Pharmaceutical compositions comprising Anti-beta amyloid antibodies

Abstract

To provide pharmaceutical compositions comprising anti-beta amyloid antibodies.SOLUTION: The disclosure provides pharmaceutical compositions comprising an anti-beta amyloid (Aβ) antibody or Aβ-binding fragment thereof. These pharmaceutical compositions find use in the treatment of abnormal accumulation or deposition of Aβ in the central nervous system, mild cognition impairment, and Aβ-related disorders such as Alzheimer's disease. In some embodiments, the anti- Aβ antibody or Aβ-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and immunoglobulin light chain variable domain (VL) where the VH and VL comprise BIIB037 CDRs.SELECTED DRAWING: Figure 7

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 548,583, filed August 22, 2017, the entire contents of which are incorporated herein by reference.

[0002] Field The present application generally relates to pharmaceutical compositions containing anti-beta amyloid (Aβ) antibodies and uses thereof. [Background technology]

[0003] Aβ is a peptide produced by the metabolism of amyloid precursor protein (APP). Several Aβ peptide alloforms exist (e.g., Aβ40 and Aβ42). These monomeric peptides have a variable tendency to aggregate into higher-order dimers and oligomers. Soluble oligomers can transition to insoluble deposits with a β-pleated sheet structure through a process of fibril formation. These deposits, also called amyloid plaques, consist primarily of fibrillar amyloid (Hampel et al., Exp Neurol., 223(2):334-46 (2010); Gregory and Halliday, Neurotox Res., 7(1-2):29-41 (2005)). Both soluble and fibrillar forms of Aβ appear to contribute to the disease process in disorders characterized by Aβ deposition, such as Alzheimer's disease (AD) (Meyer-Luehmann, J Neurosci., 29(40):12636-40 (2009); Hock, Dialogues Clin Neurosci., 5(1):27-33 (2003); Selkoe, Cold Spring Harbor Perspective Biol.,3(7).pii:a004457(2011)).

[0004] AD patients with high serum titers of anti-Aβ antibodies that recognize amyloid plaques experience a slower rate of cognitive decline and disability than patients without anti-Aβ antibodies. Furthermore, patients who develop high titers of anti-Aβ antibodies exhibit reduced brain Aβ plaque counts and improved cognitive performance as assessed after long-term follow-up. These clinical data suggest that AD patients treated with anti-Aβ antibodies within the framework of passive immunotherapy may exhibit reduced cognitive impairment, lower brain Aβ deposit density, and a slowdown in cognitive decline. The anti-Aβ antibody BIIB037 is a fully human antibody containing a glycosylated human IgG1 heavy chain and a human kappa light chain. Recombinantly expressed BIIB037 binds with high apparent affinity to high-molecular-weight aggregates, presumably fibrils, of human Aβ. Immunohistochemistry shows that BIIB037 binds with high affinity to Aβ plaques in human AD brains and in brain tissue from transgenic mice expressing human APP. The affinity and specificity of BIIB037 for high-molecular-weight aggregates of human Aβ were confirmed by immunoprecipitation, immunoblotting, and immunohistochemistry. In Tg2576 AD transgenic mice, BIIB037 treatment results in measurable drug levels in the brain as assessed by ELISA. After BIIB037 administration in Tg2576 mice, BIIB037 immunoreactivity was observed in association with amyloid deposits in the brain parenchyma and blood vessels, suggesting that BIIB037 enters the brain parenchyma and binds to its target. Systemically administered anti-Aβ antibodies, such as BIIB037, are thought to enter the brain, bind to Aβ deposits, and induce their clearance from the brain via an Fc receptor-dependent mechanism. It is hypothesized that antibody-mediated removal of Aβ from the brain reduces Aβ burden, thereby preventing neuronal dysfunction, slowing disease progression, and reducing the rate of cognitive decline in AD. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Hampel et al.,Exp Neurol.,223(2):334-46(2010) [Non-patent document 2] Gregory and Halliday, Neurotox Res., 7(1-2):29-41(2005) [Non-patent document 3] Meyer-Luehmann, J Neurosci.,29(40):12636-40(2009) [Non-patent document 4] Hock, Dialogues Clin Neurosci.,5(1):27-33(2003) [Non-Patent Document 5] Selkoe,Cold Spring Harb Perspect Biol.,3(7).pii:a004457(2011) Summary of the Invention [Means for solving the problem]

[0006] The present disclosure relates, in part, to pharmaceutical compositions containing anti-Aβ antibodies or Aβ-binding fragments thereof and their use in treating abnormal accumulation or deposition of Aβ in the central nervous system, mild cognitive impairment, and Aβ-related disorders, such as Alzheimer's disease.

[0007] In one aspect, the disclosure features a pharmaceutical composition including an anti-Aβ antibody or Aβ-binding fragment thereof and arginine hydrochloride (Arg.HCl).

[0008] In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL comprise the CDRs of BIIB037. In some cases, the six CDRs of BIIB037 comprise or consist of the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

[0009] In some embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50 to 250 mg / ml. In other embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 75 to 165 mg / ml. In certain embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml. In certain embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml.

[0010] In some embodiments, the composition comprises Arg.HCl at a concentration of 50-250 mM. In other embodiments, the composition comprises Arg.HCl at a concentration of 75-175 mM. In certain embodiments, the composition comprises Arg.HCl at a concentration of 150 mM.

[0011] In some embodiments, the composition further comprises polysorbate 80 (PS80). In some embodiments, the composition comprises PS80 at a concentration of 0.01-0.1%. In other embodiments, the composition comprises PS80 at a concentration of 0.03-0.08%. In certain embodiments, the composition comprises PS80 at a concentration of 0.05%.

[0012] In some embodiments, the composition further comprises a buffering agent selected from the group consisting of histidine, acetate, succinate, and citrate. Optionally, the buffering agent is histidine. Optionally, the buffering agent is acetate. Optionally, the buffering agent is succinate. Optionally, the buffering agent is citrate. In certain embodiments, the composition comprises histidine, acetate, succinate, or citrate at a concentration of 10-30 mM. In certain embodiments, the composition comprises histidine, acetate, succinate, or citrate at a concentration of 20 mM. In certain embodiments, the composition comprises histidine at a concentration of 10-30 mM. In certain embodiments, the composition comprises histidine at a concentration of 20 mM.

[0013] In some embodiments, the composition further comprises methionine. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 150 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 125 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 100 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 75 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 50 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 20 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 15 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 50 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 75 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 100 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 125 mM. In other embodiments, the composition comprises methionine at a concentration of 5-150 mM. In certain embodiments, the composition comprises methionine at a concentration of 10 mM. In certain embodiments, the composition comprises methionine at a concentration of 50 mM. In certain embodiments, the composition comprises methionine at a concentration of 75 mM. In certain embodiments, the composition comprises methionine at a concentration of 100 mM. In certain embodiments, the composition comprises methionine at a concentration of 125 mM. In certain embodiments, the composition comprises methionine at a concentration of 150 mM.

[0014] In some embodiments, the composition further comprises sucrose. In some embodiments, the composition comprises sucrose at a concentration of 0.01-5%. In other embodiments, the composition comprises sucrose at a concentration of 1-4%. In certain embodiments, the composition comprises sucrose at a concentration of 3%.

[0015] In some embodiments, the pH of the composition is 5.2 to 6.2. In certain embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5.

[0016] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50-250 mg / ml, Arg.HCl at a concentration of 50-200 mM, methionine at a concentration of 0-20 mM, histidine at a concentration of 10-30 mM, PS80 at a concentration of 0.01-0.1%, and sucrose at a concentration of 0-3%. In some cases, the pH of the composition is 5.2-6.2. In some cases, the pH of the composition is 5.2-6.0. In certain embodiments, the pH of the composition is 5.3-5.7. In other embodiments, the pH of the composition is 5.5.

[0017] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml, Arg.HCl at a concentration of 150 mM, methionine at a concentration of 10 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some cases, the pH of the composition is 5.2 to 6.2. In some cases, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5.

[0018] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml, Arg.HCl at a concentration of 150 mM, methionine at a concentration of 10 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some cases, the pH of the composition is 5.2 to 6.2. In some cases, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5.

[0019] In some embodiments, the VH comprises or consists of a sequence that is at least 80% identical to SEQ ID NO: 7, and the VL comprises or consists of a sequence that is at least 80% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of a sequence that is at least 90% identical to SEQ ID NO: 7, and the VL comprises or consists of a sequence that is at least 90% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of the sequence of SEQ ID NO: 7, and the VL comprises or consists of the sequence of SEQ ID NO: 8.

[0020] In some embodiments, the anti-Aβ antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain. In some cases, the heavy chain comprises or consists of a sequence at least 80% identical to SEQ ID NO:9, and the light chain comprises or consists of a sequence at least 80% identical to SEQ ID NO:10. In other examples, the heavy chain comprises or consists of a sequence at least 90% identical to SEQ ID NO:9, and the light chain comprises or consists of a sequence at least 90% identical to SEQ ID NO:10. In yet other examples, the heavy chain comprises or consists of the sequence of SEQ ID NO:9, and the light chain comprises or consists of the sequence of SEQ ID NO:10.

[0021] In another aspect, the disclosure features a method of treating abnormal accumulation or deposition of Aβ in the central nervous system in a human subject in need thereof, the method including administering to the human subject a pharmaceutical composition described herein.

