WO2017072090A1 - Polythérapie - Google Patents

Polythérapie Download PDF

Info

Publication number
WO2017072090A1
WO2017072090A1 PCT/EP2016/075607 EP2016075607W WO2017072090A1 WO 2017072090 A1 WO2017072090 A1 WO 2017072090A1 EP 2016075607 W EP2016075607 W EP 2016075607W WO 2017072090 A1 WO2017072090 A1 WO 2017072090A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
sap
seq
depleting compound
amyloid
Prior art date
Application number
PCT/EP2016/075607
Other languages
English (en)
Inventor
Duncan Brett RICHARDS
Original Assignee
Glaxosmithkline Intellectual Property Development Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Intellectual Property Development Limited filed Critical Glaxosmithkline Intellectual Property Development Limited
Publication of WO2017072090A1 publication Critical patent/WO2017072090A1/fr

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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification

Definitions

  • the present invention relates to the administration of anti-beta-amyloid ( ⁇ ) antibodies with Serum Amyloid P component (SAP) depleting compounds for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise or consist of oligomers or fibrils derived from ⁇ .
  • ⁇ anti-beta-amyloid
  • SAP Serum Amyloid P component
  • AD Alzheimer's disease
  • Citron M (2002) Nat. Neurosci 5, Suppl 1055-1057
  • the earliest stages of the disease are characterized by a progressive loss of memory with associated cognitive decline and language and behavioural deficits.
  • patients develop global amnesia and have greatly reduced motor function.
  • Death typically occurs 9 years following diagnosis and is often associated with other conditions, typically pneumonia (Davis K.L. and Samules S.C. (1998) in Pharmacological Management of Neurological and Psychiatric Disorders eds Enna SJ. and Coyle J.T. (McGraw-Hill, New York pp267-316)).
  • ⁇ -amyloid peptide is key to the progression of Alzheimer's disease (Selkoe, D. J. (2001) Physiological Reviews 81 : 741-766).
  • ⁇ is known to be produced through the cleavage of the beta amyloid precursor protein
  • BACE1 also known as ⁇ -secretase, Asp2 or Memapsin-2
  • AD Alzheimer's Disease
  • insoluble amyloid plaques are found early in AD and in Mild Cognitive Impairment (MCI)
  • MCI Mild Cognitive Impairment
  • ADDLs ⁇ - derived diffusible ligands
  • Amyloid deposits are composed predominantly of amyloid fibrils, but also contain heparin, dermatan proteoglycans, and amyloid P component, which is identical to and derived from the normal circulating plasma protein of the pentraxin family, serum amyloid P component (SAP) (Pepys 1994).
  • SAP serum amyloid P component
  • SAP Human SAP is a constitutive protein in the plasma, at a concentration of around 20-40 mg/l (Nelson et al. (1991) Clin. Chim. Acta, 200: 191-200). Animal experiments and in vitro studies suggest a role for circulating SAP in host defence (Noursadeghi et al. (2000) PNAS, 97: 14584- 14589)). SAP is also a normal tissue matrix constituent associated with elastic fibres and the glomerular basement membrane although its function there is not known.
  • SAP bound to amyloid fibrils is in equilibrium with SAP in the circulation and extracellular fluid. SAP undergoes avid (Kd ⁇ 1 ⁇ / ⁇ ), calcium-dependent, reversible binding to amyloid fibrils of all types, which makes both the fibrils and the SAP more resistant to proteolysis [Tennent 1995]. In this way SAP may contribute to the persistence of amyloid deposits in vivo.
  • human SAP binds to and enters cerebral neurones and causes neuronal apoptosis in vitro and in vivo (Urbanyi, Z., et al., (1994). Eur. J. Pharmacol., 270: 375-387, Duong, T., et al., (1998) Brain Res., 813: 303-312, Urbanyi, Z., et al., (2003) Brain Res., 988: 69-77, Urbanyi, Z., et al., (2007) Brain Res., 1145: 221-226, Pisalyaput, K. Et al.,(2008). J. Neurochem., 104: 696-707).
  • CPHPC carboxy pyrrolidine hexanoyl pyrrolidine carboxylate
  • Reducing the levels of ⁇ and SAP might reduce the load and formation of amyloid deposits and offer neuroprotection against the effects of SAP on synaptic transmission. It will be appreciated that therapy using two therapeutics with differing mechanisms of action may offer advantages over the use of a single therapeutic or multiple therapeutics all with the same mechanism of action.
  • amyloid deposits comprise or consist of oligomers or fibrils derived from ⁇ : Age-related macular degeneration (AMD), Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), Fragile X syndrome, Down's syndrome, Autism, Huntington's disease, Parkinson's disease, mild cognitive impairment, hereditary cerebral haemorrhage with ⁇ -amyloidosis of the Dutch type, cerebral ⁇ -amyloid angiopathy and various types of degenerative dementias, such as those associated with progressive supranuclear palsy and cortical basal degeneration.
  • ASD Age-related macular degeneration
  • AD Alzheimer's disease
  • CAA cerebral amyloid angiopathy
  • Fragile X syndrome Fragile X syndrome
  • Down's syndrome Autism
  • Huntington's disease Parkinson's disease
  • mild cognitive impairment hereditary cerebral haemorrhage with ⁇ -amyloidosis of the Dutch type
  • cerebral ⁇ -amyloid angiopathy and various
  • anti- ⁇ antibodies are disclosed with variable heavy chain and variable light chain regions comprising the following CDRs: CDRH1 (SEQ ID NO: l), CDRH2 (SEQ ID NO:2), CDRH3 (SEQ ID NO:3) within the heavy chain variable region and; CDRL1 (SEQ ID NO:4), CDRL2 (SEQ ID NO:5), CDRL3 (SEQ ID NO:6) within the light chain variable region.
  • WO2007/113172 is an antibody with a humanised heavy chain variable region variant H2 (SEQ ID No:28 therein, SEQ ID NO:7 herein) and a humanised light chain variable region variant LI (SEQ ID No:32 therein, SEQ ID NO:8 herein).
  • WO2007/113172 is an antibody with a mature heavy chain amino acid sequence (Fc double mutation, bold) (SEQ ID No:36 therein; SEQ ID NO:9 herein) and a mature light chain amino acid sequence (SEQ ID No:40 therein; SEQ ID NO: 10 herein).
  • anti- ⁇ antibodies include solanezumab, crenezumab, bapineuzumab, gantenerumab and aducanumab.
  • EP0915088 discloses D-proline derivative compounds that are competitive inhibitors of binding of SAP to amyloid fibrils, as well as methods for their manufacture.
  • a preferred compound disclosed in EP0915088 is (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyl] pyrrolidine-2-carboxylic acid (CPHPC) according to Formula (I):
  • PCT/EP2015/058998 discloses a compound (2R,2'R)-bis(((((tetrahydro-2H-pyran-4- yl)oxy)carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine-2-carboxylate) according to Formula (II):
  • Priority application GB1518950.9 discloses a compound (2R,2'R)-bis(((tetrahydro-2H-pyran 4-carbonyl)oxy)methyl) l,l'-adi to Formula (III):
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise or consist of oligomers or fibrils derived from ⁇ .
