is a therapeutic, i.e. after on-set of disease symptoms, or prophylactic, i.e. to prevent the on-set of disease symptoms.
- the patient is human and the therapeutic agent is to be administered by injection.
- the amount of immunogen or therapeutic agent to be employed will also depend on whether an adjuvant is to be administered either concomitantly or sequentially, with higher doses being employed in the absence of an adjuvant.
- an immunogen or therapeutic agent to be administered will vary, but amounts ranging from 0.5-50 ⁇ g of peptide (based on the A ⁇ peptide content) per injection are considered for human use. Those skilled in the art would know how to formulate compositions comprising antigens of the type described herein.
- the administration regimen would consist of a primary immunization followed by booster injections at set intervals.
- the intervals between the primary immunization and the booster immunization, the intervals between the booster injections, and the number of booster immunizations will depend on the antibody titers and duration elicited by the vaccine. It will also depend on the functional efficacy of the antibody responses, namely, levels of antibody titers required to prevent AD development or exerting therapeutic effects in AD patients.
- a typical regimen will consist of an initial set of injections at 1, 2 and 6 months. Another regimen will consist of initial injections at 1 and 2 months. For either regimen, booster injections will be given either every six months or yearly, depending on the antibody titers and durations.
- An administration regimen can also be on an as-needed basis as determined by the monitoring of immune responses in the patient.
- peptides were modified by the addition of triple lysine (KKK) (SEQ ID NOS: 52, 53, 54, 56, 59, 60, 62, 64 and 65) or glutamine (EEE) (SEQ ID NOS: 50, 51 and 61) residues or the use of a polyethelyene glycol (PEG) (SEQ E) NOS: 55 and 63) spacer.
- KKK triple lysine
- EEEE glutamine
- peptides spanning the sequences of A ⁇ corresponding to residues (11-18) and (13-20) were made in multiple forms, the first with a 6-aminohexanoic acid (Aha) spacer plus a functional group for chemical cross-linking at N-terminus and the other form with Aha and the functional group at C- terminus.
- Aha 6-aminohexanoic acid
- the immunogenic fragments may be 8-mer peptides (eight amino acid residues) derived from the naturally occurring, i.e. wild type, or synthetic A ⁇ (SEQ ID NO:1) or any mutation or variation thereof.
- Such mutation or variant can be produced by synthetic or recombinant means known to those of ordinary skill in the art.
- One example of such a variant is the EV substrate (EVEFRHDSGYEVHHQKLVFFAEDVGSNKGA ⁇ GLMVGGVVIA) (SEQ ID NO: 66) a peptide corresponding to A ⁇ (1-42) in which positions 1 and 2 of wild type A ⁇ have been varied.
- a ⁇ conjugates for use in formulating a vaccine was based on the immunogenicity of the 8-mers.
- the 29 peptides (Figure 2A) were conjugated to EXH to form an A ⁇ conjugate and tested in guinea pigs ( Figure 3).
- a ⁇ (1-18)-KLH (SEQ ID NO: 37) was included in this analysis.
- Guinea pigs were immunized as described in Example 3.B with conjugated immunogens formulated in alum plus 50 ⁇ g of ISCOMATRIX® (CSL, Ltd., Parkville, Australia).
- ISCOMATRIX® CSL, Ltd., Parkville, Australia.
- guinea pigs were immunized three times at four week intervals.
- blood samples were collected and tested by ELISA for antibody titers against A ⁇ 40 peptide. These titers are shown in Figure 3 as post- dose 1 (PDl), post-dose 2 (PD2) and post-dose 3 (PD3), respectively.
- regions corresponding to A ⁇ amino acids 1-8, 3- 10, 7-14, 11-18, 13-20, 15-22, 19-26, 21-28, 23-30, 27-34 and 29-36 were highly immunogenic (>1: 10000) including: regions 1-8, 15-22, 21-28, 23-30 and 29-36.
- regions 1-8, 15-22, 21-28, 23-30 and 29-36 are highly immunogenic, while other regions (e.g., 5-12, 25-32, 31-38 and 35-42) are non-immunogenic (titers ⁇ 1:300).
- the results also demonstrate that while the A ⁇ conjugates were capable of eliciting an A ⁇ 4o peptide-specific antibody response, not all fragments of A ⁇ were equally immunogenic.
- FIG. 4 the immunogenic response produced by the A ⁇ (3-1O)-KLH (SEQ ID NO: 40) conjugate produced an antibody response that was directed against human AD brain tissue.
- Figure 4A demonstrates immunoreactivity of the monoclonal anti-A ⁇ antibody 6F3D (Vector Laboratories). As shown, this brain has extensive A ⁇ deposits in a manner expected to be typical for human AD.
- Figure 4B demonstrates a lack of immunoreactivity of sera from a pre-immunized guinea pig.
- Figure 4C shows positive immunoreactivity of sera from this same guinea pig following two injections of the A ⁇ (3-1O)-KLH (SEQ ID NO: 40) conjugate.
- the invention described herein includes multivalent peptide conjugates such as those shown in Figures 5, 6A and 6B.
- Multivalent branched MAP-OMPC conjugates ( Figures 6A and 6B) were generated by using a lysine-based scaffold, whereas multivalent linear 8-mer-OMPC conjugates ( Figure 5) were prepared using a PEG linker.
- a PEG linker compared to conventional amino acid linkers that can also be used herein, offers the advantage of lower immunogenicity and greater peptide solubility.
- the immunogenic fragment is a multivalent MAP conjugated to OMPC.
- ISCOMATRK® (CSL, Ltd., Parkville, Australia). Blood samples were collected and used to determine the antibody titers against A ⁇ . Interim analysis of this ongoing study demonstrated that at post-dose 1 (PDl) the monkeys receiving 5 ⁇ g vaccine in alum failed to develop any detectable titers, while those receiving 30 ⁇ g vaccine in alum developed low A ⁇ 4o specific titers. All monkeys that received the alum plus ISCOMATRK® formulation developed significant antibody titers.
- the peptides intended for conjugation to maleimide derivatized carrier proteins were synthesized with a cysteine residue at the carboxy terminus.
- the spacer, Aha (6-aminohexanoic acid) was incorporated between the primary peptide sequence and the carboxy terminal cysteine as a structural element for minimizing steric accessibility to carrier protein during conjugation.