[0022] In another aspect, the disclosure features a method of treating mild cognitive impairment in a human subject in need thereof, the method including administering to the human subject a pharmaceutical composition described herein.

[0023] In another aspect, the disclosure features a method of treating Alzheimer's disease in a human subject in need thereof, the method including administering to the human subject a pharmaceutical composition described herein.

[0024] In some embodiments of these aspects, the pharmaceutical composition is administered subcutaneously to the human subject. In some embodiments of these aspects, the pharmaceutical composition is administered intravenously to the human subject.

[0025] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-Aβ antibody or Aβ-binding fragment thereof, a thiol-containing antioxidant, and arginine hydrochloride (Arg.HCl).

[0026] In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL comprise the CDRs of BIIB037. In some cases, the six CDRs of BIIB037 comprise or consist of the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

[0027] In some embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50 to 250 mg / ml. In other embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 75 to 165 mg / ml. In certain embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml. In certain embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml.

[0028] In some embodiments, the thiol-containing antioxidant in the composition is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. Optionally, the thiol-containing antioxidant is GSH. Optionally, the thiol-containing antioxidant is GSSG. Optionally, the thiol-containing antioxidant is GSH and GSSG. In certain embodiments, the concentration of the thiol-containing antioxidant is 0.02-4 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 0.02-2 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 0.2 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 0.4 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 1 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 2 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 4 mM. In some cases, the thiol-containing antioxidant in the composition is GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM. In some cases, the thiol-containing antioxidant in the composition is GSH at a concentration of 4 mM and GSSG at a concentration of 2 mM. In some cases, the thiol-containing antioxidant in the composition is GSH at a concentration of 2 mM and GSSG at a concentration of 1 mM. In some cases, the thiol-containing antioxidant in the composition is cysteine ​​at a concentration of 0.4 mM and cystine at a concentration of 0.2 mM.

[0029] In some embodiments, the composition comprises Arg.HCl at a concentration of 50-250 mM. In other embodiments, the composition comprises Arg.HCl at a concentration of 75-175 mM. In certain embodiments, the composition comprises Arg.HCl at a concentration of 150 mM.

[0030] In some embodiments, the composition further comprises polysorbate 80 (PS80). In some embodiments, the composition comprises PS80 at a concentration of 0.01-0.1%. In other embodiments, the composition comprises PS80 at a concentration of 0.03-0.08%. In certain embodiments, the composition comprises PS80 at a concentration of 0.05%.

[0031] In some embodiments, the composition further comprises a buffering agent selected from the group consisting of histidine, acetate, succinate, and citrate. Optionally, the buffering agent is histidine. Optionally, the buffering agent is acetate. Optionally, the buffering agent is succinate. Optionally, the buffering agent is citrate. In certain embodiments, the composition comprises histidine, acetate, succinate, or citrate at a concentration of 10-30 mM. In certain embodiments, the composition comprises histidine, acetate, succinate, or citrate at a concentration of 20 mM. In certain embodiments, the composition comprises histidine at a concentration of 10-30 mM. In certain embodiments, the composition comprises histidine at a concentration of 20 mM.

[0032] In some embodiments, the composition further comprises sucrose. In some embodiments, the composition comprises sucrose at a concentration of 0.01-5%. In other embodiments, the composition comprises sucrose at a concentration of 1-4%. In certain embodiments, the composition comprises sucrose at a concentration of 3%.

[0033] In some embodiments, the composition further comprises methionine. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 150 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 125 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 100 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 75 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 50 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01 to 20 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 15 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 50 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 75 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 100 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 125 mM. In other embodiments, the composition comprises methionine at a concentration of 5 to 150 mM. In certain embodiments, the composition comprises methionine at a concentration of 10 mM. In certain embodiments, the composition comprises methionine at a concentration of 50 mM. In certain embodiments, the composition comprises methionine at a concentration of 75 mM. In certain embodiments, the composition comprises methionine at a concentration of 100 mM. In certain embodiments, the composition comprises methionine at a concentration of 125 mM. In certain embodiments, the composition comprises methionine at a concentration of 150 mM. In some embodiments, the pH of the composition is 5.2 to 6.2. In certain embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5.

[0034] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50 to 250 mg / ml, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM, Arg.HCl at a concentration of 50 to 200 mM, histidine at a concentration of 10 to 30 mM, PS80 at a concentration of 0.01 to 0.1%, and sucrose at a concentration of 0 to 3%. In some cases, the pH of the composition is 5.2 to 6.2. In some cases, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5. In some cases, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some cases, the thiol-containing antioxidant is GSH. In some cases, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0035] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml, Arg.HCl at a concentration of 150 mM, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some embodiments, the pH of the composition is 5.2 to 6.2. In some embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some embodiments, the thiol-containing antioxidant is GSH. In some embodiments, the thiol-containing antioxidant is GSSG. In some embodiments, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0036] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml, Arg.HCl at a concentration of 150 mM, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some embodiments, the pH of the composition is 5.2 to 6.2. In some embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some embodiments, the thiol-containing antioxidant is GSH. In some embodiments, the thiol-containing antioxidant is GSSG. In some embodiments, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0037] In some embodiments, the VH comprises or consists of a sequence that is at least 80% identical to SEQ ID NO: 7, and the VL comprises or consists of a sequence that is at least 80% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of a sequence that is at least 90% identical to SEQ ID NO: 7, and the VL comprises or consists of a sequence that is at least 90% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of the sequence of SEQ ID NO: 7, and the VL comprises or consists of the sequence of SEQ ID NO: 8.

[0038] In some embodiments, the anti-Aβ antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain. In some cases, the heavy chain comprises or consists of a sequence at least 80% identical to SEQ ID NO:9, and the light chain comprises or consists of a sequence at least 80% identical to SEQ ID NO:10. In other examples, the heavy chain comprises or consists of a sequence at least 90% identical to SEQ ID NO:9, and the light chain comprises or consists of a sequence at least 90% identical to SEQ ID NO:10. In yet other examples, the heavy chain comprises or consists of the sequence of SEQ ID NO:9, and the light chain comprises or consists of the sequence of SEQ ID NO:10.

[0039] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-Aβ antibody or Aβ-binding fragment thereof, a thiol-containing antioxidant, methionine, and arginine hydrochloride (Arg.HCl).

[0040] In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL comprise the CDRs of BIIB037. In some cases, the six CDRs of BIIB037 comprise or consist of the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

[0041] In some embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50 to 250 mg / ml. In other embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 75 to 165 mg / ml. In certain embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml. In certain embodiments, the composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml.

[0042] In some embodiments, the thiol-containing antioxidant in the composition is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. Optionally, the thiol-containing antioxidant is GSH. Optionally, the thiol-containing antioxidant is GSSG. Optionally, the thiol-containing antioxidant is GSH and GSSG. In certain embodiments, the concentration of the thiol-containing antioxidant is 0.02-4 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 0.02-2 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 0.2 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 0.4 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 1 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 2 mM. In certain embodiments, the concentration of the thiol-containing antioxidant is 4 mM. In some cases, the thiol-containing antioxidant in the composition is GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM. In some cases, the thiol-containing antioxidant in the composition is GSH at a concentration of 4 mM and GSSG at a concentration of 2 mM. In some cases, the thiol-containing antioxidant in the composition is GSH at a concentration of 2 mM and GSSG at a concentration of 1 mM. In some cases, the thiol-containing antioxidant in the composition is cysteine ​​at a concentration of 0.4 mM and cystine at a concentration of 0.2 mM.

[0043] In some embodiments, the composition comprises methionine at a concentration of 0.01-150 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01-125 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01-100 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01-75 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01-50 mM. In some embodiments, the composition comprises methionine at a concentration of 0.01-20 mM. In other embodiments, the composition comprises methionine at a concentration of 5-15 mM. In other embodiments, the composition comprises methionine at a concentration of 5-50 mM. In other embodiments, the composition comprises methionine at a concentration of 5-75 mM. In other embodiments, the composition comprises methionine at a concentration of 5-100 mM. In other embodiments, the composition comprises methionine at a concentration of 5-125 mM. In other embodiments, the composition comprises methionine at a concentration of 5-150 mM. In certain embodiments, the composition comprises methionine at a concentration of 10 mM. In certain embodiments, the composition comprises methionine at a concentration of 50 mM. In certain embodiments, the composition comprises methionine at a concentration of 75 mM. In certain embodiments, the composition comprises methionine at a concentration of 100 mM. In certain embodiments, the composition comprises methionine at a concentration of 125 mM. In certain embodiments, the composition comprises methionine at a concentration of 150 mM.

[0044] In some embodiments, the composition comprises Arg.HCl at a concentration of 50-250 mM. In other embodiments, the composition comprises Arg.HCl at a concentration of 75-175 mM. In certain embodiments, the composition comprises Arg.HCl at a concentration of 150 mM.

[0045] In some embodiments, the composition further comprises polysorbate 80 (PS80). In some embodiments, the composition comprises PS80 at a concentration of 0.01-0.1%. In other embodiments, the composition comprises PS80 at a concentration of 0.03-0.08%. In certain embodiments, the composition comprises PS80 at a concentration of 0.05%.