  • the present invention also provides methods of preventing and/or treating a subject susceptible to or afflicted with a disease associated with amyloid deposition, which method comprises the step of administering a prophylactically or therapeutically effective amount of an anti- ⁇ antibody and a SAP depleting compound to said subject.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise or consist of oligomers or fibrils derived from ⁇ .
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody has variable heavy and variable light chain regions comprising the following CDRs: CDRH1 (SEQ ID NO: l), CDRH2 (SEQ ID NO:2), CDRH3 (SEQ ID NO:3) within the heavy chain variable region and; CDRLl (SEQ ID NO:4), CDRL2 (SEQ ID NO:5), CDRL3 (SEQ ID NO:6) within the light chain variable region.
  • CDRH1 SEQ ID NO: l
  • CDRH2 SEQ ID NO:2
  • CDRH3 SEQ ID NO:3
  • CDRLl SEQ ID NO:4
  • CDRL2 SEQ ID NO:5
  • CDRL3 SEQ ID NO:6
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody has variable heavy and variable light chain regions comprising the following CDRs: CDRH1 (SEQ ID NO: l), CDRH2 (SEQ ID NO:2), CDRH3 (SEQ ID NO:3) within the heavy chain variable region and; CDRLl (SEQ ID NO:4), CDRL2 (SEQ ID NO:5), CDRL3 (SEQ ID NO:6) within the light chain variable region.
  • CDRH1 SEQ ID NO: l
  • CDRH2 SEQ ID NO:2
  • CDRH3 SEQ ID NO:3
  • CDRLl SEQ ID NO:4
  • CDRL2 SEQ ID NO:5
  • CDRL3 SEQ ID NO:6
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody comprises a variable heavy region comprising a polypeptide having an amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising a polypeptide having an amino acid sequence of SEQ ID NO:8.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody comprises a variable heavy region comprising a polypeptide having an amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising a polypeptide having an amino acid sequence of SEQ ID NO:8.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody has mature heavy and light chains having amino acid sequences of SEQ ID NO 9: and 10, respectively.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody has mature heavy and light chains having amino acid sequences of SEQ ID NO 9: and 10, respectively.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody is selected from solanezumab, crenezumab, bapineuzumab, gantenerumab and aducanumab.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody is selected from solanezumab, crenezumab, bapineuzumab, gantenerumab and aducanumab.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody comprises the CDRs or the variable regions from any one of solanezumab, crenezumab, bapineuzumab, gantenerumab and aducanumab.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody comprises the CDRs or the variable regions from any one of solanezumab, crenezumab, bapineuzumab, gantenerumab and aducanumab.
  • the anti- ⁇ antibody comprises all six CDRs from any one of solanezumab, crenezumab, bapineuzumab, gantenerumab and aducanumab.
  • the CDRs are defined by any one of the standard numbering conventions for CDR sequences, including “Kabat” (Sequences of Proteins of Immunological Interest, 5th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1991)), “Chothia” ((1989) Nature 342: 877-883), “AbM” (University of Bath) and “contact” (University College London) methods.
  • the CDRs are the Kabat CDRs.
  • the anti- ⁇ antibody comprises the heavy chain variable region and the light chain variable region from any one of solanezumab, crenezumab, bapineuzumab, gantenerumab and aducanumab.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody is a single domain antibody fused to an Fc region (a "dAb-Fc").
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody is a single domain antibody fused to an Fc region (a "dAb-Fc").
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody comprises a wild-type Fc region.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody comprises a wild-type Fc region.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody comprises an enhanced Fc region.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the anti- ⁇ antibody comprises an enhanced Fc region.
  • the enhanced Fc region enhances complement-dependant cytotoxic activity.
  • the enhanced Fc region enhances Fc-mediated phagocytosis.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the SAP-depleting compound is selected from (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyl] pyrrolidine- 2-carboxylic acid (CPHPC, Formula (I)) or a diester thereof, (2R,2'R)-bis(((((tetrahydro-2H-pyran-4- yl)oxy)carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine-2-carboxylate) (Formula(II)) and (2R,2'R)- bis(((tetrahydro-2H-pyran-4-carbonyl)oxy)methyl) 1, l'
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the SAP- depleting compound is selected from (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyi] pyrrolidine-2-carboxylic acid (CPHPC, Formula (I)) or a diester thereof, (2R,2'R)-bis((((tetrahydro- 2H-pyran-4-yl)oxy)carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine-2-carboxylate) (Formula(II)) and (2R,2'R)-bis(((tetrahydro-2H-pyran-4-carbonyl
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the SAP-depleting compound is (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyi] pyrrolidine-2-carboxylic acid (CPHPC, Formula (I)) or a diester thereof.
  • the SAP-depleting compound is (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyi] pyrrolidine-2-carboxylic acid (CPHPC, Formula (I)) or a diester thereof.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the SAP- depleting compound is (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyi] pyrrolidine-2- carboxylic acid (CPHPC, Formula (I)) or a diester thereof.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the SAP-depleting compound is (2R,2'R)-bis(((((tetrahydro-2H-pyran-4-yl)oxy)carbonyl)oxy)methyl) 1,1'- adipoylbis(pyrrolidine-2-carboxylate) (Formula (II)).
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the SAP- depleting compound is (2R,2'R)-bis(((((tetrahydro-2H-pyran-4-yl)oxy)carbonyl)oxy)methyl) 1,1'- adipoylbis(pyrrolidine-2-carboxylate) (Formula (II)).
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the SAP-depleting compound is (2R,2'R)-bis(((tetrahydro-2H-pyran-4-carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine- 2-carboxylate) (Formula (III)).
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the SAP- depleting compound is (2R,2'R)-bis(((tetrahydro-2H-pyran-4-carbonyl)oxy)methyl) 1,1'- adipoylbis(pyrrolidine-2-carboxylate) (Formula (III)).
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the disease associated with amyloid deposition is selected from Age-related macular degeneration (AMD),
  • AD Alzheimer's disease
  • CAA cerebral amyloid angiopathy
  • Fragile X syndrome Downs syndrome
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the disease associated with amyloid deposition is selected from Age-related macular degeneration (AMD),
  • AD Alzheimer's disease