- solubilizing residues represented by EEE, KKK or PEG were introduced at the C-terminus in sequences 14,15,16 17,18,19,20,23,24,25,26,27,28,29.
- the PEG unit was introduced as, O-(N ⁇ Fmoc-2- aminoethyl)-O'-(2-carboxyethyl)-undecaethylenegIycol [FmOC-NHCH 2 CH 2 O(CH 2 CH 2 O)I 0 CH 2 CH 2 OCH 2 CH 2 CO 2 H].
- the A ⁇ peptides were prepared by solid-phase synthesis on an automated peptide synthesizer using Fmoc chemistry protocols as supplied by the manufacturer (Applied Biosystems, Foster City, CA). Following assembly the resin bound peptide was deprotected and cleaved from the resin using a cocktail of 94.5% trifluoroacetic acid, 2.5% 1,2- ethanedithiol, 1% triisopropylsilane and 2.5% H 2 O. Following a two hour treatment the reaction was filtered, concentrated and the resulting oil triturated with ethyl ether. The solid product was filtered, dissolved in 50% acetic acid/H 2 O and freeze-dried.
- the A ⁇ peptides (8-mers), 2 mg, containing a C- terminal cysteine was suspended in 1 ml of commercial maleimide conjugation buffer (83 mM sodium phosphate, 0.1 M EDTA, 0.9 M NaCl, 0.02% sodium azide, pH 7.2 (Pierce Biotechnology, Rockford, IL).
- a 2 mg sample of commercial maleimide-activated KLH (Pierce Biotechnology, Rockford, IL) was added to the peptide and allowed to react at 25 0 C for four hours.
- the conjugate was separated from unreacted peptide and reagents by exhaustive dialysis versus PBS buffer using 100,000 Da dialysis tubing.
- the amount of peptide incorporated into the conjugate was estimated by amino acid analysis following a 70 hour acid hydrolysis. Peptide concentrations were determined to be between 0.24 and 0.03 mg/ml.
- Bromoacetylated peptides were prepared by standard t-Boc solid-phase synthesis, using a double coupling protocol for the introduction of amino acids on the Applied Biosystems model 430A automated synthesizer. Starting with p-methylbenzhydrylamine resin the carboxy terminal amino acid t- B oc-Ly s (Fmoc)-OH was introduced followed by the subsequent amino acids in the sequence. Aha was introduced as a spacer to all of these sequences and a PEG unit in sequences 35 and 37 to aid in aqueous solubility.
- the PEG unit was introduced as O-(N-Boc-2-aminoethyl)-O'-(N-diglycolyl-2-aminoethyl) hexaethyleneglycol [BOC-NHCH 2 CH 2 O(CH 2 CH 2 O) 6 CH 2 CH 2 NHCOCH 2 OCH 2 CO 2 H].
- the amino terminous was capped by the coupling of acetic acid.
- the Fmoc protecting group on the epsilon amino group of the carboxy terminal lysine was removed by treatment with piperidine. Subsequently the N amino group was reacted with Bromoacetic anhydride in methylene chloride as the solvent for 30 minutes.
- t-Boc protected amino acids were assembled on the ABI automated synthesizer C, Lys(Fmoc), Aha, Y, G, S, D, H, R, F, E followed by coupling with acetic acid.
- the N amino Fmoc protecting group of lysine was removed and the synthesis continued with the introduction of the following t-Boc protected amino acids: Aha, H, H, V, E, Y, G, S, D followed by coupling with acetic acid.
- the resin bound peptide was isolated, purified and characterized as in Example l.C. Note: Instead of 10% anisole as in Example l.C, a 1:1 mixture of p-cresol: p-thiocresol was used as a scavenger during HF cleavage.
- Divalent MAPs Construct Nos. 10, 13 and 14, Figure 6A, were prepared as described in Example 6.F.
- the PEG unit was introduced as 0-(N-Boc-2-aminoethyl)-0'-(N-diglycolyl-2-aminoethyl) hexaethyleneglycol (t-Boc-NHCH 2 CH 2 O(CH 2 CH 2 O) 6 CH 2 CH 2 NHCOCH 2 OCH 2 CO 2 H).
- Fmoc-Lys (t-Boc)-OH was coupled to MBHA resin. Following removal of the t-Boc protecting group on the N ⁇ amino group of lysine the sequence was extended with the introduction of the following t-Boc protected amino acids: Aha, Y,G, S, D, H, R, F, E, followed by coupling of acetic acid. The Na Fmoc protecting group on lysine was removed by manual treatment with piperidine.
- This example presents the chemical conjugation of peptides derived from human A ⁇ 42 to purified Outer Membrane Protein Complex (OMPC) of Neisseria meningitidis, type B.
- OMPC Outer Membrane Protein Complex
- the chemical nature of the coupling is reaction between haloacetyl-derivatized peptide and thiol-derivatized protein of the membrane complex.
- Amyloid peptides were synthesized as described above with a bromoacetyl functionality on the N-terminus for divalent linear epitope peptides or on the C-terminus or attached through the epsilon amino group of a lysine residue for monovalent linear and branched MAP forms.
- the BrAc group was separated from the mature peptide by a spacer consisting of 6-aminohexanoic acid (Aha). Refer to sequences described above. Conjugation will be described for the representative peptide, A ⁇ (3-10). All manipulation of OMPC-containing solutions was performed in a laminar flow environment following standard aseptic techniques.
- OMPC Purified, sterile OMPC, obtainable from a process such as that described in Fu, U.S. Pat. No. 5,494,808 used for the production of PedvaxHIB® and pneumococcal conjugate vaccines, was thiolated on a portion of its surface-accessible lysine residues using the reagent N- acetylhomocysteinethiolactone (NAHT, Aldrich, St. Louis, MO). OMPC in water, 117mg, was pelleted by centrifugation at 289,000 x g for 60 minutes at 4°C and the supernatant was discarded.
- NAHT N- acetylhomocysteinethiolactone
- N2-sparged activation buffer (0.11 M sodium borate, pH 11) was added to the centrifuge tube and the pellet was dislodged with a glass stir rod. The suspension was transferred to a glass Dounce homogenizer and resuspended with 30 strokes. The centrifuge tube was washed and the wash dounced with 30 strokes. Re-suspended pellet and wash were combined in a clean vessel to give a OMPC concentration of 10 mg/mL. Solid DTT and EDTA were dissolved in N2-sparged activation buffer and charged to the reaction vessel at a ratio of 0.106 mg DTT/mg OMPC and 0.57 mg EDTA/mg OMPC.
