Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
• • 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
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• the present invention relates to a combination of an ⁇ antibody and a BACE1 inhibitor. Background of the invention
• AD Alzheimer's Disease
• ⁇ amyloid- ⁇ - peptides
• ⁇ is derived from the ⁇ -amyloid precursor protein through proteolytic processing by BACE1 ( ⁇ -secretase) and ⁇ -secretase.
• Abeta ( ⁇ ) comprises a family of peptides which differ in length at their C-terminus, ⁇ 40 is the predominant species but a minor peptide of 42 amino acid length, ⁇ 42, is considered to be the most pathogenic peptide because of its high propensity to form toxic aggregates.
• the transgenic mouse model hAPP-TG which was used in this study carries a mutation in its APP transgene, V717I, which increases the formation of ⁇ 42 relative to ⁇ 40 and thus causes an aggressive amyloidosis which starts around 9-10 months of age Tanghe et al 2010) 1 .
• the transgene is under the control of a mouse Thyl promoter which directs is expression preferentially to neuronal cells (Andra et al 1996, Vidal et al 1990) 2 .
• a combination of the specific ⁇ antibody (Cmpd 1) and the specific BACE1 inhibitor 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2- amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof lead to a surprisingly high amyloid lowering effect (Cmpd 2).
• Alzheimer's Disease is the sixth leading cause of death in the United States and is a fast growing disease. Despite considerable progress of AD research in recent years and evolving paradigm shifts in both pathophysiological concepts as well as in diagnostic criteria fundamental challenges have not yet been reso lved (Hampel et al. 2011) 6 . It is an object of the present invention to provide a composition suitable for control, treatment and/or prevention of Alzheimer's Disease.
• WO 2007068412 7 related to monoclonal antibodies used in methods and compositions for the therapeutic and diagnostic use in the treatment of diseases and disorders which are caused by or associated with amyloid or amyloid-like proteins including amyloidosis, a group of disorders and abnormalities associated with amyloid protein such as Alzheimer's disease.
• WO 2006014944 8 relates to ⁇ secretase inhibitors.
• WO 03070760 9 relates to antibody molecules capable of specifically recognizing two regions of the R-A4 peptide.
• WO 2011069934 10 relates to 2-Amino-5,5-difluoro-5,6-dihydro-4H-[l,3]oxazin-4-yl)- phenyl]-amide derivatives having BACE1 and/or BACE2 inhibitory activity.
• Chow et al. 11 describes a combination therapy for the treatment of Alzheimer's Disease.
• Wang et al. 12 describes a mouse model of Alzheimer's Disease.
• Guo et a/. 13 describes the role of ⁇ in the treatment of glaucoma.
• the present invention provides a combination of an ⁇ antibody and a BACE1 inhibitor, pharmaceutical products based on that combination in accordance with the invention and their the use thereof in the control, treatment and/or prevention of illnesses such as Alzheimer's disease.
• compound 1 (Cmpd 1) shall herein refer to the ⁇ antibody.
• Abeta antibody and “an antibody that binds to Abeta” refer to an antibody that is capable of binding ⁇ peptide with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting ⁇ peptide.
• the term “anti- ⁇ antibody” can be used.
• antibody encompasses the various forms of antibody structures including but not being limited to whole antibodies and antibody fragments.
• the antibody according to the invention is preferably a humanized antibody, chimeric antibody, or further genetically engineered antibody as long as the characteristic properties according to the invention are retained.
• the terms “monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of a single amino acid composition.
• the term "mono-glycosylated Abeta antibody” relates to an antibody molecule comprising an N-glycosylation at position 52 of Seq. Id. No. 1 in one (VH)-region of an individual antibody molecule.
• the term "double-glycosylation Abeta antibody” defines an antibody molecule which is N-glycosylated at position 52 of Seq. Id. No. 1 on both variable regions of the heavy chain” (figure 1).
• Antibody molecules which lack a N-glycosylation on both heavy chain (VH)-domains are named "non-glycosylated antibodies”.
• the mono-glycosylated antibody, the double- glycosylated antibody and the non-glycosylated antibody may comprise the identical amino acid sequences or different amino acid sequences.