[0046] In some embodiments, the composition further comprises a buffering agent selected from the group consisting of histidine, acetate, succinate, and citrate. Optionally, the buffering agent is histidine. Optionally, the buffering agent is acetate. Optionally, the buffering agent is succinate. Optionally, the buffering agent is citrate. In certain embodiments, the composition comprises histidine, acetate, succinate, or citrate at a concentration of 10-30 mM. In certain embodiments, the composition comprises histidine, acetate, succinate, or citrate at a concentration of 20 mM. In certain embodiments, the composition comprises histidine at a concentration of 10-30 mM. In certain embodiments, the composition comprises histidine at a concentration of 20 mM.

[0047] In some embodiments, the composition further comprises sucrose. In some embodiments, the composition comprises sucrose at a concentration of 0.01-5%. In other embodiments, the composition comprises sucrose at a concentration of 1-4%. In certain embodiments, the composition comprises sucrose at a concentration of 3%.

[0048] In some embodiments, the pH of the composition is 5.2 to 6.2. In certain embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5.

[0049] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50-250 mg / ml, a thiol-containing antioxidant at a concentration of 0.02-4 mM, methionine at a concentration of 5-150 mM, Arg.HCl at a concentration of 50-200 mM, histidine at a concentration of 10-30 mM, PS80 at a concentration of 0.01-0.1%, and sucrose at a concentration of 0-3%. In some embodiments, the pH of the composition is 5.2-6.2. In some embodiments, the pH of the composition is 5.2-6.0. In certain embodiments, the pH of the composition is 5.3-5.7. In other embodiments, the pH of the composition is 5.5. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some embodiments, the thiol-containing antioxidant is GSH. In some cases, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0050] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml, Arg.HCl at a concentration of 150 mM, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM, methionine at a concentration of 10 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some embodiments, the pH of the composition is 5.2 to 6.2. In some embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some embodiments, the thiol-containing antioxidant is GSH. In some embodiments, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0051] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml, Arg.HCl at a concentration of 150 mM, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM, methionine at a concentration of 150 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some embodiments, the pH of the composition is 5.2 to 6.2. In some embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some embodiments, the thiol-containing antioxidant is GSH. In some embodiments, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0052] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml, Arg.HCl at a concentration of 150 mM, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM, methionine at a concentration of 10 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some embodiments, the pH of the composition is 5.2 to 6.2. In some embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some embodiments, the thiol-containing antioxidant is GSH. In some embodiments, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0053] In certain embodiments, the pharmaceutical composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml, Arg.HCl at a concentration of 150 mM, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM, methionine at a concentration of 150 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some embodiments, the pH of the composition is 5.2 to 6.2. In some embodiments, the pH of the composition is 5.2 to 6.0. In certain embodiments, the pH of the composition is 5.3 to 5.7. In other embodiments, the pH of the composition is 5.5. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some embodiments, the thiol-containing antioxidant is GSH. In some embodiments, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0054] In some embodiments, the VH comprises or consists of a sequence that is at least 80% identical to SEQ ID NO: 7, and the VL comprises or consists of a sequence that is at least 80% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of a sequence that is at least 90% identical to SEQ ID NO: 7, and the VL comprises or consists of a sequence that is at least 90% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of the sequence of SEQ ID NO: 7, and the VL comprises or consists of the sequence of SEQ ID NO: 8.

[0055] In some embodiments, the anti-Aβ antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain. In some cases, the heavy chain comprises or consists of a sequence at least 80% identical to SEQ ID NO:9, and the light chain comprises or consists of a sequence at least 80% identical to SEQ ID NO:10. In other examples, the heavy chain comprises or consists of a sequence at least 90% identical to SEQ ID NO:9, and the light chain comprises or consists of a sequence at least 90% identical to SEQ ID NO:10. In yet other examples, the heavy chain comprises or consists of the sequence of SEQ ID NO:9, and the light chain comprises or consists of the sequence of SEQ ID NO:10.

[0056] In another aspect, the disclosure features a method of treating abnormal accumulation or deposition of Aβ in the central nervous system in a human subject in need thereof, the method including administering to the human subject a pharmaceutical composition described herein.

[0057] In another aspect, the disclosure features a method of treating mild cognitive impairment in a human subject in need thereof, the method including administering to the human subject a pharmaceutical composition described herein.

[0058] In another aspect, the disclosure features a method of treating Alzheimer's disease in a human subject in need thereof, the method including administering to the human subject a pharmaceutical composition described herein.

[0059] In some embodiments of these aspects, the pharmaceutical composition is administered subcutaneously to the human subject. In some embodiments of these aspects, the pharmaceutical composition is administered intravenously to the human subject.

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present invention, exemplary methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0061] Other features and advantages of the invention will become apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0062] [Figure 1] 1 is a bar graph depicting the % HMW of the indicated formulations stored at 40° C. over a 4-week period. [Figure 2] 1 is a graph showing the % HMW of the indicated formulations stored at 40° C. over a 6-week period. [Figure 3] 1 is a graph showing the trend of % HMW at various pH when stored at 25° C.+60% relative humidity. [Figure 4] 1 is a graph showing the trend of % HMW for various excipients when stored at 25° C.+60% relative humidity. [Figure 5] 1 is a bar graph showing the viscosity of the formulations at 20° C. [Figure 6] 1 is a bar graph depicting % HMW results for polysorbate 80 formulations after 72 hours at room temperature. [Figure 7] FIG. 1 is a graph showing the effect of the combination of GSH and GSSG on the stability of aducanumab formulations at 25° C. and 60% relative humidity. [Figure 8] FIG. 1 is a graph showing the effect of the combination of cysteine ​​and cystine on the stability of aducanumab formulations at 25° C. and 60% relative humidity. [Figure 9]1 is a graph showing that the reduced forms of thiol-containing excipients have the same impact on stability at 25° C. and 60% relative humidity as redox couples. [Figure 10] FIG. 10 is a graph illustrating that methionine, when used in combination with GSH, provides limited benefit to the stability of aducanumab formulations at 25° C. and 60% relative humidity. [Figure 11] 1 is a pair of graphs showing the effect of various antibody concentrations and GSH on stability at 25° C. and 60% relative humidity. [Figure 12] FIG. 1 is a pair of graphs showing that GSH can improve HMW stability even at low concentrations. [Figure 13] 1 is a graph showing that 4 mM GSH has the same effect on HMW reduction as 0.5-2 mM GSH. [Figure 14] 1 is a pair of graphs showing the effect of increasing methionine on HMW levels at 25° C. (top) and 40° C. (bottom). DETAILED DESCRIPTION OF THE INVENTION

[0063] The present application provides pharmaceutical compositions containing anti-Aβ antibodies and Aβ-binding fragments thereof, and their use in treating abnormal accumulation or deposition of Aβ in the central nervous system, mild cognitive impairment, and Aβ-related disorders (e.g., Alzheimer's disease).

[0064] Amyloid beta (Aβ or Abeta) The Aβ peptide is an important risk factor and plays a central role in the development and progression of Alzheimer's disease. Aβ is produced in normal individuals, but under certain circumstances this molecule aggregates, leading to disease progression.

[0065] Aβ refers to a 36-43 amino acid peptide involved in forming the amyloid plaques found in the brains of patients with Alzheimer's disease. Similar plaques appear in some variants of dementia with Lewy bodies and in inclusion body myositis. Aβ also forms aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy.

[0066] Aβ peptides are formed by cleavage of amyloid precursor protein (APP) by the enzymes beta-secretase and gamma-secretase. Aβ molecules can aggregate to form flexible soluble oligomers that can exist in several forms. There are several Aβ peptide alloforms, Aβ40 and Aβ42. The amino acid sequence of human amyloid β peptide (1-40) is provided below: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV (SEQ ID NO: 11). The amino acid sequence of human amyloid beta peptide (1-42) is provided below: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA (SEQ ID NO: 12). Soluble oligomeric forms of Aβ peptide are believed to be causative agents in the development of Alzheimer's disease.

[0067] Anti-Aβ antibody In some embodiments, an anti-Aβ antibody or Aβ-binding fragment thereof used in the compositions and methods described herein comprises the three heavy chain variable domain complementarity-determining regions (CDRs) of the antibody designated "BIIB037" or aducanumab. In some embodiments, an anti-Aβ antibody or Aβ-binding fragment thereof comprises the three light chain variable domain CDRs of BIIB037. In yet other embodiments, an anti-Aβ antibody or Aβ-binding fragment thereof comprises the three heavy chain variable domain CDRs and three light chain variable domain CDRs of BIIB037.

[0068] BIIB037 is a fully human antibody containing a glycosylated human IgG1 heavy chain and a human kappa light chain, with the mature heavy chain amino acid sequence set forth in SEQ ID NO:9 and the mature light chain amino acid sequence set forth in SEQ ID NO:10.

[0069] The VH and VL of BIIB037 have amino acid sequences identical to those of the VH and VL of antibody NI-101.12F6A described in U.S. Patent No. 8,906,367 (see Tables 2-4, which are incorporated by reference in their entireties). Specifically, antibody BIIB037 has an antigen-binding domain comprising the VH and VL variable regions shown in Table 1 (VH) and Table 2 (VL), corresponding complementarity-determining regions (CDRs) shown in Table 3, and heavy and light chains shown in Table 4(H) and Table 5(L). [Table 1] [Table 2] [Table 3-1] [Table 3-2]

[0070] The amino acid sequence of the mature heavy chain of BIIB037 is shown in Table 4 below. [Table 4]

[0071] The amino acid sequence of the mature light chain of BIIB037 is shown in Table 5 below. [Table 5]

[0072] In some aspects, the anti-Aβ antibody or Aβ-binding fragment thereof comprises a VH CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 2, and a VH CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises a VL CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 6.