- NAHT was dissolved in N2-sparged water and charged to the reaction at the ratio of 0.89 mg NAHT/mg OMPC. Reaction proceeded for three hours at ambient temperature, protected from light in a N2 hood.
- OMPC was pelleted as described above and re-suspended at 6 mg/mL by Dounce homogenization in N2-sparged conjugation buffer (25 mM sodium borate, pH 8.5, 0.15 M NaCl) to wash the pellet.
- N2-sparged conjugation buffer 25 mM sodium borate, pH 8.5, 0.15 M NaCl
- the OMPC was pelleted as above and re-suspended at 10 mg/mL by Dounce homogenization in N2-sparged conjugation buffer. An aliquot was removed for free thiol determination by Ellman assay and the bulk product was stored on ice in dark until use. Measured thiol content was between 0.2 to 0.3 ⁇ mol/mL.
- conjugate and control were transferred to 100,000 Da molecular weight cut-off dialysis units and dialyzed exhaustively against at least five changes of conjugation buffer.
- samples were transferred to 15 ml polypropylene centrifuge tubes and centrifuged at 2,280 x g for five minutes at 4°C to remove any aggregated material. Aliquots were removed for analysis and the bulk was stored at 4°C.
- Total protein was determined by the modified Lowry assay and samples of conjugate and control were analyzed by quantitative amino acid analysis (AAA).
- AAA quantitative amino acid analysis
- Peptide to OMPC molar ratios were determined from quantitation of the unique residue S-carboxymethylhomocysteine which was released upon acid hydrolysis of the nascent peptide-OMPC bond.
- the OMPC-specific concentration was determined from hydrolysis-stable residues which were absent from the peptide sequence and thus unique to OMPC protein. Assuming 1 mol of peptide for every mol SCMHC, the ratio of SCMHC/OMPC was thus equivalent to the peptide/OMPC content.
- the mass loading of peptide could be calculated from this ratio using the peptide molecular weight and an average OMPC mass ' of 40,000,000 Da.
- the covalent nature of the conjugation was qualitatively confirmed by SDS-PAGE analysis using 4-20% Tris-glycine gels (Invitrogen, Carlsbad, CA) where an upward shift in mobility was observed for the Coomassie-stained conjugate bands relative to control.
- This example describes the formulation and administration of the A ⁇ conjugates capable of inducing an immune response in the form of antibodies to A ⁇ .
- a second adjuvant such as the saponin-based adjuvant, ISCOMATRDC (CSL Ltd.,
- conjugates are diluted one times saline at a designated peptide concentration and mixed with two times alum (Merck, Product No. 39943), which corresponds to 900 ⁇ g/mL Merck alum prepared in sterile saline (150 mM sterile sodium chloride solution).
- target concentration in the vaccine is 450 ⁇ g/mL Merck alum or one time Merck alum.
- Target peptide (antigen) concentrations for animal studies were as follows: for mice - 12.1 ⁇ g/mL (Dose 0.1 mL); for monkeys - 10 ⁇ g/mL or 60 ⁇ g/mL (Dose 0.5 mL) and for guinea pigs - 12.5 ⁇ g/mL (Dose 0.4 mL). The mix is incubated for two hours at room temperature. To obtain the injection dose, the alum-absorbed conjugates are diluted with one time alum to reach the target peptide concentration. Where a second ® adjuvant is needed, i.e. ISCOMATRIX, the target concentration was 10 ⁇ g/ML for mice studies, 0, 100 or 200 ⁇ g/mL for monkey studies and 125 ⁇ g/mL for guinea pigs.
- ISCOMATRIX is dialyzed into sterile saline solution at 2-8° C. Sterile saline solution is
- ISCOMATRIX changed 2-3 times during dialysis.
- ISCOMATRIX is filter sterilized using a syringe filter (0.22 uM Millex-GV syringe filter, Millipore, Billerica, MA).
- concentration of sterile, dialyzed ISCOMATRIX R is determined by RP-HPLC.
- ISCOMATRIX is stored sterile at 2-8°C until use. 2.
- a ⁇ peptide-OMPC conjugate stocks are diluted into sterile IX saline solution.
- the diluted AD peptide-OMPC conjugate stocks are then added to 2X Merck alum in IX sterile saline solution and mixed for one hour on a rotating wheel at room temperature.
- the mixture is allowed to settle on the bench top for 15 minutes at room temperature and is then centrifuged at 1500 rpm for ten minutes.
- the supernatant is decanted off gently (UV analysis of supernatant is performed to determine % A ⁇ peptide-OMPC conjugate bound to alum) and the pellet is resuspended in sterile IX saline.
- the mixture is aliquoted into sterile 3 mL tubing glass vials and then stored at 2-8 0 C until final formulation with ISCOMATRIX®.
- OMPC/alum in saline is determined by static light scattering to confirm binding and monitor particle stability.
- the sterile, dialyzed ISCOMATRIX R in IX saline is added to A ⁇ peptide-OMPC/alum in sterile 150 mM NaCl while vortexing. Vials are stoppered, capped and crimped to completely seal.
- Vaccine is stored at 2-8 0 C prior to injection. Prior to injection, each vaccine is vortexed for 3-5 minutes.
- Two animals per group were immunized with the A ⁇ peptide - E-LH conjugates shown in Figure 2A intramuscularly with 400 ⁇ l of a conjugate vaccine (8 ⁇ g by peptide content or 50 ⁇ g by total conjugate) in the presence of 40 ⁇ g of ISCOMATRIX.®
- the immunizations were performed three times in four-week intervals. Serum samples were collected before first immunization (pre-bleeds) and three weeks after each immunization and stored at 4°C prior to antibody titer determinations.
- the antibody titers were determined by ELISA according to the protocol that follows using A ⁇ 40 as the target antigen.
- the ELISA based analysis is as follows: Ninety six-well plates were coated with 50 ⁇ l per well of A ⁇ at a concentration of 4 ⁇ g/ml in 50 mM bicarbonate buffer, pH 9.6, at 4°C overnight. Plates were washed with phosphate buffered saline (PBS) and blocked with 3% skim milk in PBS containing 0.05% Tween-20 (milk-PBST). Testing samples were diluted in a 4-fold series in PBST. One hundred ⁇ l of a diluted sample was added to each well, and the plates were incubated at 24°C for two hours and then washed six times with PBST.