• the mono-glycosylated antibody and the double- glycosylated antibody are herein referred to as "glycosylated antibody isoforms".
• a purified antibody molecule characterized in that at least one antigen binding site comprises a glycosylation in the variable region of the heavy chain (VH) is a mono-glycosylated antibody which is free of or to a very low extent associated with an isoform selected from a double- glycosylated antibody and a nonglycosylated antibody, i.e. a "purified mono-glycosylated antibody".
• a double-glycosylated antibody in context of this invention is free of or to a very low extent associated with an isoform selected from a mono-glycosylated antibody and a nonglycosylated antibody, i.e. a "purified double-glycosylated antibody".
• Compound 2 (Cmpd 2) shall herein refer to 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2- amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide of the following structure
• excipient or “pharmaceutically acceptable excipient” refers to surfactans, disintegrants, fillers, binders, glidants, lubricants and there like.
• surfactant refers to excipients that lower the surface tension of a liquid, the interfacial tension between two liquids, or that between a liquid and a solid.
• disintegrant refers to excipients that expand and dissolve when wet causing the tablet to break apart in the body and release the active ingredient for absorption.
• filler refers to excipients that fill out the size of a tablet by increasing the bulk volume. Fillers make it possible for the final product to have the proper volume for patient handling.
• binder refers to excipients that hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets.
• glidant refers to excipients that enhance product flow by reducing interparticulate friction.
• lubricant refers to excipients that prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low fraction between active ingredient and wall.
• pharmaceutically acceptable salt refers to any conventional salt or base addition salt that retains the biological effectiveness and properties of the compound and which is formed from a suitable non-toxic organic or inorganic acid or organic or inorganic base.
• suitable non-toxic organic or inorganic acid or organic or inorganic base An example is the hydrochloride salt.
• therapeutically effective means an amount of drug, or composition, which is effective for producing a desired therapeutic effect upon administration to a patient, for example, to control, treat and/or prevent Alzheimer's Disease.
• the present invention relates to a combination of an ⁇ antibody and a BACEl inhibitor.
• the combination of the ⁇ antibody and the BACEl inhibitor 5-Cyano-pyridine-2- carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4- fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof can be used in the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated ⁇ - amyloid levels and/or ⁇ -amyloid oligomers and/or ⁇ -amyloid plaques and further deposits, particularly Alzheimer's disease.
• the invention relates to a composition comprising an ⁇ antibody and a BACEl inhibitor.
• a specific embodiment relates to a composition comprising i) gantenerumab, and ii) 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6- dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof.
• a specific embodiment relates to a composition consisting of i) gantenerumab, and ii) 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6- dihydro-4H-[ 1 ,3]oxazin-4-yl)-4-fluoro-phenyl]-amide hydrochloride.
• a specific embodiment relates to a composition
• a composition comprising i) an ⁇ antibody, wherein the heavy chain thereof comprises a VH domain which comprises:
• a CDR3 sequence comprising the amino acid sequence of Seq. Id. No. 5; and ii) a BACEl inhibitor which is 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5- difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof.
• a specific embodiment relates to a composition
• a composition comprising i) an ⁇ antibody, wherein the light chain thereof comprises a VL domain which comprises:
• a CDR3 sequence comprising the amino acid sequence of Seq. Id. No. 8; and ii) a BACEl inhibitor which is 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5- difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof.
• a specific embodiment relates to a composition
• a composition comprising i) an ⁇ antibody, wherein the VH domain thereof comprises the amino acid sequence of Seq. Id. No. 1 and the VL domain thereof comprises the amino acid sequence of Seq. Id. No. 2; and ii) a BACEl inhibitor which is 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5- difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof.
• a specific embodiment relates to a composition
• a composition comprising i) an ⁇ antibody, wherein the heavy chain thereof comprises the amino acid sequence of Seq. Id. No. 9; and ii) a BACEl inhibitor which is 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5- difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof.
• a specific embodiment relates to a composition
• a composition comprising i) an ⁇ antibody, wherein the light chain thereof comprises the amino acid sequence of Seq. Id. No. 10; and ii) a BACEl inhibitor which is 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5- difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof.