  • CAA cerebral amyloid angiopathy
  • Fragile X syndrome Downs syndrome
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the disease associated with amyloid deposition is Alzheimer's Disease.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the disease associated with amyloid deposition is Alzheimer's Disease.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the disease associated with amyloid deposition is Age-related macular degeneration.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the disease associated with amyloid deposition is Age-related macular degeneration.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits comprise oligomers or fibrils derived from ⁇ , wherein the disease associated with amyloid deposition is cerebral amyloid angiopathy.
  • the present invention provides the use of an anti- ⁇ antibody and a SAP depleting compound for the treatment or prophylaxis of diseases associated with amyloid deposition where the amyloid deposits consist of oligomers or fibrils derived from ⁇ , wherein the disease associated with amyloid deposition is cerebral amyloid angiopathy.
  • the present invention also provides methods of preventing and/or treating a subject susceptible to or afflicted with a disease associated with amyloid deposition, which method comprises the step of administering a prophylactically or therapeutically effective amount of an anti- ⁇ antibody and a SAP depleting compound to said subject.
  • the present invention provides a method of preventing and/or treating a subject susceptible to or afflicted with a disease associated with amyloid deposition, which method comprises the step of administering a prophylactically or therapeutically effective amount of an anti- ⁇ antibody and a SAP depleting compound to said subject, wherein the anti- ⁇ antibody has variable heavy and variable light chain regions comprising the following CDRs: CDRHl (SEQ ID No: l), CDRH2 (SEQ ID NO:2), CDRH3 (SEQ ID NO:3) within the heavy chain variable region and; CDRL1 (SEQ ID NO:4), CDRL2 (SEQ ID No:5),CDRL3 (SEQ ID No:6) within the light chain variable region.
  • the present invention provides a method of preventing and/or treating a subject susceptible to or afflicted with a disease associated with amyloid deposition, which method comprises the step of administering a prophylactically or therapeutically effective amount of an anti- ⁇ antibody and a SAP depleting compound to said subject, wherein the anti- ⁇ antibody is selected from selected from solanezumab, crenezumab, bapineuzumab, gantenerumab and aducanumab.
  • the present invention provides a method of preventing and/or treating a subject susceptible to or afflicted with a disease associated with amyloid deposition, which method comprises the step of administering a prophylactically or therapeutically effective amount of an anti- ⁇ antibody and a SAP depleting compound to said subject, wherein the SAP-depleting compound is selected from a compound of Formula (I), (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyl] pyrrolidine-2-carboxylic acid (CPHPC) or a diester thereof, a compound of Formula (II), (2R,2'R)-bis(((((tetrahydro-2H-pyran-4-yl)oxy)carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine- 2-carboxylate) and a compound of Formula (III), compound (2R,2'R)-bis(
  • the present invention provides a method of preventing and/or treating a subject susceptible to or afflicted with a disease associated with amyloid deposition, which method comprises the step of administering a prophylactically or therapeutically effective amount of an anti- ⁇ antibody and a SAP depleting compound to said subject, wherein the SAP-depleting compound is a compound of Formula (I), (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyl] pyrrolidine- 2-carboxylic acid (CPHPC) or a diester thereof.
  • the SAP-depleting compound is a compound of Formula (I), (R)-l-[6-[(R)-2-Carboxy-pyrrolidin-l-yl]-6-oxo oxohexanoyl] pyrrolidine- 2-carboxylic acid (CPHPC) or a diester thereof.
  • the present invention provides a method of preventing and/or treating a subject susceptible to or afflicted with a disease associated with amyloid deposition, which method comprises the step of administering a prophylactically or therapeutically effective amount of an anti- ⁇ antibody and a SAP depleting compound to said subject, wherein the SAP-depleting compound is a compound of Formula (II), (2R,2'R)-bis(((((tetrahydro-2H-pyran-4-yl)oxy)carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine-2-carboxylate).
  • the SAP-depleting compound is a compound of Formula (II), (2R,2'R)-bis(((((tetrahydro-2H-pyran-4-yl)oxy)carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine-2-carboxylate).
  • the present invention provides a method of preventing and/or treating a subject susceptible to or afflicted with a disease associated with amyloid deposition, which method comprises the step of administering a prophylactically or therapeutically effective amount of an anti- ⁇ antibody and a SAP depleting compound to said subject, wherein the SAP-depleting compound is a compound of Formula (III), compound (2R,2'R)-bis(((tetrahydro-2H-pyran-4-carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine-2-carboxylate).
  • the SAP-depleting compound is a compound of Formula (III), compound (2R,2'R)-bis(((tetrahydro-2H-pyran-4-carbonyl)oxy)methyl) l,l'-adipoylbis(pyrrolidine-2-carboxylate).
  • antibody is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain and includes monoclonal, recombinant, polyclonal, chimeric, humanised, bispecific and heteroconjugate antibodies; a single variable domain, a domain antibody, a single variable domain fused to an Fc region (dAb-Fc), antigen binding fragments, immunologically effective fragments, single chain Fv, diabodies, TandabsTM, etc. (for a summary of alternative "antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126- 1136).
  • domain refers to a folded protein structure which retains its tertiary structure independent of the rest of the protein. Generally domains are responsible for discrete functional properties of proteins and in many cases may be added, removed or transferred to other proteins without loss of function of the remainder of the protein and/or of the domain.
  • single variable domain refers to a folded polypeptide domain comprising sequences characteristic of antibody variable domains. It therefore includes complete antibody variable domains such as VH, VHH and VL and modified antibody variable domains, for example, in which one or more loops have been replaced by sequences which are not characteristic of antibody variable domains, or antibody variable domains which have been truncated or comprise N- or C- terminal extensions, as well as folded fragments of variable domains which retain at least the binding activity and specificity of the full-length domain.
  • a single variable domain is capable of binding an antigen or epitope independently of a different variable region or domain.