- PBS phosphate buffered saline
- milk-PBST 0.05% Tween-20
- regions corresponding to A ⁇ amino acids 1-8, 3-10, 7-14, 11-18, 13- 20, 15-22, 19-26, 21-28, 23-30, 27-34 and 29-36 were highly immunogenic (>1: 10000) including: regions 1-8, 15-22, 21-28, 23-30 and 29-36.
- the results demonstrate that 8-mer conjugates are capable of eliciting an A ⁇ 4o specific antibody response.
- fragments of A ⁇ were equally immunogenic.
- regions of A ⁇ e.g., 5-12, 25-32, 31-38 and 35-42 are non-immunogenic (titers ⁇ 1:300).
- ISCOMATRJX® can provide an improved immune response.
- Applicants used an A ⁇ (1-18) peptide conjugated to OMPC as the model antigen.
- Rhesus monkeys (Macaca mulatto) were maintained in accordance with the institutional animal care protocols of Merck Research Laboratories and New Iberia Research Center (The University of Louisiana at Lafayette, New Iberia, LA).
- a ⁇ (1-18)-OMPC conjugates Five groups of monkeys, three per group, were given the following A ⁇ (1-18)-OMPC conjugates: (1) 5 ⁇ g conjugate (based on peptide content) in alum, (2) 5 ⁇ g conjugate in alum + 100 ⁇ g ISCOMATRK®, (3) 5 ⁇ g conjugate in alum + 50 mg ISCOMATRK®, (4), 30 ⁇ g conjugate in alum, (2) 30 ⁇ g conjugate in alum + 100 ⁇ g ISCOMATRK®.
- the immunizations were carried out by intramuscular injections in 0.5 ml aliquots at weeks 0, 8 and 24 using tuberculin syringes (Becton- Dickinson, Franklin Lakes, NJ). Serum samples were collected at four week intervals starting from week 0 (pre-bleed) and the tested for antibody titers against A ⁇ 40 by ELISA, performed as described in the preceding example.
- Sections were blocked by a ten minute exposure to 10% goat serum followed by a five minute wash with PBS. Sections were then incubated with diluted guinea pig sera at 4° C overnight or for one hour at room temperature. Following a five minute PBS wash, sections were incubated for ten minutes with diluted biotinylated goat anti- guinea pig IgG or biotinylated horse anti-mouse antibody (1 drop in 5 ml PBS). Sections were washed for five minutes in PBS and subsequently incubated with ABC solution (Vectorstain ABC kit; Vector Laboratories, Inc.) for thirty minutes. Sections were washed with PBS for five minutes.
- ABC solution Vectorstain ABC kit; Vector Laboratories, Inc.
- Sections were then stained with DAB (DakoCytomation) for five minutes and washed with dd H2O. Sections were then counterstained in hematoxylin for thirty seconds and dehydrated in graded EtOH and Xylenes (70% EtOH for five minutes, 80% EtOH for five minutes, 100% EtOH for five minutes and xylenes for five minutes). Sections were then cover-slipped and evaluated by light microscopy.
- the immunogenic response produced by the A ⁇ (3-1O)-KLH conjugate produced an antibody response that was directed against human AD brain tissue. As shown in Figure 4, this human brain section has extensive A ⁇ deposition in a manner typical to that expected for human AD.
- Enzyme-Linked ImmunoSpot Assay
- Immunogen fragments possessing T-cell epitopes are identified by the presence of a dark spot on the surface of a white membrane; each spot indicates the presence of a T- cell that has secreted interferon gamma (IFN- ⁇ ) in response to the antigen (i.e. immunogenic fragment).
- IFN- ⁇ interferon gamma
- PBMCs peripheral blood monocytes
- PBMCs were centrifuged and re-suspended in RlO. PBMCs were counted on a Z2 Coulter counter (Beckman Coulter, Fullerton, CA).
- Each well of the aspirated plate received either 0.4 ⁇ g of A ⁇ 1-40, A ⁇ 1-20, PHA (phytohemagglutinin, Cat No. L-8902, Sigma, St. Louis, MO, positive control), or diluted DMSO (Sigma, negative control); 400000 PBMCs were then added to each well. Plates were incubated for 18- 24 hours at 37 0 C in a humid CO 2 incubator. Plates were washed in PBS with 5% FBS and 0.005%
- Applicants have established that spot forming cells per million PBMCs (SFC/ 10 6 PBMCs) must exceed 55 and must exceed 4-fold the negative control to be defined as a positive result; failing to meet both these criteria defines a negative result.
- Rhesus macaques were vaccinated with either a MAP construct comprising A ⁇ (3-10)/(21-28) (Construct No. 12, Figure 6A) conjugated to OMPC or with both of two monomeric constructs, A ⁇ (3-10) (SEQ ID NO: 69) and A ⁇ (21-28) (SEQ ID NO: 73) conjugated to OMPC.
- the rhesus primates received vaccinations every four weeks with bleeds collected and analyzed four weeks following each injection. Anti-A ⁇ 4o titers and total A ⁇ .40 levels were determined.
- Plasma A ⁇ i.40 levels were determined in these immunized animals using a 6E10/G210 ELISA.
- This assay measures A ⁇ i.40 using a sandwich ELISA comprising an N-terminal capture antibody 6E10 (A ⁇ 1-8) (Signet Laboratories, Dedham, MA) and a C-terminal A ⁇ 4o neo-epitope antibody (G210) (The Genetics Company, Inc., Zurich, Switzerland) conjugated with alkaline phosphatase.
- the antibody, 6E10 was coated onto plates at a concentration of 5ug/ml. Diluted plasma samples (1:3) were used at 50 ⁇ l/well in triplicates.
- a ⁇ i_4o standards were prepared from 400 pM - 3pM in 6E10 immuno-depleted rhesus plasma matrix. This assay has a signal-to-noise ratio of about 5-20.
- the CDP-star alkaline phosphatase substrate was obtained from Applied Biosystems, Foster City, CA.