[0073] In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises a CDR comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 1-6.

[0074] In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises a VH comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof selectively binds to a peptide comprising or consisting of amino acids 1-16 of human Aβ and comprises a VH domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of the VH domain of BIIB037 (SEQ ID NO: 7) or differs by at least 1-5 amino acid residues but fewer than 40, 30, 20, 15, or 10 residues from SEQ ID NO: 7. In some embodiments, these anti-Aβ antibodies or Aβ-binding fragments thereof selectively bind to a peptide comprising or consisting of amino acids 3-6 of human Aβ.

[0075] In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises a VL comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof selectively binds to a peptide comprising or consisting of amino acids 1-16 of human Aβ and comprises a VL domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of the VL domain of BIIB037 (SEQ ID NO: 8) or differs by at least 1-5 amino acid residues but fewer than 40, 30, 20, 15, or 10 residues from SEQ ID NO: 8. In some embodiments, these anti-Aβ antibodies or Aβ-binding fragments thereof selectively bind to a peptide comprising or consisting of amino acids 3-6 of human Aβ.

[0076] In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises a VH having the amino acid sequence set forth in SEQ ID NO:7 and a VL having the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof selectively binds to a peptide comprising or consisting of amino acids 1-16 of human Aβ, and comprises (i) a VH domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of the VH domain of BIIB037 (SEQ ID NO:7), and (ii) a VL domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of the VL domain of BIIB037 (SEQ ID NO:8); or differs by at least 1-5 amino acid residues but fewer than 40, 30, 20, 15, or 10 residues compared to SEQ ID NO:7 and / or SEQ ID NO:8. In some embodiments, these anti-Aβ antibodies or Aβ-binding fragments thereof selectively bind to a peptide comprising or consisting of amino acids 3-6 of human Aβ.

[0077] In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises a heavy chain (HC) having the amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof selectively binds to a peptide comprising or consisting of amino acids 1-16 of human Aβ, and comprises an HC that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9, or that differs from SEQ ID NO: 9 by at least 1-5 amino acid residues but fewer than 40, 30, 20, 15, or 10 residues. In some embodiments, these anti-Aβ antibodies or Aβ-binding fragments thereof selectively bind to a peptide comprising or consisting of amino acids 3-6 of human Aβ.

[0078] In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises a light chain (LC) having the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof selectively binds to a peptide comprising or consisting of amino acids 1-16 of human Aβ, and comprises an LC that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 10, or that differs from SEQ ID NO: 10 by at least 1-5 amino acid residues but fewer than 40, 30, 20, 15, or 10 residues. In some embodiments, these anti-Aβ antibodies or Aβ-binding fragments thereof selectively bind to a peptide comprising or consisting of amino acids 3-6 of human Aβ.

[0079] In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof comprises an HC having the amino acid sequence set forth in SEQ ID NO: 9 and an LC having the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof selectively binds to a peptide comprising or consisting of amino acids 1-16 of human Aβ, and (i) is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence (SEQ ID NO: 9) or at least 1-5 amino acid residues different from SEQ ID NO: 9. and (ii) an HC that differs from the amino acid sequence of SEQ ID NO: 10 by fewer than 40, 30, 20, 15, or 10 residues, and (iii) an LC that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 10 or that differs from SEQ ID NO: 10 by at least 1-5 amino acid residues but fewer than 40, 30, 20, 15, or 10 residues. In some embodiments, these anti-Aβ antibodies or Aβ-binding fragments thereof selectively bind to a peptide comprising or consisting of amino acids 3-6 of human Aβ.

[0080] In certain embodiments, the anti-Aβ antibody is an IgG antibody. In specific embodiments, the anti-Aβ antibody has a heavy chain constant region selected from, e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE. In one embodiment, the anti-Aβ antibody is of the human IgG1 isotype. In another embodiment, the anti-Aβ antibody is of the human IgG2 isotype. In yet another embodiment, the anti-Aβ antibody is of the human IgG3 isotype. In yet another embodiment, the anti-Aβ antibody is of the human IgG4 isotype. In further embodiments, the antibody has a light chain constant region selected from, e.g., a human kappa or human lambda light chain. In certain embodiments, the anti-Aβ antibody is a human IgG1 / human kappa antibody. In some cases, the heavy chain constant region is human or a modified version of a human constant region. In some cases, the human constant region may contain at least one substitution, but not more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 substitutions. In certain embodiments, the modified human Fc region is a modified human IgG1 Fc region. In some cases, the constant region of the anti-Aβ antibody is modified by mutation of one or more amino acid residues that impart a desired functional property (e.g., altered effector function or half-life, reduced glycosylation). For example, N-linked glycosylation sites may be substituted to prevent or reduce N-linked glycosylation of the Fc region (e.g., human IgG1 Fc region).

[0081] In some embodiments, the anti-Aβ antibody is a full-length (complete) antibody or substantially full-length. The protein may comprise at least one, preferably two, complete heavy chains and at least one, preferably two, complete light chains. In some embodiments, the anti-Aβ antibody is an Aβ-binding fragment. In some cases, the Aβ-binding fragment is a Fab, Fab', F(ab')2, Facb, Fv, single-chain Fv (scFv), sc(Fv)2, or diabody.

[0082] An antibody, such as BIIB037, or an Aβ-binding fragment thereof, can be made, for example, by creating and expressing a synthetic gene encoding the recited amino acid sequence, or by mutating a human germline gene to form a gene encoding the recited amino acid sequence. Additionally, this and other anti-Aβ antibodies can be produced, for example, using one or more of the following methods.

[0083] Methods for producing antibodies Anti-Aβ antibodies or Aβ-binding fragments can be produced in bacterial cells or eukaryotic cells. Some antibodies, such as Fab', can be produced in bacterial cells, such as E. coli cells. Antibodies can also be produced in eukaryotic cells, such as transformed cell lines (e.g., CHO, 293E, COS). In addition, yeast cells, such as Pichia (e.g., Powers Antibodies (e.g., scFv's) can be expressed in Saccharomyces cerevisiae (see, e.g., Saccharomyces cerevisiae ...

[0084] When anti-Aβ antibodies or Aβ-binding fragments are to be expressed in bacterial cells (e.g., E. coli), the expression vector must have characteristics that allow the vector to propagate in the bacterial cells. In addition, when E. coli, e.g., JM109, DH5α, HB101, or XL1-Blue, is used as a host, the vector should contain a promoter that allows efficient expression in E. coli, e.g., the lacZ promoter (Ward The expression vector must have an araB promoter (Better et al., Science, 240:1041-1043 (1988)), an araB promoter (Better et al., Science, 240:1041-1043 (1988)), or a T7 promoter. Examples of such vectors include M13-series vectors, pUC-series vectors, pBR322, pBluescript, pCR-Script, pGEX-5X-1 (Pharmacia), the QIAexpress system (QIAGEN), pEGFP, and pET (when using this expression vector, the host is preferably BL21, which expresses T7 RNA polymerase). The expression vector may also contain a signal sequence for antibody secretion. For production into the periplasm of E. coli, the pelB signal sequence (Lei et al., J. Bacteriol., 169:4379 (1987)) may be used as the signal sequence for antibody secretion. For bacterial expression, the expression vector may be introduced into bacterial cells using the calcium chloride method or electroporation.

[0085] When antibodies are to be expressed in animal cells, such as CHO, COS, and NIH3T3 cells, the expression vector contains a promoter necessary for expression in these cells, such as the SV40 promoter (Mulligan et al., Nature, 277:108 (1979)), the MMLV-LTR promoter, the EF1α promoter (Mizushima et al., Nucleic Acids Res., 18:5322 (1990)), or the CMV promoter. In addition to the nucleic acid sequence encoding an immunoglobulin or a domain thereof, the recombinant expression vector may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. The selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. Nos. 4,399,216, 4,634,665, and 5,179,017). For example, typically the selectable marker gene confers resistance to drugs, such as G418, hygromycin, or methotrexate, on a host cell into which the vector has been introduced. Examples of vectors having selectable markers include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, and pOP13.

[0086] In one embodiment, the antibody is produced in mammalian cells. Exemplary mammalian host cells for expressing the antibody include Chinese hamster ovary (CHO) cells (e.g., the dhfr gene described in Urlaub and Chasin (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220 used with a DHFR selection marker, such as that described in Kaufman and Sharp (1982) Mol. Biol. 159:601-621). - Examples of suitable cells include human ovarian cancer cells (including CHO cells), human embryonic kidney 293 cells (e.g., 293, 293E, 293T), COS cells, NIH3T3 cells, lymphoid cell lines such as NS0 myeloma cells and SP2 cells, and cells from transgenic animals, e.g., transgenic mammals. For example, the cell is a mammary epithelial cell.