  • a "domain antibody” or “dAb (TM) may be considered the same as a "single variable domain".
  • a single variable domain may be a human single variable domain, but also includes single variable domains from other species such as rodent nurse shark and Camelid VHH dAbsTM.
  • Camelid VHH are immunoglobulin single variable domain polypeptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain antibodies naturally devoid of light chains.
  • Such VHH domains may be humanised according to standard techniques available in the art, and such domains are considered to be "single variable domains".
  • VH includes camelid VHH domains.
  • a dAb-Fc describes an engineered immunoglobulin molecule comprising a single variable domain attached to one or more constant region domains and/or hinge.
  • a dAb-Fc comprises a single variable domain fused to an Fc region of an antibody.
  • Such constant region(s) or Fc region permits Fc receptor binding (e.g. to one or both of Fc receptors CD64 and CD32) and complement activation via the interaction with Clq, whilst at the same time providing the molecule with a longer half-life than a single variable heavy chain domain in isolation.
  • a dAb-Fc comprises the constant region domains CH2 and/or CH3.
  • the Fc region is the Fc region of an IgG molecule, such as an IgGl, IgG2, IgG3, iGG4 or IgG4PE; or an IgA antibody.
  • IgG molecules such as an IgGl, IgG2, IgG3, iGG4 or IgG4PE; or an IgA antibody.
  • the binding affinity of the anti- ⁇ antibody may be measured by BIAcoreTM, for example by antigen capture with ⁇ coupled onto a carboxymethydextran chip by primary amine coupling and antibody capture onto this surface.
  • the binding affinity can be measured by BIAcoreTM by binding of anti- ⁇ antibodies to human ⁇ immobilised on a CM5 chip.
  • CDRs are defined as the complementarity determining region amino acid sequences of an antibody. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.
  • the interaction between the Fc region of an antibody and various Fc receptors is believed to mediate phagocytosis and half-life/clearance of an antibody or antibody fragment.
  • ADCC Antibody dependant cell mediated cytotoxic activity
  • CDC Complement-dependant cytotoxic activity
  • ADCP antibody dependant cellular phagocytosis
  • FcR Fc receptors
  • FcR FcyRI
  • FcyRII CD32
  • FcyRIII CD16
  • Effector function can be measured in a number of ways including for example via binding of the FcyRIII to Natural Killer cells or via FcyRI to monocytes/macrophages to measure for ADCC effector function.
  • an antigen binding protein of the present invention can be assessed for ADCC effector function in a Natural Killer cell assay.
  • Practical approaches to evaluate ADCC and/or CDC function can be found in Kellner et al (Methods, 2014, 65(1): 105-13). Human IgGl constant regions containing specific mutations or altered glycosylation on residue Asn297 have also been described to enhance binding to Fc receptors. In some cases these mutations have also been shown to enhance ADCC and CDC, see for example, Kellner (2014).
  • such mutations are in one or more of positions selected from 239, 332 and 330 (IgGl), or the equivalent positions in other IgG isotypes.
  • suitable mutations are S239D and I332E and A330L.
  • the antibody of the invention herein described is mutated at positions 239 and 332, for example S239D and I332E or in a further embodiment it is mutated at three or more positions selected from 239 and 332 and 330, for example S239D and I332E and A330L (EU index numbering).
  • an antibody comprising a chimaeric heavy chain constant region, for example an antibody comprising a chimaeric heavy chain constant region with at least one CH2 domain from IgG3 such that the antibody has enhanced effector function, for example wherein it has enhanced ADCC or enhanced CDC, or enhanced ADCC and CDC functions.
  • the antibody may comprise one CH2 domain from IgG3 or both CH2 domains may be from IgG3.
  • Purified preparations of an antibody as described herein may be incorporated into pharmaceutical compositions for use in the treatment of the human diseases, disorders and conditions described herein.
  • the terms diseases, disorders and conditions are used interchangeably.
  • the pharmaceutical composition can be used in the treatment of any diseases where amyloid deposits are present in the tissues and contribute to structural and functional damage leading to clinical illness.
  • the pharmaceutical preparation may comprise an antibody in combination with a pharmaceutically acceptable carrier.
  • the antibody may be administered alone, or as part of a pharmaceutical composition.
  • compositions comprise a pharmaceutically acceptable carrier as known and called for by acceptable pharmaceutical practice, see e.g. Remingtons Pharmaceutical Sciences, 16th edition (1980) Mack Publishing Co.
  • pharmaceutically acceptable carriers include sterilised carriers such as saline, Ringers solution or dextrose solution, optionally buffered with suitable buffers to a pH within a range of 5 to 8.
  • compositions may be administered by injection or continuous infusion (e.g. intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular or intraportal). Such compositions are suitably free of visible particulate matter. Pharmaceutical compositions may also be administered orally, specifically those containing orally available CPHPC. Pharmaceutical compositions may comprise between lmg to lOg of antibody, for example between 5 mg and 1 g of antibody. Alternatively, the composition may comprise between 5 mg and 500 mg, for example between 5 mg and 50 mg.
  • compositions may comprise between 1 mg to 10 g of antibody in unit dosage form, optionally together with instructions for use. Pharmaceutical compositions may be lyophilised (freeze dried) for reconstitution prior to administration according to methods well known or apparent to those skilled in the art. Where antibodies have an IgGl isotype, a chelator of copper, such as citrate (e.g. sodium citrate) or EDTA or histidine, may be added to the pharmaceutical composition to reduce the degree of copper-mediated degradation of antibodies of this isotype, see EP0612251.
  • Pharmaceutical compositions may also comprise a solubiliser such as arginine base, a detergent/anti-aggregation agent such as polysorbate 80, and an inert gas such as nitrogen to replace vial headspace oxygen.
  • Effective doses and treatment regimes for administering the antibody are generally determined empirically and may be dependent on factors such as the age, weight and health status of the patient and disease or disorder to be treated. Such factors are within the purview of the attending physician. Guidance in selecting appropriate doses may be found in e.g. Smith et al (1977) Antibodies in human diagnosis and therapy, Raven Press, New York.