• a specific embodiment relates to a composition
• a composition comprising i) an monoclonal ⁇ antibody, which is a mixture of mono-glycosylated ⁇ antibodies and double-glycosylated ⁇ antibodies, wherein the mono-glycosylated ⁇ antibody comprises a glycosylated asparagine (Asn) at position 52 of Seq. Id. No. 1 in the VH domain of one antibody binding site and wherein the double-glycosylated antibody comprises a glycosylated asparagine (Asn) at position 52 of Seq. Id. No. 1 in the VH domain of both antibody binding sites and whereby said mixture comprises less than 5% of an antibody being non-glycosylated at position 52 of Seq. Id. No.
• a BACEl inhibitor which is 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5- difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof.
• a specific embodiment relates to a composition as described herein, wherein the a BACEl inhibitor is 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6- dihydro-4H-[ 1 ,3]oxazin-4-yl)-4-fluoro-phenyl]-amide hydrochloride.
• a specific embodiment relates to a composition as described herein, wherein the ⁇ antibody and 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6- dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof are administered separately, simultaneously, in a fixed combination or sequentially in any order.
• a specific embodiment relates to a composition as described herein, wherein the ⁇ antibody and 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6- dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof are administered separately.
• a specific embodiment relates to a composition as described herein, wherein the ⁇ antibody and 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6- dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof are administered simultaneously.
• a specific embodiment relates to a composition as described herein, wherein the ⁇ antibody and 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6- dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof are administered in a fixed combination.
• a specific embodiment relates to a composition as described herein, wherein the ⁇ antibody and 5-Cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6- dihydro-4H-[l,3]oxazin-4-yl)-4-fluoro-phenyl]-amide, or a pharmaceutically acceptable salt thereof are administered sequentially in any order.
• a specific embodiment relates to a pharmaceutical product comprising a composition as described herein and one or more pharmaceutically acceptable excipients.
• a specific embodiment relates to a pharmaceutical product comprising a composition as described herein which is in the form suitable for oral administration.
• a specific embodiment relates to a pharmaceutical product comprising a composition as described herein which is in the form suitable for intravenous administration.
• a specific embodiment relates to a use of a composition as described herein for the manufacture of a medicament for the treatment and/or prevention of Alzheimer's Disease.
• a specific embodiment relates to a use of a composition as described herein for the manufacture of a medicament for the treatment of Alzheimer's Disease.
• a specific embodiment relates to a use of a composition as described herein for the manufacture of a medicament for the prevention of Alzheimer's Disease.
• a specific embodiment relates to a composition as described herein for the use in the treatment and/or prevention of Alzheimer's Disease.
• a specific embodiment relates to a composition as described herein for the use in the control of Alzheimer's Disease.
• a specific embodiment relates to a composition as described herein for the use in the treatment of Alzheimer's Disease.
• a specific embodiment relates to a composition as described herein for the use in the prevention of Alzheimer's Disease.
• a specific embodiment of the invention relates to a method of treatment and/or prevention of Alzheimer's Disease by administering a composition as described herein.
• a specific embodiment of the invention relates to a kit comprising a preparation as described herein and instructions for the separate, simultaneous, fixed-dose or sequential in any order administration of the preparations to a patient in need thereof.
• BACEl inhibitor Cmpd 2 and ⁇ antibody (Cmpd 1) as mono -treatments was confirmed in the tgAPP mouse model of CNS amyloidosis. A significantly enhanced treatment effect of combination-therapy was demonstrated.
• the different read-outs which we employed to assess brain amyloidosis reveal remarkable differences in efficacy for each treatment modality, pointing to their different mechanisms of action which are inhibition of de novo production vs enhanced clearance.
• BACEl inhibition decreases total brain ⁇ 40 and ⁇ 42 to similar extends and with a clear dose-response as measured by specific immune-assays.
• the antibody by itself reduces ⁇ 42 but has little effect on ⁇ 40 in this specific mouse model. Since the ⁇ antibody recognizes an epitope in the N-terminus of ⁇ this differential effect does not reflect a preference for ⁇ 42 per se but is likely due its different conformation or aggregation state as compared to Ab40. the ⁇ antibody prefers ⁇ aggregates to monomers and it is thus conceivable that ⁇ 42'8 higher propensity for aggregate formation favors its binding to the ⁇ antibody and thus enhances its clearance.