[0087] In an exemplary system for antibody expression, a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain of an anti-Aβ antibody (e.g., BIIB037) is transfected with dhfr - The antibody heavy and light chain genes are then introduced into CHO cells. Within the recombinant expression vector, each antibody heavy and light chain gene is operably linked to an enhancer / promoter regulatory element (e.g., derived from SV40, CMV, adenovirus, etc., e.g., a CMV enhancer / AdMLP promoter regulatory element or an SV40 enhancer / AdMLP promoter regulatory element) to promote high-level transcription of the gene. The recombinant expression vector also carries a DHFR gene, which allows CHO cells transfected with the vector to be selected using methotrexate selection / amplification. The selected transformed host cells are cultured to express the antibody heavy and light chains, and the antibody is recovered from the culture medium.

[0088] Antibodies can also be produced by transgenic animals. For example, U.S. Patent No. 5,849,992 describes a method for expressing an antibody in the mammary gland of a transgenic mammal. A transgene is constructed containing a milk-specific promoter, a nucleic acid encoding the antibody of interest, and a signal sequence for secretion. The milk produced by female transgenic mammals contains the antibody of interest secreted therein. The antibody can be purified from the milk or used directly in some applications. Animals containing one or more of the nucleic acids described herein are also provided.

[0089] The antibodies of the present disclosure can be isolated from the inside or outside of host cells (e.g., culture medium) and purified as substantially pure and homogeneous antibodies. Isolation and purification of antibodies can be performed using methods commonly used for antibody purification, but the methods are not limited to any particular method. For example, antibodies can be isolated and purified by appropriately selecting and combining column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, and recrystallization. Examples of chromatography include affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reversed-phase chromatography, and adsorption chromatography (Strategies for Protein Purification and Characterization: A Laboratory Course Manual. Ed. Daniel R. Marshak et al., Cold Spring Harbor Laboratory Press, 1996). Chromatography can be performed using liquid-phase chromatography such as HPLC and FPLC. Columns used for affinity chromatography include protein A columns and protein G columns. Examples of columns using Protein A columns include Hyper D, POROS, and Sepharose FF (GE Healthcare Biosciences). The present disclosure also includes antibodies highly purified by these purification methods.

[0090] Anti-Aβ antibody composition The present disclosure further provides compositions (e.g., pharmaceutical compositions) comprising the anti-Aβ antibodies or Aβ-binding fragments thereof described herein. For example, the anti-Aβ antibody composition includes an anti-Aβ antibody or Aβ-binding fragment thereof comprising an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH comprises the H-CDR of BIIB037 and the VL comprises the L-CDR of BIIB037. In some cases, the heavy chain CDR (H-CDR) comprises or consists of the amino acid sequence set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and the light chain CDR (L-CDR) comprises or consists of the amino acid sequence set forth in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6. In some embodiments, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof, comprising: (i) a VH comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:7; and (ii) a VL comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO:8. In certain embodiments, an anti-Aβ antibody composition comprises an anti-Aβ antibody comprising: (i) a heavy chain comprising or consisting of an amino acid sequence at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 9; and (ii) a light chain comprising or consisting of an amino acid sequence at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-Aβ antibody selectively binds to a peptide comprising or consisting of amino acids 1-16 of human Aβ. In some embodiments, the anti-Aβ antibody selectively binds to a peptide comprising or consisting of amino acids 3-6 of human Aβ.

[0091] In certain embodiments, these compositions are high-concentration anti-Aβ antibody compositions. A "high-concentration anti-Aβ antibody composition" refers to a composition comprising an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration greater than 50 mg / ml and less than 300 mg / ml. In some cases, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50-250 mg / ml. In some cases, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50-225 mg / ml. In other examples, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 75-225 mg / ml. In other examples, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 75-165 mg / ml. In other examples, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100-225 mg / ml. In yet another example, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 125 to 225 mg / ml. In another example, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 125 to 175 mg / ml. Optionally, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 240 mg / ml. Optionally, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 225 mg / ml. Optionally, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 200 mg / ml. Optionally, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 175 mg / ml. Optionally, the anti-Aβ antibody composition comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml. In other examples, the anti-Aβ antibody composition contains the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 125 mg / ml. In some cases, the anti-Aβ antibody composition contains the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml.

[0092] Compositions (e.g., pharmaceutical compositions) comprising the anti-Aβ antibodies or Aβ-binding fragments thereof described herein can be in any one of a variety of forms. These include, for example, liquid solutions (e.g., injection and infusion solutions), dispersions, or suspensions. The preferred form can depend on the intended mode of administration and therapeutic application. In certain embodiments, the pharmaceutical compositions described herein are in the form of sterile injection or infusion solutions.

[0093] Sterile injectable solutions can be prepared by mixing the required amount of the antibody described herein with one or a combination of ingredients, followed by sterile filtration. Generally, dispersions are prepared by incorporating the antibody described herein into a sterile vehicle containing a basic dispersion medium and other necessary ingredients. In the case of sterile powders for preparing sterile injectable solutions, exemplary preparation methods include vacuum drying and freeze-drying, which are obtained by combining a powder of the antibody described herein with any additional desired ingredients from a solution that has previously been sterile-filtered. The proper fluidity of the solution can be maintained, for example, by using a coating agent such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

[0094] The anti-Aβ antibody composition (eg, pharmaceutical composition) may further comprise one or more excipients.

[0095] In one embodiment, the excipient reduces / decreases antibody aggregation and / or viscosity in the composition compared to antibody aggregation and / or viscosity in a pharmaceutical composition without the excipient. In a specific embodiment, such an excipient is arginine. In one example, the excipient is L-arginine hydrochloride. Arginine (e.g., L-arginine hydrochloride) can be present in the composition at a concentration of 40-260 mM, 50-250 mM, 50-200 mM, 50-150 mM, 50-125 mM, 50-100 mM, 75-250 mM, 75-200 mM, 75-150 mM, or 75-100 mM. In a specific embodiment, arginine (e.g., Arg.HCl) is present in the composition at a concentration of 50-250 mM. In other embodiments, arginine (e.g., Arg.HCl) is present in the composition at a concentration of 50-200 mM. In some cases, arginine (e.g., arginine hydrochloride) can be included in the composition at a concentration of 80 mM, 100 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 220 mM, or 260 mM. In a specific example, arginine (e.g., arginine hydrochloride) can be included in the composition at a concentration of 100 mM. In another specific example, arginine (e.g., arginine hydrochloride) can be included in the composition at a concentration of 150 mM.

[0096] Solutions containing arginine may develop visible particles after incubation at room temperature or higher temperatures (e.g., 40°C). The addition of sucrose can reduce or prevent the formation of visible particles. Furthermore, sucrose can reduce the number of non-visible particles. In some embodiments, the anti-Aβ antibody composition contains sucrose at a concentration of 0.05-5%, 0.05-4%, 0.05-3%, 1-5%, 1-4%, 1-3%, 2-5%, 2-4%, or 2-3%. In certain embodiments, the anti-Aβ antibody composition contains sucrose at a concentration of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%. In some embodiments, the anti-Aβ antibody composition contains sucrose at a concentration of 3%. In other embodiments, the anti-Aβ antibody composition contains sucrose at a concentration of 1%.

[0097] In one embodiment, the anti-Aβ antibody composition contains methionine. In one example, methionine is present in the composition at a concentration of 0.5 to 150 mM. In another example, methionine is present in the composition at a concentration of 0.5 to 25 mM. In yet another example, methionine is present in the composition at a concentration of 5 to 150 mM. In one example, methionine is present in the composition at a concentration of 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 50 mM, 75 mM, 100 mM, 125 mM, or 150 mM. In one example, methionine is present in the composition at a concentration of 10 mM. In another example, methionine is present in the composition at a concentration of 150 mM.

[0098] Antibody product manufacturing is a complex process that can involve several steps, such as drug substance and bulk formulation, filtration, shipping, pooling, filling, lyophilization, testing, packaging, and storage. During these steps, antibodies can be exposed to a variety of forms of stress, such as agitation, temperature, light exposure, and oxidation. These types of stress can lead to antibody denaturation and aggregation, which can deteriorate product quality and even result in the loss of production batches. Agitation is one of the common physical stresses that antibody therapeutics are exposed to during the manufacturing process. Agitation occurs, for example, during mixing, ultrafiltration / diafiltration, pumping, shipping, and filling. To protect antibody compositions from stress caused by agitation, the compositions can include polysorbates. In certain embodiments, the composition contains polysorbate 80 at a concentration of 0.01-0.5%, 0.01-0.1%, 0.01-0.09%, 0.01-0.08%, 0.01-0.07%, 0.01-0.06%, 0.01-0.05%, 0.01-0.04%, or 0.01-0.03%. In certain embodiments, the composition contains polysorbate 80 at a concentration of 0.02-0.08%. In some embodiments, the composition contains polysorbate 80 at a concentration of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%. In certain embodiments, the composition contains polysorbate 80 at a concentration of 0.05%.