  • the dosage of antibody administered to a subject is generally between 1 ⁇ g/kg to 150 mg/kg, between 0.1 mg/kg and 100 mg/kg, between 0.5 mg/kg and 50 mg/kg, between 1 and 25 mg/kg or between 1 and 10 mg/kg of the subject's body weight.
  • the dose may be 10 mg/kg, 30 mg/kg, or 60 mg/kg.
  • the antibody may be administered parenterally, for example subcutaneously, intravenously or intramuscularly.
  • the effective daily dose of a therapeutic composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the antibody may be administered in a single large dose or in smaller repeated doses.
  • the administration of a dose may be by slow continuous infusion over a period of from 2 to 24 hours, such as from 2 to 12 hours, or from 2 to 6 hours. This may result in reduced toxic side effects.
  • the administration of a dose may be repeated one or more times as necessary, for example, three times daily, once every day, once every 2 days, once a week, once a fortnight, once a month, once every 3 months, once every 6 months, or once every 12 months.
  • the antibodies may be administered by maintenance therapy, for example once a week for a period of 6 months or more.
  • the antibodies may be administered by intermittent therapy, for example for a period of 3 to 6 months and then no dose for 3 to 6 months, followed by administration of antibodies again for 3 to 6 months, and so on in a cycle.
  • the dose may be administered subcutaneously, once every 14 or 28 days in the form of multiple sub-doses on each day of administration.
  • the antibody may be administered to the subject in such a way as to target therapy to a particular site.
  • the antibody may be injected locally into a circumscribed local amyloid mass in the tissues, or infused into the blood supply to an amyloidotic organ.
  • the anti- ⁇ antibody and SAP depleting compound may be co-administered or sequentially administered.
  • Sequential administration may involve two or more sequential treatments with SAP depleting compound followed by two or more sequential treatments with the anti- ⁇ antibody, or vice versa.
  • the sequential/subsequent dose may be an amount that is more than the initial/previous dose or less than the initial/previous dose.
  • the SAP-depleting compound of Formula (I) may be parenterally administered at a dose of between 0.1 mg/kg and 2 mg/kg, depending on its activity.
  • the SAP-depleting compound may be administered as a fixed dose, independent of a dose per subject weight ratio.
  • the SAP- depleting compound may be administered in one or more separate, simultaneous or sequential parenteral doses of 100 mg or less, of 50 mg or less, 25 mg or less, or 10 mg or less.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • tabletting lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Oral liquid preparations may be in the form of, for example, oily suspension, non-aqueous solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with suitable aqueous or non-aqueous vehicle immediately prior to administration.
  • Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), nonaqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g.
  • the dosage form for compounds of Formula (II) and Formula (III) is a tablet or a capsule.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of a compound of Formula (II) or Formula (III), depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 5000 mg, 1.0 to 1000 mg, or 100 to 600 mg, for example 100, 200 or 300 mg, and such unit doses may be administered more than once a day, for example two or three times a day.
  • Such therapy may extend for a number of days, weeks, months or years.
  • the administration may use a pre-determined or routine schedule for administration, thereby resulting in a predetermined designated period of time between dose administrations.
  • the schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined. Any particular combination would be covered by the schedule as long as it is determined ahead of time that the appropriate schedule involves administration on a certain day.
  • the pharmaceutical composition may comprise a kit of parts of the antibody together with other medicaments, optionally with instructions for use.
  • the kit may comprise the reagents in predetermined amounts with instructions for use.
  • the terms "individual”, “subject” and “patient” are used herein interchangeably.
  • the subject may be a primate (e.g. a marmoset or monkey).
  • the subject is typically a human.
  • Treatment can be therapeutic, prophylactic or preventative.
  • the subject will be one who is in need thereof.
  • Those in need of treatment may include individuals already suffering from a particular medical disease in addition to those who may develop the disease in the future.
  • a SAP depleting compound with the anti- ⁇ antibody described herein can be used for prophylactic or preventative treatment.
  • the sequential treatments described herein are administered to an individual in order to prevent or delay the onset of one or more aspects or symptoms of the disease.
  • the subject can be asymptomatic or may have a genetic predisposition to the disease, as amyloid deposits are known to be present in the tissues and to accumulate for periods of time before they cause sufficient damage to produce clinical symptoms.
  • Such sub-clinical amyloid deposition can be detected by histological examination of tissue biopsies or by non-invasive imaging procedures, including radiolabeled ⁇ scintigraphy, echocardiography and magnetic resonance imaging.
  • a prophylactically effective amount of the anti- ⁇ antibody and SAP depleting compound is administered to such an individual.
  • a prophylactically effective amount is an amount which prevents or delays the onset of one or more aspects or symptoms of a disease described herein.
  • the antibodies and SAP depleting compounds described herein are to be used in methods of therapy.
  • therapy encompasses alleviation, reduction, or prevention of at least one aspect or symptom of a disease. For example, to ameliorate or reduce one or more aspects or symptoms of a disease described herein.
  • an anti- ⁇ antibody and a SAP depleting compound need not affect a complete cure, or eradicate every symptom or manifestation of the disease to constitute a viable therapeutic treatment.
  • drugs employed as therapeutic agents may reduce the severity of a given disease state, but need not abolish every manifestation of the disease to be regarded as useful therapeutic agents.
  • a prophylactically administered treatment need not be completely effective in preventing the onset of a disease in order to constitute a viable prophylactic agent.