• mice of an average age of 13.5 months were randomized to 7 groups of 15 animals each.
• mice CD4 antibody 0.5mg, i.v.
• the purpose was to deplete the CH4- positive T-cells and thus prevent the formation of an immune response against the human Cmpd 1 antibody.
• the efficacy and validity of this procedure has been shown previously in chronic mono-therapies with Cmpd 1 alone (Bohrmann et al 2012) 14 .
• Preparations of brain lysates Frozen left brain halves (cerebellum removed) were homogenized in four volumes of 9M Urea/ 50mM Tris (vol/wet weight) using a MagNa Lyzer (Roche Applied Science) for 20" at 4000rpm in Green Bead Tubes (Roche Applied Science). The homogenates were incubated on ice for 2 hours, and then centrifuged for 20 minutes at 20'000g at 4°C. The supernatants were diluted from 1 :200 to 1 : 100'000 in AlphaLlSA assay buffer depending on ⁇ content and assay sensitivity. ⁇ was determined by a AlphaLlSA assays.
• AlphaLlSA Brain extracts was diluted in AlphaLlSA Assay Buffer (25mM Hepes pH 7.4,
• fluorescence images were obtained from entire brain sections scanned with a Metafer4 slide scanner (MetaSystems, Altlussheim, Germany). Quantitative image analysis was done by a customized rule set developed in-house for automated detection of stained amyloid plaques after interactive selection of ROI in most affected brain regions using the Definiens XD 2.0 software package (Definiens Ltd., Munich, Germany). Calculations were made with common spreadsheet software (Microsoft Excel, Redmond, WA, USA). Statistical evaluation was done using a two -tailed Student's t-test and One-way ANOVA with Bonferroni's Multiple Comparison test (GraphPad Prism).
• the mean ⁇ 42 content thus exceeds that for ⁇ 40 by 8 fold, reflecting the increased ⁇ 42 production due to the V717I London mutation in the transgenic mice.
• the total amounts for the individual animals vary considerably; the extremes for ⁇ 42 are 31 and 47ng/mg brain. However, such variability of brain ⁇ is commonly seen in APP-transgenic mice.
• Fig.2 representative brain sections stained for human ⁇ are shown for an animal at study begin (a) and for a vehicle treated animal at study end (b). Typical dense plaques and diffuse plaques of various sizes are clearly shown and it is obvious that 13.5m old animals have already a significant amyloid load, thus confirming an established amyloidosis for this age group at study start. Quantitative data for amyloid plaque deposition are reported below.
• Cmpd 2 was applied in two doses, a medium dose of 30mg/kg and a high dose of 90mg/kg, once daily per os.
• Cmpd 1 was applied once weekly at 20mg/kg, iv via tail vein injection.
• This antibody has a much higher affinity for aggregated ⁇ over soluble, monomeric ⁇ (Bohrmann et al 2012) M . It is presumed that in this mouse model ⁇ 40 is largely in a non- aggregated state and thus less accessible for binding by antibody Cmpd 1.
• Fig.4 compares the brain ⁇ level in the mono -treatment arms (same as in Fig.3) to the two combination arms.
• Cmpd 1 treatment in addition to Cmpd 2 leads to a substantial enhancement of the amyloid activity.
• the amyloid reduction more than doubles for the lower dose arm, i.e. Cmpd 2 at 30mg/kg decreases ⁇ 42 by 28%, the addition of Cmpd 1 treatment causes a reduction of 66%.
• the difference is highly significant (p ⁇ 0.0001).
• the corresponding number are 58% for Cmpd 2 alone and 79% after addition of Cmpd 1, the combined effect is less, but still reaches statistical significance (p ⁇ 0.001).
• the less-than-additive combo effect at the higher dose is probably due to the very high dose of Cmpd 2, which already approaches maximal inhibition. Nevertheless, for ⁇ 42 there is a clear benefit for combination treatment.