[0099] A buffer that provides good buffering capacity is useful for any antibody composition. In certain embodiments, the antibody composition comprises histidine as a buffer. In certain embodiments, the composition comprises histidine at a concentration of 5-50 mM, 5-40 mM, 5-35 mM, 5-30 mM, 5-25 mM, 10-50 mM, 10-40 mM, 10-30 mM, 10-25 mM, 15-50 mM, 15-40 mM, 15-30 mM, or 15-25 mM. In certain embodiments, the composition comprises histidine at a concentration of 5-35 mM. In certain embodiments, the composition comprises histidine at a concentration of 10-30 mM. In some embodiments, the composition comprises histidine at a concentration of 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, or 35 mM. In certain embodiments, the composition comprises histidine at a concentration of 20 mM. In certain embodiments, the antibody composition comprises acetate as a buffer. In certain embodiments, the composition comprises acetate at a concentration of 5-50 mM, 5-40 mM, 5-35 mM, 5-30 mM, 5-25 mM, 10-50 mM, 10-40 mM, 10-30 mM, 10-25 mM, 15-50 mM, 15-40 mM, 15-30 mM, or 15-25 mM. In certain embodiments, the composition comprises acetate at a concentration of 5-35 mM. In certain embodiments, the composition comprises acetate at a concentration of 10-30 mM. In some embodiments, the composition comprises acetate at a concentration of 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, or 35 mM. In certain embodiments, the composition comprises acetate at a concentration of 20 mM. In certain embodiments, the antibody composition comprises succinate as a buffer. In certain embodiments, the composition comprises succinate at a concentration of 5-50 mM, 5-40 mM, 5-35 mM, 5-30 mM, 5-25 mM, 10-50 mM, 10-40 mM, 10-30 mM, 10-25 mM, 15-50 mM, 15-40 mM, 15-30 mM, or 15-25 mM. In certain embodiments, the composition comprises succinate at a concentration of 5-35 mM. In certain embodiments, the composition comprises succinate at a concentration of 10-30 mM. In some embodiments, the composition comprises succinate at a concentration of 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, or 35 mM. In certain embodiments, the composition comprises succinate at a concentration of 20 mM.In certain embodiments, the antibody composition comprises citrate as a buffer. In certain embodiments, the composition comprises citrate at a concentration of 5-50 mM, 5-40 mM, 5-35 mM, 5-30 mM, 5-25 mM, 10-50 mM, 10-40 mM, 10-30 mM, 10-25 mM, 15-50 mM, 15-40 mM, 15-30 mM, or 15-25 mM. In certain embodiments, the composition comprises citrate at a concentration of 5-35 mM. In certain embodiments, the composition comprises citrate at a concentration of 10-30 mM. In some embodiments, the composition comprises citrate at a concentration of 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, or 35 mM. In certain embodiments, the composition comprises citrate at a concentration of 20 mM.

[0100] The antibody composition may have a pH of 5.0 to 6.5. Optionally, the antibody composition may have a pH of 5.2 to 6.2. Optionally, the antibody composition has a pH of 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5. In certain embodiments, the antibody composition has a pH of 5.5.

[0101] In some instances, the Aβ composition includes arginine (e.g., Arg.HCl). In other instances, the Aβ composition includes arginine (e.g., Arg.HCl) and methionine.

[0102] In certain embodiments, the Aβ composition comprises L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 10 mM), histidine (e.g., 20 mM), and PS80 (e.g., 0.05%), and has a pH of 5.2 to 6.2. In some embodiments, the Aβ composition comprises L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 10 mM, 150 mM), histidine (e.g., 20 mM), and PS80 (e.g., 0.05%), and has a pH of 5.5. In certain embodiments, the Aβ composition comprises L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 10 mM, 150 mM), histidine (e.g., 20 mM), PS80 (e.g., 0.05%), and sucrose (3% or less), and has a pH of 5.2 to 6.2. In some embodiments, the Aβ composition comprises L-arginine hydrochloride, methionine, histidine, PS80, and sucrose, and has a pH of 5.5. In all of these embodiments, the anti-Aβ antibody is present at a concentration of 100-165 mg / ml. In one example, the anti-Aβ antibody is present at a concentration of 150 mg / ml. In one example, the anti-Aβ antibody is present at a concentration of 100 mg / ml.

[0103] In some cases, the anti-Aβ composition may contain a thiol-containing antioxidant (e.g., reduced glutathione (GSH), oxidized glutathione (GSSG), GSH + GSSG, cysteine, cystine, cysteine ​​+ cystine) at a concentration of 0.02 to 4 mM (e.g., 0.02, 0.03, 0.05, 0.06, 0.08, 0.1, 0.2, 0.3, 0.4, 0.5, The thiol-containing antioxidants may be present at a concentration of 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 mM). Such thiol-containing antioxidants can cleave undesired or mis-bridged disulfide bonds and promote the formation of favorable or properly bridged disulfide bonds. This will result in stabilization of the native identity of the antibody or fragment thereof and slow the rate of aggregation. The antioxidant properties of these molecules can slow the oxidative process that leads to aggregation. In some cases, the composition contains GSH at a concentration of 0.4 mM. In some cases, the composition contains GSSG at a concentration of 0.2 mM. In some cases, the composition contains GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM. In some cases, the composition contains GSH at a concentration of 4 mM and GSSG at a concentration of 2 mM. In some cases, the composition contains GSH at a concentration of 2 mM and GSSG at a concentration of 1 mM. In some cases, the composition contains cysteine ​​at a concentration of 0.4 mM. In some cases, the composition contains cystine at a concentration of 0.2 mM. In some cases, the composition contains cysteine ​​at a concentration of 0.4 mM and cystine at a concentration of 0.2 mM.

[0104] In certain embodiments, the Aβ composition comprises arginine (eg, Arg.HCl), a thiol-containing antioxidant, and methionine.

[0105] In certain embodiments, the Aβ composition comprises L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 10 mM), histidine (e.g., 20 mM), a thiol-containing antioxidant, e.g., GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine ​​and cystine (e.g., 0.02-4 mM), and PS80 (e.g., 0.05%), and has a pH of 5.2-6.2. In some embodiments, the Aβ composition comprises L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 10 mM, 150 mM), histidine (e.g., 20 mM), a thiol-containing antioxidant, e.g., GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine ​​and cystine (e.g., 0.02-4 mM), and PS80 (e.g., 0.05%), and has a pH of 5.5. In certain embodiments, the Aβ composition comprises L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 10 mM, 150 mM), histidine (e.g., 20 mM), PS80 (e.g., 0.05%), a thiol-containing antioxidant, e.g., GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine ​​and cystine (e.g., 0.02-4 mM), and sucrose (3% or less), and has a pH of 5.2-6.2. In some embodiments, the Aβ composition comprises L-arginine hydrochloride, methionine, histidine, PS80, a thiol-containing antioxidant, e.g., GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine ​​and cystine, and sucrose, and has a pH of 5.5. In all of these embodiments, the anti-Aβ antibody is present at a concentration of 100-165 mg / ml. In one example, the anti-Aβ antibody is present at a concentration of 150 mg / ml. In one example, the anti-Aβ antibody is present at a concentration of 100 mg / ml.

[0106] In certain embodiments, the composition (e.g., pharmaceutical composition) comprises an anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50-250 mg / ml, arginine (e.g., L-arginine hydrochloride) at a concentration of 50-200 mM, methionine at a concentration of 1-150 mM (e.g., 1-20 mM), polysorbate 80 at a concentration of 0.01-0.1%, histidine at a concentration of 10-30 mM, and sucrose at a concentration of 0-3%. In some cases, the pH of the composition is 5.2-6.2. In other examples, the pH of the composition is 5.2-6.0. In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof of the composition comprises a VH and a VL comprising the CDRs of BIIB037 (e.g., SEQ ID NOs: 1, 2, 3, 4, 5, and 6). In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof of the composition comprises a VH and a VL comprising SEQ ID NOs: 7 and 8, respectively. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof of the composition comprises heavy and light chains comprising SEQ ID NOs: 9 and 10, respectively. In one embodiment, the composition has a pH of 5.5 and comprises BIIB037 or a BIIB037-binding fragment thereof at a concentration of 150 mg / ml, L-arginine hydrochloride at a concentration of 150 mM, methionine at a concentration of 10 mM or 150 mM, polysorbate 80 at a concentration of 0.05%, and histidine at a concentration of 20 mM (16.2 mM L-histidine HCl monohydrate, 3.8 mM L-histidine free base). In certain embodiments, the composition further comprises a thiol-containing antioxidant (e.g., GSH, GSSG, GSH + GSSG, cysteine, cystine, cysteine ​​+ cystine) at a concentration of 0.02-4 mM. In some embodiments, the composition further comprises sucrose at a concentration of 0.01-3%. In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof of the composition comprises a VH and a VL comprising the CDRs of BIIB037 (e.g., SEQ ID NOs: 1, 2, 3, 4, 5, and 6). In certain embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof of the composition comprises a VH and a VL comprising SEQ ID NOs: 7 and 8, respectively. In some embodiments, the anti-Aβ antibody or Aβ-binding fragment thereof of the composition comprises a heavy chain and a light chain comprising SEQ ID NOs: 9 and 10, respectively.

[0107] In one embodiment, the composition has a pH of 5.5 and comprises BIIB037 or a BIIB037-binding fragment thereof at a concentration of 150 mg / ml, L-arginine hydrochloride at a concentration of 150 mM, a thiol-containing antioxidant (e.g., GSH, GSSG, GSH + GSSG, cysteine, cystine, cysteine ​​+ cystine) at a concentration of 0.02-4 mM, polysorbate 80 at a concentration of 0.05%, and histidine at a concentration of 20 mM. In one embodiment, the thiol-containing antioxidant is GSH at a concentration of 0.4 mM. In one embodiment, the thiol-containing antioxidant is GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM. In one embodiment, the thiol-containing antioxidant is GSH at a concentration of 4 mM and GSSG at a concentration of 2 mM. In one embodiment, the thiol-containing antioxidant is GSH at a concentration of 2 mM and GSSG at a concentration of 1 mM. In another embodiment, the thiol-containing antioxidant is cysteine ​​at a concentration of 0.4 mM.In another embodiment, the thiol-containing antioxidant is cysteine ​​at a concentration of 0.4 mM and cystine at a concentration of 0.2 mM.