- the identification of immunogens, either 8-mers or MAPs, lacking a T-cell epitope, that elevate plasma A ⁇ following immunization provides a method for selecting said 8-mers or MAPs for use in a vaccine construct.
- those skilled in the art are now able to characterize said vaccine constructs both quantitatively (i.e., immunogenicity) and qualitatively (i.e., nature of the polyclonal antibody response - ability to elevate plasma AB levels).
- the invention herein is not limited to 8-amino acid A ⁇ fragments, but is inclusive of any antigen capable of producing a polyclonal antibody response in the host organism that is reactive to A ⁇ .
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Microbiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2006246382A AU2006246382A1 (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for the prevention and treatment of Alzheimer's disease |
AT06751930T ATE535252T1 (en) | 2005-05-05 | 2006-05-01 | PEPTIDE CONJUGATE COMPOSITIONS AND METHODS FOR PREVENTING AND TREATING ALZHEIMER'S DISEASE |
CN2006800153890A CN101171031B (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
BRPI0610093-7A BRPI0610093A2 (en) | 2005-05-05 | 2006-05-01 | pharmaceutical composition, and method for preventing or treating a disease associated with alpha-beta amyloid deposits in a patient's brain |
NZ562434A NZ562434A (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
JP2008510087A JP2008540417A (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for prevention and treatment of Alzheimer's disease |
CA002607868A CA2607868A1 (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
US11/919,897 US7850973B2 (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
MX2007013825A MX2007013825A (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease. |
EP06751930A EP1879613B1 (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
ZA2007/08635A ZA200708635B (en) | 2005-05-05 | 2007-10-10 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimers disease |
IL186793A IL186793A0 (en) | 2005-05-05 | 2007-10-18 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
NO20076239A NO20076239L (en) | 2005-05-05 | 2007-12-04 | Peptide conjugate preparations and methods for the prevention and treatment of Alzheimer's disease |
US12/907,493 US20110052611A1 (en) | 2005-05-05 | 2010-11-08 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US67788605P | 2005-05-05 | 2005-05-05 | |
US60/677,886 | 2005-05-05 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/907,493 Division US20110052611A1 (en) | 2005-05-05 | 2010-11-08 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2006121656A2 true WO2006121656A2 (en) | 2006-11-16 |
WO2006121656A3 WO2006121656A3 (en) | 2007-01-04 |
Family
ID=37019042
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2006/016481 WO2006121656A2 (en) | 2005-05-05 | 2006-05-01 | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease |
Country Status (16)
Country | Link |
---|---|
US (2) | US7850973B2 (en) |
EP (2) | EP2269633A1 (en) |
JP (1) | JP2008540417A (en) |
KR (1) | KR20080005260A (en) |
CN (1) | CN101171031B (en) |
AT (1) | ATE535252T1 (en) |
AU (1) | AU2006246382A1 (en) |
BR (1) | BRPI0610093A2 (en) |
CA (1) | CA2607868A1 (en) |
IL (1) | IL186793A0 (en) |
MX (1) | MX2007013825A (en) |
NO (1) | NO20076239L (en) |
NZ (1) | NZ562434A (en) |
RU (1) | RU2406529C2 (en) |
WO (1) | WO2006121656A2 (en) |
ZA (1) | ZA200708635B (en) |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007064917A2 (en) * | 2005-11-30 | 2007-06-07 | Abbott Laboratories | Methods of preparation of recombinant forms of human beta-amyloid protein and uses of these proteins |
WO2008150949A1 (en) * | 2007-05-30 | 2008-12-11 | Abbott Laboratories | HUMANIZED ANTIBODIES TO Aß(20-42) GLOBULOMER AND USES THEREOF |
WO2008156621A1 (en) | 2007-06-12 | 2008-12-24 | Ac Immune S.A. | Monoclonal anti beta amyloid antibody |
EP2020602A1 (en) * | 2007-08-02 | 2009-02-04 | Araclon Biotech | High sensitivty immunoassays and kits for the determination of peptides and proteins of biological interest |
WO2009054537A1 (en) | 2007-10-25 | 2009-04-30 | Kagoshima University | PEPTIDE VACCINE USING MIMIC MOLECULE OF AMYLOID β-PEPTIDE |
WO2009047002A3 (en) * | 2007-10-12 | 2009-08-06 | Fond I R C C S Istituto Neurol | Products and their use for the diagnosis, prevention, and/or care of human and/or animal pathologies characterised by the anomalous deposition of b-amyloid and/or amyloid-like substance in human and/or animal organs and tissues, and screening method for determining the risk of such pathologies |
WO2010002251A1 (en) * | 2008-07-01 | 2010-01-07 | De Staat Der Nederlanden, Vert. Door De Minister Van Vws | Vaccine against amyloid folding intermediate |
WO2010005858A1 (en) * | 2008-07-08 | 2010-01-14 | Merck & Co., Inc. | Vaccine for the treatment of alzheimer's disease |
EP2149380A1 (en) * | 2008-07-29 | 2010-02-03 | Medivet Pharma, S.L. | Veterinary immunotherapy compositions for the Aged Related Cognitive Dysfunction. |
WO2010136487A1 (en) * | 2009-05-26 | 2010-12-02 | Araclon Biotech S.L. | Albumin-amyloid peptide conjugates and uses thereof |
WO2011106732A1 (en) | 2010-02-25 | 2011-09-01 | Wyeth Llc | Pet monitoring of ab-directed immunotherapy |
WO2012072611A1 (en) * | 2010-11-29 | 2012-06-07 | Philipps-Universität Marburg | SYNTHETIC LIGANDS FOR HUMAN ANTI-Aβ ANTIBODIES |
WO2013020723A1 (en) | 2011-08-05 | 2013-02-14 | Glaxosmithkline Biologicals S.A. | Compositions and uses thereof for the treatment or prevention of alzheimer's disease |
US8535673B2 (en) | 1997-12-02 | 2013-09-17 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidogenic disease |