  • amyloid refers to extracellular deposits in the tissues of insoluble protein fibres composed of fibrils with characteristic ultrastructural morphology, a cross- ⁇ sheet core structure and the pathognomonic histochemical tinctorial property of binding Congo red dye from alkaline alcoholic solution and then giving red-green dichroism when viewed microscopically in strong cross polarised light. About 25 different unrelated proteins are known to form amyloid fibrils which deposit in human tissues and share all these typical properties. Amyloid deposits in the brain substance, cerebral amyloid, differ somewhat from amyloid deposits elsewhere in the body in that they are always focal and microscopic in size, and are commonly referred to as amyloid plaques.
  • Example 2 taken from PCT/ EP2015/ 058998
  • HPLC was conducted on a Waters X-Terra MS C18 column (3.5 ⁇ 30 x 4.6 mm id) eluting with 0.01M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B), using the following elution gradient 0-0.5 minutes 5% B, 0.5-3.75 minutes 5% to 100% B, 3.75-4.5 100% B, 4.5-5 100% to 5% B, 5-5.5 5% B at a flow rate of 1.3 ml/minute at 40°C.
  • MS mass spectra
  • the solution B was added to the solution A.
  • the reaction mixture was stirred at 80°C for 18 h.
  • the reaction mixture was filtered and concentrated under reduced pressure. The residue was taken up in EtOAc (400 mL) and washed with an aq. solution of NaHCC>3 (2 x 100 mL), an aq. solution of sodium thiosulfate (50 mL) and with 0.5N HCI (100 mL). The organic layer was dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo. The yellow oil was solubilized in 2- MeTHF(100 mL) and sonicated until crystallization occurred. The mixture was left to stand for 1 h at RT.
  • XRPD data were acquired on a PANalytical X'Pert Pro powder diffractometer, model PW3040/60 using an X'Celerator detector.
  • the acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 45 mA, start angle: 2.0° 2 ⁇ , end angle: 40.0° 2 ⁇ , step size: 0.0167° 2 ⁇ , time per step: 31.75 seconds.
  • the sample was prepared by mounting a few milligrams of sample (compound of Formula (II)) on a silicon wafer (zero background plate), resulting in a thin layer of powder.
  • Characteristic XRPD angles and d-spacings for the compound of Formula (II) are recorded in Table 1.
  • the margin of error is approximately ⁇ 0.1° 2 ⁇ for each of the peak assignments. Peak intensities may vary from sample to sample due to preferred orientation.
  • HPLC was conducted on a Waters X-Terra MS C18 column (3.5 ⁇ 30 x 4.6 mm id) eluting with 0.01M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B), using the following elution gradient 0-0.5 minutes 5% B, 0.5-3.75 minutes 5% to 100% B, 3.75-4.5 100% B, 4.5-5 100% to 5% B, 5-5.5 5% B at a flow rate of 1.3 mL/minute at 40 °C.
  • MS mass spectra
  • Tetrabutylammonium iodide (6.51 g, 17.63 mmol) was added to a solution of chloromethyl tetrahydro-2H-pyran-4-carboxylate (36.2 g, 203 mmol) dissolved in 1,4- dioxane (100 mL). After 10 min stirring at RT, the precipitate was filtered and the orange filtrate was added drop wise over 30 min in the reaction mixture prepared above. After 8 h at 80 °C, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in EtOAc (300 mL) and washed with NaHCC>3 aq. solution (1 x 100 mL), sodium sulfite aq.
  • the mixture was filtered, washed successively with iPr 2 0 (1 x 150 mL) and pentane (2 x 100 mL).
  • the product was dried at 35 °C and 5 mbars for 5 h to afford the product as a white powder (82.5 g, 80 %).
  • XRPD data were acquired on a PANalytical X'Pert Pro powder diffractometer, model PW3040/60 using an X'Celerator detector.
  • the acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 45 mA, start angle: 2.0° 2 ⁇ , end angle: 40.0° 2 ⁇ , step size: 0.0167° 2 ⁇ , time per step: 31.75 seconds.
  • the sample was prepared by mounting a few milligrams of sample (compound of Formula (III)) on a silicon wafer (zero background plate), resulting in a thin layer of powder.
  • Characteristic XRPD angles and d-spacings for Form I of the compound of Formula (III) are recorded in Table 2.
  • the margin of error is approximately ⁇ 0.1° 2 ⁇ for each of the peak assignments. Peak intensities may vary from sample to sample due to preferred orientation.
  • Humanised V regions were synthesised de novo by build up of overlapping oligos and PCR amplification. Restriction sites for cloning into mammalian expression vectors RLD-bshe and RLN- bshe and human immunoglobulin signal sequences derived from the chosen human acceptor frameworks were included.
  • the DNAs encoding the humanised V regions (HI (SEQ ID NO:27 therein), H2 (SEQ ID NO:29 therein), H3 (SEQ ID NO:31 therein), LI (SEQ ID NO:33 therein)) together with signal sequences and restriction sites were then cloned in frame into mammalian expression vectors: HI, H2 and H3 into RLD-bshe to generate DNA encoding three full length human IgGl Fc mutated heavy chains each containing mutations L235A and G237A, full length HI (SEQ ID NO:35 therein), full length H2 (SEQ ID NO:37 therein) and full length H3 (SEQ ID NO:39 therein); LI was cloned in frame into RLN-bshe containing the DNA encoding human kappa constant region to generate DNA encoding a full length human kappa light chain (SEQ ID NO:41 therein).
  • CHOK1 cells were transiently transfected at small scale with all combinations of humanised light and heavy chain DNA constructs: Ll+Hl, L1+H2, L1+H3 (SEQ ID NOs: 35 + 41, 37 + 41, 39 + 41 therein) in 6-well plates.
  • CHOK1 cells passaged in DMEM F12, with 5% ultra low IgG foetal bovine serum and 2mM glutamine were grown to confluency in 6-well plates.
  • the confluent cells were transfected with a total of 7.5 ⁇ g DNA: 30 ⁇ g Transfast lipid (Promega) in Optimem Glutamax medium (Invitrogen). Transfected cells were incubated at 37°C with 5% C02. At 72 hours supernatants were harvested and assayed for antibody concentration and then tested for binding to human ⁇ by ELISA.
  • Humanized LI combined with the three humanized heavy chains all expressed complete antibody that bound to human ⁇ .
  • Humanized antibodies were also expressed in large scale transient CHOK1 cell transfections using liposomal delivery of DNA (eg TransFast (Promega)) and expression in culture bottles.
  • DNA eg TransFast (Promega)
  • a heavy to light chain expression vector DNA ratio of 1:6 was used for optimization of expression levels in transient transfections a heavy to light chain expression vector DNA ratio of 1:6 was used. Material from transient transfection was purified using ProSepA columns or FPLC with ProSepA HiTrap columns.
  • DIVMTOSPLSLPVTPG EPASISCRVSOSLLHSNGYTYLHWYLOKPGOSPOLLIYKVSNRFSGVPDRFSGSGSGTD FTLKISRVEAEDVGVYYCSOTRHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEOLKSGTASWCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Mycology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne l'utilisation d'anticorps anti-Aβ et d'un composant amyloïde P sérique (SAP) d'appauvrissement de composés dans le traitement de maladies associées au dépôt amyloïde, telles que la maladie d'Alzheimer.
PCT/EP2016/075607 2015-10-27 2016-10-25 Polythérapie WO2017072090A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562246736P 2015-10-27 2015-10-27
US62/246,736 2015-10-27