[0108] Treatment method BIIB037 recognizes aggregated forms of Aβ, including plaques. In vitro characterization studies demonstrated that the antibody BIIB037 recognizes a conformational epitope present in Aβ aggregates, the accumulation of which is thought to underlie the development and progression of Alzheimer's disease (AD). In vivo pharmacology studies suggest that a murine IgG2a chimeric version of an antibody with similar properties (ch12F6A) significantly reduces amyloid plaque burden in the brain of aged Tg2576 mice, a mouse model of AD. As reported for certain anti-Aβ antibodies, the reduction in parenchymal amyloid was not accompanied by changes in vascular amyloid.

[0109] The compositions disclosed herein are useful for treating abnormal accumulation or deposition of Aβ in the central nervous system in a human subject in need thereof. The compositions disclosed herein are also useful for treating mild cognitive impairment in a human subject in need thereof. As used herein, the terms "treat," "treating," or "treatment" generally refer to obtaining a desired pharmacological and / or physiological effect.

[0110] In certain embodiments, the compositions disclosed herein are useful for treating AD in a human subject in need thereof, hi other embodiments, the compositions disclosed herein are useful for preventing AD in a human subject in need thereof.

[0111] The compositions disclosed herein can be used to (a) prevent AD from occurring in a subject who may be susceptible to AD but has not yet been diagnosed with it; (b) inhibit AD, e.g., arrest its progression; (c) alleviate AD, e.g., cause regression of AD; or (d) prolong survival compared to expected survival if not treated.

[0112] A therapeutically effective amount or dose of an anti-Aβ antibody or Aβ-binding fragment thereof is administered to a human subject in need thereof. A therapeutically effective amount refers to the amount of antibody sufficient to ameliorate the signs or symptoms associated with AD. The therapeutic efficacy and toxicity of the antibody can be determined by standard pharmaceutical procedures. Ideally, the antibody is used in an amount sufficient to restore normal behavior and / or cognitive characteristics in the case of Alzheimer's disease, or at least slow or prevent the progression of AD in the patient.

[0113] In some embodiments, the composition comprising the anti-Aβ antibody or Aβ-binding fragment thereof is administered intravenously to the human subject. In certain embodiments, the composition comprising the anti-Aβ antibody or Aβ-binding fragment thereof is administered subcutaneously to the human subject.

[0114] The following are examples of the practice of the present invention, which should not be construed as limiting the scope of the invention in any way. [Example]

[0115] Example 1: pH and buffers screened for optimal formulation The following formulations were prepared and screened to determine optimal buffer and pH. [Table 6]

[0116] The formulations were stored at 40°C + 75% relative humidity (RH) for 4 weeks (Figure 1). Conclusion: 1) Histidine buffer showed the smallest change in percent high molecular weight species (% HMW) compared to acetate, succinate, and citrate buffers. 2) The trend was consistent across the pH range of 5.5 to 6.5.

[0117] Example 2: Arginine as an optimal excipient for controlling HMW The following formulations were prepared to determine the optimal stabilizing excipient(s): Most contained L-arginine HCl alone or in combination with another excipient; two formulations contained no arginine but only sugar (sucrose or trehalose). [Table 7]

[0118] The formulations were stored at 40°C + 75% RH for 6 weeks and tested for %HMW (Figure 2). Conclusion: 1) The formulation containing arginine (solid line) performed better than the formulation without arginine (dashed line). 2) The combination of arginine and methionine (the two bottom solid lines in the graph) performed better than arginine alone and combinations of arginine with other excipients. 3) The performance of formulations prepared at both pH 5.5 and 6.0 was always better at pH 5.5.

[0119] Example 3: Formulation robustness to pH and protein concentration Further formulation optimization was performed by preparing various formulations (Table 8) based roughly on the lead formulation and screening for various quality attributes. [Table 8]

[0120] Figure 3 shows the trend of %HMW at various pH values ​​when stored at 25°C + 60% relative humidity. The rate of increase in %HMW over time is consistent across this pH range.

[0121] Figure 4 shows the trend in %HMW for various excipients when stored at 25°C + 60% relative humidity. Whether the stabilizing excipient is 150 mM L-arginine HCl + 10 mM methionine, 100 mM L-arginine HCl + 10 mM methionine, 150 mM L-arginine HCl without methionine, or 100 mM L-arginine HCl + 3% sucrose, the rate of increase in %HMW is consistent.

[0122] Example 4: Arginine reduces the viscosity of formulations The viscosity of each formulation was measured at room temperature (20°C). Protein concentration had a significant effect on viscosity, while other changes in formulation method did not. A viscosity of less than 50 cP is optimal for manufacturing processes and administration route options. Arginine-based formulations consistently exhibit low viscosity (approximately 20 cP) at high protein concentrations (approximately 220 mg / mL) (Figure 5).

[0123] Example 5: Formulation robustness to polysorbate 80 concentration The following formulations were prepared to evaluate the optimal level of surfactant (polysorbate 80) in the formulation. [Table 9]

[0124] Agitation studies were conducted to determine the appropriate level of surfactant required to maintain product stability during physical stress. The formulations in Table 9 were dispensed into 3 mL glass vials and 1 mL glass syringes with needles, then agitated at 650 rpm for 72 hours at room temperature. An unagitated control was stored in a glass vial for the same time and temperature.

[0125] The %HMW results were consistent across all of the agitated formulations (Figure 6). The unagitated control vials show a gradual increase in HMW as % Polysorbate 80 decreases from 0.05% to 0.00%. Any results are within the method variability (noise) (±0.2%) and may not be true differences. Stability is similar across a wide range of % Polysorbate 80.

[0126] Example 6: Thiol-containing excipients improve the aggregation stability of aducanumab formulations The addition of thiol-containing excipients to aducanumab formulations reduces aggregation during storage as determined by the development of high molecular weight species.

[0127] The control aducanumab formulation contained 165 mg / mL aducanumab, 20 mM histidine, 150 mM L-arginine HCl, 10 mM methionine, 0.05% polysorbate 80, and a pH of 5.5. The control formulation was spiked with the thiol-containing excipients GSH and GSSG. The formulations were stored at 25°C and 60% relative humidity. As shown in Figure 7, the addition of GSH and GSSG mitigates the development of HMW species during storage.

[0128] The same control aducanumab formulations were spiked with cysteine ​​and cystine. These formulations were also stored at 25°C and 60% relative humidity. As with GSH and GSGG, the addition of cysteine ​​and cystine inhibits the development of HMW species during storage (Figure 8).

[0129] Example 7: Reduced forms of thiol-containing excipients are as effective in controlling HMW as redox couples Addition of the reduced form of a thiol-containing excipient alone has the same effect as addition of a redox couple.

[0130] The control aducanumab formulation contained 165 mg / mL aducanumab, 20 mM histidine, 150 mM L-arginine HCl, 10 mM methionine, 0.05% polysorbate 80, and a pH of 5.5. This formulation was spiked with GSH + GSSG, GSH alone, or GSSG alone. The formulations were stored at 25°C and 60% relative humidity. As shown in Figure 9, the addition of GSH, GSSG, and GSH + GSSG all reduced the formation of HMW species.

[0131] Example 8: Thiol-containing excipients are superior to methionine in controlling HMW The addition of methionine does not improve the stability seen with GSH alone.

[0132] The control aducanumab formulation contained 165 mg / mL aducanumab, 20 mM histidine, 150 mM L-arginine HCl, and a pH of 5.5. GSH, or GSH plus methionine, was added to the control formulation. These formulations were stored at 25°C and 60% relative humidity. The addition of methionine did not provide any additional benefit over the reduction of HMW species seen with GSH alone (Figure 10).

[0133] Example 9: Robustness of thiol-containing excipient formulations at multiple concentrations of protein and GSH Reduction of HMW species by addition of GSH was observed at multiple concentrations of protein and multiple concentrations of GSH.

[0134] Aducanumab (165 or 200 mg / mL aducanumab, 20 mM histidine, 150 mM L-arginine HCl, 10 mM methionine, 0.05% polysorbate 80, pH 5.5) was stored at 25°C and 60% relative humidity with various concentrations of GSH. As shown in Figure 11, at protein concentrations of 200 mg / mL or less, GSH inhibits HMW species formation at concentrations of 0.2 to 1.0 mM.

[0135] Example 10: Thiol-containing excipients are effective in controlling HMW to very low concentrations Thiol-containing excipient concentrations as low as 0.02 mM improved the stability of various concentrations of aducanumab.

[0136] Aducanumab at various concentrations of GSH (165 or 225 mg / mL aducanumab, 20 mM histidine, 150 mM L-arginine HCl, 10 mM methionine, 0.05% polysorbate 80, pH 5.5) was stored at 25°C and 60% relative humidity. As shown in Figure 12, GSH in formulations containing up to 225 mg / mL aducanumab inhibits HMW species formation at concentrations as low as 0.02 mM.