US8613920B2 (en) | 2007-07-27 | 2013-12-24 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
US20140039155A1 (en) * | 2008-10-06 | 2014-02-06 | Commonwealth Scientific And Industrial Research Organisation | Amyloid-beta peptide crystal structure |
US8784810B2 (en) | 2006-04-18 | 2014-07-22 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
US8916165B2 (en) | 2004-12-15 | 2014-12-23 | Janssen Alzheimer Immunotherapy | Humanized Aβ antibodies for use in improving cognition |
US9051363B2 (en) | 1997-12-02 | 2015-06-09 | Janssen Sciences Ireland Uc | Humanized antibodies that recognize beta amyloid peptide |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9067981B1 (en) | 2008-10-30 | 2015-06-30 | Janssen Sciences Ireland Uc | Hybrid amyloid-beta antibodies |
US9175094B2 (en) | 2007-06-12 | 2015-11-03 | Ac Immune S.A. | Monoclonal antibody |
EP2952524A1 (en) | 2007-10-17 | 2015-12-09 | Janssen Sciences Ireland UC | Immunotherapy regimes dependent on apoe status |
US9822171B2 (en) | 2010-04-15 | 2017-11-21 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9951125B2 (en) | 2006-11-30 | 2018-04-24 | Abbvie Inc. | Aβ conformer selective anti-Aβ globulomer monoclonal antibodies |
RU2679059C1 (en) * | 2018-04-17 | 2019-02-05 | Александр Олегович Морозов | Peptide and method of treatment of alzheimer's disease |
RU2679080C1 (en) * | 2018-04-17 | 2019-02-05 | Александр Олегович Морозов | Peptide and method of treatment of alzheimer's disease |
US10208109B2 (en) | 2005-11-30 | 2019-02-19 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
US10464976B2 (en) | 2003-01-31 | 2019-11-05 | AbbVie Deutschland GmbH & Co. KG | Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof |
US10538581B2 (en) | 2005-11-30 | 2020-01-21 | Abbvie Inc. | Anti-Aβ globulomer 4D10 antibodies |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8895004B2 (en) | 2007-02-27 | 2014-11-25 | AbbVie Deutschland GmbH & Co. KG | Method for the treatment of amyloidoses |
US8048420B2 (en) | 2007-06-12 | 2011-11-01 | Ac Immune S.A. | Monoclonal antibody |
PT2238166E (en) | 2007-10-05 | 2014-02-11 | Genentech Inc | Use of anti-amyloid beta antibody in ocular diseases |
EP2440234A4 (en) * | 2009-06-10 | 2013-11-06 | Univ New York | Immunological targeting of pathological tau proteins |
RU2607368C2 (en) | 2010-07-30 | 2017-01-10 | Ац Иммуне С.А. | Safe and functional humanized antibodies |
US20120328605A1 (en) * | 2010-10-27 | 2012-12-27 | Daniel Larocque | Compositions and uses |
WO2013059322A2 (en) * | 2011-10-17 | 2013-04-25 | Lawrence Steinman | Amyloid beta peptide as a therapy for inflammation |
WO2015157820A1 (en) * | 2014-04-15 | 2015-10-22 | Griffith University | Group a streptococcus vaccine |
EP3166688A4 (en) | 2014-07-08 | 2017-12-20 | New York University | Tau imaging ligands and their uses in the diagnosis and treatment of tauopathy |
WO2017027685A2 (en) | 2015-08-13 | 2017-02-16 | New York University | Antibody-based molecules specific for the truncated asp421 epitope of tau and their uses in the diagnosis and treatment of tauopathy |
ES2571055B1 (en) * | 2016-02-15 | 2016-12-28 | Araclon Biotech, S.L. | Amyloid conjugate and its uses and procedures |
EP3444344A4 (en) * | 2016-04-14 | 2020-02-19 | TAO Health Life Pharma Co., Ltd. | Amylospheroid (aspd)-like structure and pharmaceutical composition |
KR101898623B1 (en) | 2016-11-10 | 2018-09-13 | 주식회사 브레인숲 | Paper toy brock |
MX2020004338A (en) | 2017-10-25 | 2020-10-14 | Janssen Pharmaceuticals Inc | Compositions of phosphorylated tau peptides and uses thereof. |
CN116063382A (en) * | 2022-11-17 | 2023-05-05 | 山东大学 | Polypeptide material with third-order nonlinear optical performance and preparation method and application thereof |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5494808A (en) | 1994-09-15 | 1996-02-27 | Merck & Co., Inc. | Defined medium OMPC fermentation process |
US7964192B1 (en) * | 1997-12-02 | 2011-06-21 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidgenic disease |
US6787523B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
TWI239847B (en) | 1997-12-02 | 2005-09-21 | Elan Pharm Inc | N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease |
US6905686B1 (en) * | 1997-12-02 | 2005-06-14 | Neuralab Limited | Active immunization for treatment of alzheimer's disease |
JP3854481B2 (en) * | 2000-11-17 | 2006-12-06 | 三菱重工業株式会社 | Wet flue gas desulfurization apparatus and wet flue gas desulfurization method |
EP1397380B1 (en) * | 2001-06-20 | 2006-12-27 | Ramot at Tel Aviv University Ltd. | Multiple antigenic peptide displaying multiple copies of an epitope of a plaque-forming polypeptide and methods of using same |
MY144532A (en) * | 2001-08-20 | 2011-09-30 | Lundbeck & Co As H | Novel method for down-regulation of amyloid |
EP1594969B1 (en) * | 2003-02-01 | 2015-05-20 | Janssen Sciences Ireland UC | Active immunization to generate antibodies to soluble a-beta |
WO2005058940A2 (en) * | 2003-12-17 | 2005-06-30 | Wyeth | Immunogenic peptide carrier conjugates and methods of producing same |
-
2006
- 2006-05-01 CN CN2006800153890A patent/CN101171031B/en not_active Expired - Fee Related
- 2006-05-01 AU AU2006246382A patent/AU2006246382A1/en not_active Abandoned
- 2006-05-01 JP JP2008510087A patent/JP2008540417A/en active Pending
- 2006-05-01 KR KR1020077025682A patent/KR20080005260A/en not_active Application Discontinuation
- 2006-05-01 EP EP10181823A patent/EP2269633A1/en not_active Withdrawn
- 2006-05-01 AT AT06751930T patent/ATE535252T1/en active
- 2006-05-01 NZ NZ562434A patent/NZ562434A/en not_active IP Right Cessation