Publications (1)

Publication Number Publication Date
WO2017072090A1 true WO2017072090A1 (fr) 2017-05-04

Family

ID=57223663

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/075607 WO2017072090A1 (fr) 2015-10-27 2016-10-25 Polythérapie

Country Status (1)

Country Link
WO (1) WO2017072090A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021071830A1 (fr) * 2019-10-07 2021-04-15 University Of Virginia Patent Foundation Modulation de vaisseaux lymphatiques dans une maladie neurologique
CN113508133A (zh) * 2019-02-01 2021-10-15 长春金赛药业有限责任公司 人源化抗Aβ单克隆抗体及其应用
CN113508131A (zh) * 2019-02-01 2021-10-15 长春金赛药业有限责任公司 人源化抗Aβ单克隆抗体及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0915088A1 (fr) * 1997-10-31 1999-05-12 F. Hoffmann-La Roche Ag Dérivés de D-Proline
WO2003051836A1 (fr) * 2001-12-14 2003-06-26 F. Hoffmann-La Roche Ag Promedicaments de d-prolines
WO2007113172A2 (fr) * 2006-03-30 2007-10-11 Glaxo Group Limited Anticorps
WO2009000926A1 (fr) * 2007-06-27 2008-12-31 Pentraxin Therapeutics Limited Combinaisons d'agents d'appauvrissement et d'anticorps anti-sap
US20120225055A1 (en) * 2011-03-01 2012-09-06 Bhinder Tejinder Kaur Antigen binding proteins