• Plaque load and amyloid- ⁇ plaque numbers were measured by quantitative morphometry.
• the plaque load i.e., area covered by amyloid deposits, was significantly reduced by all treatment arms (Fig.6).
• the reduction by treatment with Cmpd 1 alone was much stronger than what observed previously for its effect on total brain ⁇ (Fig.3 and 4) and equaled or exceeded the reduction observed with Cmpd 2 alone. This is in accordance with the known preference for aggregated ⁇ as it is in plaques.
• Combination treatments essentially prevented any increase of amyloid load over the entire treatment period.
• the findings for plaque load are mirrored in an additional read-out for the treatment effects on plaque number (Fig.7). All treatments significantly reduced total plaque number compared to the vehicle group.
• Cmpd 1 as mono -treatment was highly efficacious in this read-out and for the cortex sections its effect alone was comparable to the reduction seen in the combination arms, i.e., the reduction was almost exclusively antibody-driven. In contrast, in cortex and subiculum the reduction in the combination arms exceeded the mono -treatments. In cortex the plaque number in the Cmpd 1 alone and in the combination arms are even lower than in the baseline group.
• Fig 1 ⁇ 40 and ⁇ 42 from brain extracts at 13.5m of age (start) and 17.5m (vehicle), expressed as ng per mg brain wet weight. Each point represents a single animal; the line shows the group median.
• Fig.2 Representative brain sections stained for ⁇ deposits showing amyloid plaque load in the hippocampal formation and dorsal cortical regions in an animal at study start (a) and in a vehicle-treated animal at study end (b).
• Fig.3 Treatment with Cmpd 2 (BI30; BI90) and Cmpd 1 (mAb). Shown are the group means and standard deviations. Bars with or 'ns' indicate significant or non-significant group differences.
• Cmpd 1 (mAb) alone or in combination with Cmpd 2 (BI30+mAb; BI90+mAb). Shown are the group means and standard deviations at end of treatment (17.5m). Bars with or 'ns' indicate significant or non-significant group differences.
• Fig.5 ⁇ 40 and 42 level at study start (13.5m) and study end (17.5m) in the groups receiving vehicle treatment, Cmpd 2 at 90mg/kg (BI90) or Cmpd 2 plus Cmpd 1 (BI90+mAb). Shown are the group means and standard deviations at end of treatment (17.5m). Bars with or 'ns' indicate significant or non-significant group differences.
• Fig 6 Effect on total immuno detected amyloid plaques after treatment with Cmpd 2 at two dose levels (30 and 90mg/kg) and Cmpd 1 (20 mg/kg) or in combination. Data are shown as immunostained area in indicated brain regions obtained from 5 brain sections per animal with boxes resembling 2 quantiles (50% of data), mean values (line), median (+) and whiskers spanning minimum and maximum values. Significance levels given: * p ⁇ 0.05, ** p ⁇ o0.01, *** pO.001
• Fig 7 Effect on total amyloid plaque numbers after treatment with Cmpd 2 at two dose levels (30 and 90mg/kg) and Cmpd 1 (20 mg/kg) or in combination. Data are shown as total detectable plaque numbers with boxes resembling 2 quantiles (50% of data), mean values (line), median (+) and whiskers spanning minimum and maximum values. Significance levels given: * p ⁇ 0.05, ** p ⁇ o0.01, *** pO.001
• Fig 8 Effect on amyloid plaque size distribution after treatment with Cmpd 2 at two dose levels (30 and 90mg/kg) and Cmpd 1 (20 mg/kg) or in combination. Plaque sizes are shown in colors at surface classes indicated.
• Fig 9 Representative brain sections stained for ⁇ deposits showing amyloid plaque deposition in the hippocampal formation and dorsal cortical regions in animals treated with Cmpd 2 at 30 mg/kg (a), Cmpd 2 at 90 mg/kg (b), Cmpd 1 at 20 mg/kg (c), Cmpd 2 (30 mg/kg) plus Cmpd 1 (d) and Cmpd 2 (90 mg/kg) plus Cmpd 1 (e).
• Gantenerumab a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. Journal of Alzheimer's disease : JAD 28: 49-69.

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