- 2006-05-01 WO PCT/US2006/016481 patent/WO2006121656A2/en active Application Filing
- 2006-05-01 RU RU2007145052/10A patent/RU2406529C2/en not_active IP Right Cessation
- 2006-05-01 EP EP06751930A patent/EP1879613B1/en not_active Not-in-force
- 2006-05-01 US US11/919,897 patent/US7850973B2/en not_active Expired - Fee Related
- 2006-05-01 CA CA002607868A patent/CA2607868A1/en not_active Abandoned
- 2006-05-01 MX MX2007013825A patent/MX2007013825A/en active IP Right Grant
- 2006-05-01 BR BRPI0610093-7A patent/BRPI0610093A2/en not_active IP Right Cessation
-
2007
- 2007-10-10 ZA ZA2007/08635A patent/ZA200708635B/en unknown
- 2007-10-18 IL IL186793A patent/IL186793A0/en unknown
- 2007-12-04 NO NO20076239A patent/NO20076239L/en not_active Application Discontinuation
-
2010
- 2010-11-08 US US12/907,493 patent/US20110052611A1/en not_active Abandoned
Non-Patent Citations (4)
Title |
---|
BATALIA; COLLINS, ENGELHARD ANNU REV IMMUNOL., vol. 12, 1995, pages 181 - 207,622 |
BJORKMAN ET AL., NATURE, vol. 329, 1987, pages 506 - 512 |
MADDEN ET AL., CELL, vol. 75, pages 693 - 708 |
MADDEN, ANNU REV IMMUNOL., vol. 13, 1995, pages 587 - 622 |
Cited By (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8535673B2 (en) | 1997-12-02 | 2013-09-17 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidogenic disease |
US8642044B2 (en) | 1997-12-02 | 2014-02-04 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidogenic disease |
US9051363B2 (en) | 1997-12-02 | 2015-06-09 | Janssen Sciences Ireland Uc | Humanized antibodies that recognize beta amyloid peptide |
US10464976B2 (en) | 2003-01-31 | 2019-11-05 | AbbVie Deutschland GmbH & Co. KG | Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof |
US8916165B2 (en) | 2004-12-15 | 2014-12-23 | Janssen Alzheimer Immunotherapy | Humanized Aβ antibodies for use in improving cognition |
US8263558B2 (en) | 2005-11-30 | 2012-09-11 | Abbott Laboratories | Methods of preparation of recombinant forms of human beta-amyloid protein and uses of these proteins |
US10538581B2 (en) | 2005-11-30 | 2020-01-21 | Abbvie Inc. | Anti-Aβ globulomer 4D10 antibodies |
WO2007064917A3 (en) * | 2005-11-30 | 2008-03-13 | Abbott Lab | Methods of preparation of recombinant forms of human beta-amyloid protein and uses of these proteins |
US10323084B2 (en) | 2005-11-30 | 2019-06-18 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
US10208109B2 (en) | 2005-11-30 | 2019-02-19 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
WO2007064917A2 (en) * | 2005-11-30 | 2007-06-07 | Abbott Laboratories | Methods of preparation of recombinant forms of human beta-amyloid protein and uses of these proteins |
US8784810B2 (en) | 2006-04-18 | 2014-07-22 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
US9951125B2 (en) | 2006-11-30 | 2018-04-24 | Abbvie Inc. | Aβ conformer selective anti-Aβ globulomer monoclonal antibodies |
WO2008150949A1 (en) * | 2007-05-30 | 2008-12-11 | Abbott Laboratories | HUMANIZED ANTIBODIES TO Aß(20-42) GLOBULOMER AND USES THEREOF |
US9175094B2 (en) | 2007-06-12 | 2015-11-03 | Ac Immune S.A. | Monoclonal antibody |
WO2008156621A1 (en) | 2007-06-12 | 2008-12-24 | Ac Immune S.A. | Monoclonal anti beta amyloid antibody |
EP2527366A1 (en) * | 2007-06-12 | 2012-11-28 | AC Immune S.A. | Monoclonal anti beta amyloid antibody |
AU2008267037B2 (en) * | 2007-06-12 | 2014-08-07 | Ac Immune S.A. | Monoclonal anti beta amyloid antibody |
US9585956B2 (en) | 2007-06-12 | 2017-03-07 | Ac Immune S.A. | Polynucleotides encoding anti-amyloid beta monoclonal antibodies |
US8613920B2 (en) | 2007-07-27 | 2013-12-24 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
EP2020602A1 (en) * | 2007-08-02 | 2009-02-04 | Araclon Biotech | High sensitivty immunoassays and kits for the determination of peptides and proteins of biological interest |
KR101461538B1 (en) * | 2007-08-02 | 2014-11-14 | 아라클론 바이오테크, 에스.엘. | Highly sensitive immunoassays and kits for the determination of peptides and proteins of biological interest |
WO2009015696A1 (en) * | 2007-08-02 | 2009-02-05 | Araclon Biotech | High sensitivty immunoassays and kits for the determination of peptides and proteins of biological interest |
WO2009047002A3 (en) * | 2007-10-12 | 2009-08-06 | Fond I R C C S Istituto Neurol | Products and their use for the diagnosis, prevention, and/or care of human and/or animal pathologies characterised by the anomalous deposition of b-amyloid and/or amyloid-like substance in human and/or animal organs and tissues, and screening method for determining the risk of such pathologies |
EP2952524A1 (en) | 2007-10-17 | 2015-12-09 | Janssen Sciences Ireland UC | Immunotherapy regimes dependent on apoe status |
US9644025B2 (en) | 2007-10-17 | 2017-05-09 | Wyeth Llc | Immunotherapy regimes dependent on ApoE status |
WO2009054537A1 (en) | 2007-10-25 | 2009-04-30 | Kagoshima University | PEPTIDE VACCINE USING MIMIC MOLECULE OF AMYLOID β-PEPTIDE |
WO2010002251A1 (en) * | 2008-07-01 | 2010-01-07 | De Staat Der Nederlanden, Vert. Door De Minister Van Vws | Vaccine against amyloid folding intermediate |
US9045555B2 (en) | 2008-07-01 | 2015-06-02 | De Staat Der Nederlanden, Vert. Door De Minister Van Vws | Vaccine against amyloid folding intermediate |
JP2011526885A (en) * | 2008-07-01 | 2011-10-20 | デ スタート デル ネダーランデン、フェルト.ドール デ ミニスター ファン フォルクスヘーゾンドハイド、フェルジイン アン スポルト | Vaccine against amyloid folding intermediate |
WO2010005858A1 (en) * | 2008-07-08 | 2010-01-14 | Merck & Co., Inc. | Vaccine for the treatment of alzheimer's disease |
EP2149380A1 (en) * | 2008-07-29 | 2010-02-03 | Medivet Pharma, S.L. | Veterinary immunotherapy compositions for the Aged Related Cognitive Dysfunction. |