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0915088A1 (fr) * 1997-10-31 1999-05-12 F. Hoffmann-La Roche Ag Dérivés de D-Proline
WO2003051836A1 (fr) * 2001-12-14 2003-06-26 F. Hoffmann-La Roche Ag Promedicaments de d-prolines
WO2007113172A2 (fr) * 2006-03-30 2007-10-11 Glaxo Group Limited Anticorps
WO2009000926A1 (fr) * 2007-06-27 2008-12-31 Pentraxin Therapeutics Limited Combinaisons d'agents d'appauvrissement et d'anticorps anti-sap
US20120225055A1 (en) * 2011-03-01 2012-09-06 Bhinder Tejinder Kaur Antigen binding proteins

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BERND BOHRMANN ET AL: "Gantenerumab: A Novel Human Anti-ABeta Antibody Demonstrates Sustained Cerebral Amyloid-beta Binding and Elicits Cell-Mediated Removal of Amyloid-beta", JOURNAL OF ALZHEIMER'S DISEASE, vol. 28, no. 1, 1 January 2012 (2012-01-01), pages 49 - 69, XP055067543, DOI: 10.3233/JAD-2011-110977 *
CECILIA OSERA ET AL: "Pentraxins and Alzheimer's disease: At the interface between biomarkers and pharmacological targets", AGEING RESEARCH REVIEWS, ELSEVIER, AMSTERDAM, NL, vol. 11, no. 2, 6 December 2011 (2011-12-06), pages 189 - 198, XP028467044, ISSN: 1568-1637, [retrieved on 20111215], DOI: 10.1016/J.ARR.2011.12.004 *
HIDEAKI HAMAZAKI: "AMYLOID P COMPONENT PROMOTES AGGREGATION OF ALZHEIMER'S BETA-AMYLOID PEPTIDE", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 211, no. 2, 15 June 1995 (1995-06-15), pages 349 - 353, XP055335320 *
LIKO ET AL: "Evidence for an extended interacting surface between @b-amyloid and serum amyloid P component", NEUROSCIENCE LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 412, no. 1, 6 January 2007 (2007-01-06), pages 51 - 55, XP005824340, ISSN: 0304-3940, DOI: 10.1016/J.NEULET.2006.10.052 *
NIELS D PRINS ET AL: "Treating Alzheimer?s disease with monoclonal antibodies: current status and outlook for the future", ALZHEIMERS RES, BIOMED CENTRAL LTD, LONDON, UK, vol. 5, no. 6, 11 November 2013 (2013-11-11), pages 56, XP021193607, ISSN: 1758-9193, DOI: 10.1186/ALZRT220 *
SIMON E KOLSTOE ET AL: "Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, US, vol. 106, no. 18, 5 May 2009 (2009-05-05), pages 7619 - 7623, XP007918428, ISSN: 0027-8424, [retrieved on 20090416], DOI: 10.1073/PNAS.0902640106 *
ZOLTÁN URBÁNYI ET AL: "Serum amyloid P component induces neuronal apoptosis and [beta]-amyloid immunoreactivity", BRAIN RESEARCH, vol. 988, no. 1-2, 1 October 2003 (2003-10-01), AMSTERDAM, NL, pages 69 - 77, XP055334877, ISSN: 0006-8993, DOI: 10.1016/S0006-8993(03)03345-6 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113508133A (zh) * 2019-02-01 2021-10-15 长春金赛药业有限责任公司 人源化抗Aβ单克隆抗体及其应用
CN113508131A (zh) * 2019-02-01 2021-10-15 长春金赛药业有限责任公司 人源化抗Aβ单克隆抗体及其应用
WO2021071830A1 (fr) * 2019-10-07 2021-04-15 University Of Virginia Patent Foundation Modulation de vaisseaux lymphatiques dans une maladie neurologique

Similar Documents

Publication Publication Date Title
TWI771389B (zh) 抗phf-tau抗體及其用途
JP6779876B2 (ja) 抗トランスフェリン受容体抗体及びその使用方法
CN105358578B (zh) 运铁蛋白受体的抗体及其使用方法
KR102202925B1 (ko) 항-알파-시누클레인 항체 및 사용 방법
CA3098453A1 (fr) Anticorps anti-msr1 et leurs procedes d'utilisation
JP7170316B2 (ja) タウ免疫療法
EP3221361A1 (fr) Anticorps multispécifiques anti-récepteur de la transferrine/anti-bace1 et leurs procédés d'utilisation
CA2975376A1 (fr) Anticorps anti-alk2
WO2007064911A1 (fr) Anticorps anti-souris cd20 et leurs utilisations
CN116096413A (zh) 抗人vista抗体及其用途
WO2017072090A1 (fr) Polythérapie
CA3123607A1 (fr) Analogues de rifamycine et conjugues anticorps-medicament de ceux-ci
WO2014055967A2 (fr) Compositions et méthodes de traitement de maladies d'agrégation protéique impliquant le dépôt d'ic3b
CA3150726A1 (fr) Anticorps anti-alpha-synucleine et leurs procedes d'utilisation
US20230322908A1 (en) Humanized Anti-TDP-43 Binding Molecules and Uses Thereof
EP3814378A1 (fr) Immunoconjugués ciblant l'adam9 et méthodes d'utilisation associés
IL281442B1 (en) CD200R agonist antibodies and their use
CA3166155A1 (fr) Anticorps pilra et methodes d'utilisation associees
WO2023028525A2 (fr) Anticorps pilra et méthodes d'utilisation de ceux-ci
WO2024026471A1 (fr) Domaines de liaison à l'antigène cd98hc et leurs utilisations
CN117015381A (zh) 新颖类固醇有效负载、类固醇接头、含有其的adc及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16790305

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16790305

Country of ref document: EP

Kind code of ref document: A1