WO2010012749A1 (en) * | 2008-07-29 | 2010-02-04 | Medivet Pharma, S.L. | Immunotherapy compositions for the treatment and prevention of amyloidosis |
US20140039155A1 (en) * | 2008-10-06 | 2014-02-06 | Commonwealth Scientific And Industrial Research Organisation | Amyloid-beta peptide crystal structure |
US9067981B1 (en) | 2008-10-30 | 2015-06-30 | Janssen Sciences Ireland Uc | Hybrid amyloid-beta antibodies |
EP2258398A1 (en) * | 2009-05-26 | 2010-12-08 | Araclón Biotech, S. L. | Albumin-amyloid peptide conjugates and uses thereof |
CN102458478A (en) * | 2009-05-26 | 2012-05-16 | 阿拉克隆生物技术商业有限公司 | Albumin-amyloid peptide conjugates and uses thereof |
CN102458478B (en) * | 2009-05-26 | 2014-03-19 | 阿拉克隆生物技术商业有限公司 | Albumin-amyloid peptide conjugates and uses thereof |
WO2010136487A1 (en) * | 2009-05-26 | 2010-12-02 | Araclon Biotech S.L. | Albumin-amyloid peptide conjugates and uses thereof |
WO2011106732A1 (en) | 2010-02-25 | 2011-09-01 | Wyeth Llc | Pet monitoring of ab-directed immunotherapy |
US9822171B2 (en) | 2010-04-15 | 2017-11-21 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US10047121B2 (en) | 2010-08-14 | 2018-08-14 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
WO2012072611A1 (en) * | 2010-11-29 | 2012-06-07 | Philipps-Universität Marburg | SYNTHETIC LIGANDS FOR HUMAN ANTI-Aβ ANTIBODIES |
WO2013020723A1 (en) | 2011-08-05 | 2013-02-14 | Glaxosmithkline Biologicals S.A. | Compositions and uses thereof for the treatment or prevention of alzheimer's disease |
WO2013020724A1 (en) | 2011-08-05 | 2013-02-14 | Glaxosmithkline Biologicals S.A. | Composition comprising a tlr agonist and an antibody specific for an antigen and uses thereof as vaccine |
WO2013020722A3 (en) * | 2011-08-05 | 2013-04-04 | Glaxosmithkline Biologicals S.A. | Composition comprising small peptide as amyloid beta mimotope and adjuvant for use as vaccine against alzheimer's disease |
RU2679059C1 (en) * | 2018-04-17 | 2019-02-05 | Александр Олегович Морозов | Peptide and method of treatment of alzheimer's disease |
RU2679080C1 (en) * | 2018-04-17 | 2019-02-05 | Александр Олегович Морозов | Peptide and method of treatment of alzheimer's disease |
WO2019203687A1 (en) * | 2018-04-17 | 2019-10-24 | Александр Олегович МОРОЗОВ | Peptide and method of treating alzheimer's disease |
WO2019203686A1 (en) * | 2018-04-17 | 2019-10-24 | Александр Олегович МОРОЗОВ | Peptide and method of treating alzheimer's disease |
Also Published As
Publication number | Publication date |
---|---|
EP1879613B1 (en) | 2011-11-30 |
CA2607868A1 (en) | 2006-11-16 |
ZA200708635B (en) | 2008-10-29 |
EP2269633A1 (en) | 2011-01-05 |
US20090098155A1 (en) | 2009-04-16 |
ATE535252T1 (en) | 2011-12-15 |
EP1879613A2 (en) | 2008-01-23 |
MX2007013825A (en) | 2008-01-18 |
US20110052611A1 (en) | 2011-03-03 |
RU2406529C2 (en) | 2010-12-20 |
NO20076239L (en) | 2008-01-30 |
IL186793A0 (en) | 2008-02-09 |
KR20080005260A (en) | 2008-01-10 |
BRPI0610093A2 (en) | 2008-12-09 |
CN101171031A (en) | 2008-04-30 |
CN101171031B (en) | 2011-09-28 |
AU2006246382A1 (en) | 2006-11-16 |
RU2007145052A (en) | 2009-06-10 |
JP2008540417A (en) | 2008-11-20 |
WO2006121656A3 (en) | 2007-01-04 |
NZ562434A (en) | 2010-04-30 |
US7850973B2 (en) | 2010-12-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7850973B2 (en) | Peptide conjugate compositions and methods for the prevention and treatment of alzheimer's disease | |
AU2017203425B2 (en) | Peptide vaccine for prevention and immunotherapy of dementia of the Alzheimer's type | |
RU2390350C2 (en) | Active immunisation for creating soluble a-beta antibodies | |
US9535076B2 (en) | Methods and compositions for eliciting an amyloid-selective immune response | |
JP5559789B2 (en) | Immunotherapeutic composition for the treatment of Alzheimer's disease | |
JP2006516535A (en) | Immunogens and corresponding antibodies specific for high molecular weight aggregation intermediates common to amyloids formed from proteins of different sequences | |
US20110002949A1 (en) | Vaccine for the treatment of alzheimer's disease | |
US20220023401A1 (en) | Peptide vaccine for prevention and immunotherapy of dementia of the alzheimer's type | |
RU2811687C2 (en) | Peptide vaccine for prevention and immunotherapy of alzheimer-type dementia | |
JP2023519104A (en) | Peptide immunogens targeting IAPP for preventing and treating disorders associated with aggregated islet amyloid polypeptide (IAPP) | |
JP2011201902A (en) | Active immunization to generate antibody to soluble a-beta |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200680015389.0 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 562434 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 186793 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006246382 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/a/2007/013825 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2008510087 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006751930 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2607868 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11919897 Country of ref document: US Ref document number: 1020077025682 Country of ref document: KR |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2006246382 Country of ref document: AU Date of ref document: 20060501 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 9383/DELNP/2007 Country of ref document: IN Ref document number: 2007145052 Country of ref document: RU |
|
ENP | Entry into the national phase |
Ref document number: PI0610093 Country of ref document: BR |