[0137] Example 11: Effect of increasing thiol-containing excipients on HMW This experiment was carried out to evaluate the effect of increasing concentrations of GSH on HMW reduction.

[0138] All formulations tested contained 210 mg / mL aducanumab, 20 mM histidine, 150 mM arginine, 10 mM methionine, and 0.05% polysorbate 80, and differed only in GSH concentration. GSH concentrations tested were 0 mM, 0.5 mM, 1 mM, 2 mM, and 4 mM. Samples were stored at 25°C and 60% relative humidity for up to 4.5 months.

[0139] The data showed that 4 mM GSH had the same effect on HMW reduction as 0.5-2 mM GSH (see Figure 13).

[0140] Example 12: Effect of increasing methionine concentration on HMW This experiment was carried out to evaluate the effect of increasing concentrations of methionine on HMW reduction.

[0141] All formulations tested contained 165 mg / mL aducanumab, 20 mM histidine, 150 mM arginine, and 0.05% polysorbate 80, and differed only in the concentration of methionine or GSH, as shown in Figure 14. Samples were stored at 25°C and 60% relative humidity (top) and 40°C and 75% relative humidity (bottom) for up to 3.5 months.

[0142] This experiment showed that increasing the methionine concentration to 150 mM helped reduce HMW compared to 10 mM methionine.

[0143] Example 13: A 4-week tolerability and toxicokinetic study of BIIB037 when administered by intravenous and subcutaneous injection to cynomolgus monkeys The objective of this study was to determine the tolerability of BIIB037 (150 mg / mL strength, 20 mM histidine buffer [16.2 mM L-histidine monohydrate, 3.8 mM L-histidine free base], 150 mM L-arginine hydrochloride (HCl), 10 mM methionine, 0.05% polysorbate 80, pH 5.5) when given by intravenous (IV) or subcutaneous (SC) injection once weekly for 4 weeks to 3 cynomolgus monkeys per group. In addition, the toxicokinetic properties of the test article were determined.

[0144] Both IV and SC administration of BIIB037 at 300 mg / kg / dose once weekly for 4 weeks (area under the concentration-time curve from time 0 to time t [AUC0-t] on day 22 was 324,000 μg·h / mL and 243,000 μg·h / mL for IV and SC, respectively) did not result in any clinical findings or adverse effects on body weight or food intake. Only one SC-injected animal had SC injection site findings after dosing in weeks 3 and 4, consisting of harmless minimal erythema and / or edema with mild focal neutrophilic or mononuclear cell infiltration and hemorrhage (associated only with the fourth injection site), potentially related to the procedure. The absolute percent bioavailability for AUCτ in SD1 and SD22 ranged from 56.7 to 75.1%, suggesting favorable absorption kinetics after SC administration of aducanumab. A summary of the mean TK parameters is shown in Table 10. [Table 10]

[0145] Other embodiments While the present invention has been described in conjunction with its detailed description, the above description is intended to illustrate but not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. In certain embodiments, for example, the following items are provided: (Item 1) A pharmaceutical composition comprising an anti-beta amyloid (Aβ) antibody or an Aβ-binding fragment thereof and arginine hydrochloride (Arg.HCl), wherein the anti-Aβ antibody or the Aβ-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise: (a) VH-CDR1 consists of the amino acid sequence shown in SEQ ID NO: 1, VH-CDR2 consists of the amino acid sequence shown in SEQ ID NO: 2, VH-CDR3 consists of the amino acid sequence shown in SEQ ID NO: 3; VH complementarity determining regions (CDRs), and (b) VL-CDR1 consists of the amino acid sequence shown in SEQ ID NO: 4, VL-CDR2 consists of the amino acid sequence shown in SEQ ID NO: 5, VL-CDR3 consists of the amino acid sequence shown in SEQ ID NO: 6; VL CDR wherein the pH of the composition is 5.2 to 6.2. (Item 2) 2. The pharmaceutical composition according to item 1, wherein the composition contains the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50 to 250 mg / ml. (Item 3) 2. The pharmaceutical composition according to item 1, wherein the composition contains the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 75 to 165 mg / ml. (Item 4) 2. The pharmaceutical composition of item 1, wherein the composition comprises the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml. (Item 5) 2. The pharmaceutical composition of item 1, wherein the composition comprises the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml. (Item 6) 6. The pharmaceutical composition according to any one of items 1 to 5, wherein the composition comprises Arg.HCl at a concentration of 50 to 250 mM. (Item 7) 6. The pharmaceutical composition according to any one of items 1 to 5, wherein the composition comprises Arg.HCl at a concentration of 75 to 175 mM. (Item 8) 6. The pharmaceutical composition according to any one of items 1 to 5, wherein the composition comprises Arg.HCl at a concentration of 150 mM. (Item 9) 9. The pharmaceutical composition according to any one of items 1 to 8, wherein the composition comprises polysorbate 80 (PS80). (Item 10) 10. The pharmaceutical composition according to item 9, wherein the composition contains PS80 at a concentration of 0.01 to 0.1%. (Item 11) 10. The pharmaceutical composition according to item 9, wherein the composition contains PS80 at a concentration of 0.03 to 0.08%. (Item 12) 10. The pharmaceutical composition of item 9, wherein the composition comprises PS80 at a concentration of 0.05%. (Item 13) 13. The pharmaceutical composition according to any one of items 1 to 12, wherein the composition comprises a buffer selected from the group consisting of histidine, acetate, succinate, and citrate. (Item 14) 14. The pharmaceutical composition according to item 13, wherein the composition comprises histidine, acetate, succinate or citrate at a concentration of 10 to 30 mM. (Item 15) 14. The pharmaceutical composition of claim 13, wherein the composition comprises histidine, acetate, succinate or citrate at a concentration of 20 mM. (Item 16) 14. The pharmaceutical composition of claim 13, wherein the buffering agent is histidine. (Item 17) Item 17. The pharmaceutical composition according to item 16, wherein the concentration of histidine is 10 to 30 mM. (Item 18) 17. The pharmaceutical composition according to item 16, wherein the concentration of histidine is 20 mM. (Item 19) 19. The pharmaceutical composition according to any one of items 1 to 18, wherein the composition comprises methionine. (Item 20) 20. The pharmaceutical composition according to item 19, wherein the concentration of methionine is 0.01 to 150 mM. (Item 21) 20. The pharmaceutical composition according to item 19, wherein the concentration of methionine is 5 to 15 mM. (Item 22) 20. The pharmaceutical composition according to item 19, wherein the concentration of methionine is 10 mM. (Item 23) 23. The pharmaceutical composition according to any one of items 1 to 22, wherein the composition comprises sucrose. (Item 24) 24. The pharmaceutical composition according to item 23, wherein the composition comprises sucrose at a concentration of 0.01 to 3%. (Item 25) 24. The pharmaceutical composition of claim 23, wherein the composition comprises sucrose at a concentration of 3%. (Item 26) 26. The pharmaceutical composition according to any one of items 1 to 25, wherein the pH of the composition is 5.2 to 6.0. (Item 27) 27. The pharmaceutical composition according to any one of items 1 to 26, wherein the pH of the composition is 5.3 to 5.7. (Item 28) The pharmaceutical composition according to any one of items 1 to 27, wherein the pH of the composition is 5.5. (Item 29) the anti-Aβ antibody or the Aβ-binding fragment thereof at a concentration of 50 to 250 mg / ml; Arg.HCl at a concentration of 50-200 mM, methionine at a concentration of 0–150 mM; histidine at a concentration of 10–30 mM; PS80 at a concentration of 0.01 to 0.1%, 0-3% sucrose 2. The pharmaceutical composition according to item 1, wherein the pH of the composition is 5.2 to 6.0. (Item 30) the anti-Aβ antibody or the Aβ-binding fragment thereof at a concentration of 150 mg / ml; Arg.HCl at a concentration of 150 mM, methionine at a concentration of 10 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05% 2. The pharmaceutical composition of claim 1, wherein the pH of the composition is 5.5. (Item 31) the anti-Aβ antibody or the Aβ-binding fragment thereof at a concentration of 100 mg / ml; Arg.HCl at a concentration of 150 mM, methionine at a concentration of 10 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05% 2. The pharmaceutical composition of claim 1, wherein the pH of the composition is 5.5. (Item 32) (i) the VH consists of a sequence that is at least 80% identical to SEQ ID NO: 7 and the VL consists of a sequence that is at least 80% identical to SEQ ID NO: 8; or (ii) the VH consists of a sequence at least 90% identical to SEQ ID NO: 7 and the VL consists of a sequence at least 90% identical to SEQ ID NO: 8; or (iii) the VH consists of the amino acid sequence shown in SEQ ID NO: 7, and the VL consists of the amino acid sequence shown in SEQ ID NO: 8; 32. The pharmaceutical composition according to any one of items 1 to 31. (Item 33) the anti-Aβ antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain; (i) the heavy chain consists of a sequence that is at least 80% identical to SEQ ID NO:9 and the light chain consists of a sequence that is at least 80% identical to SEQ ID NO:10; or (ii) the heavy chain consists of a sequence at least 90% identical to SEQ ID NO: 9 and the light chain consists of a sequence at least 90% identical to SEQ ID NO: 10; or (iii) the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 9, and the light chain consists of the amino acid sequence shown in SEQ ID NO: 10; 33. The pharmaceutical composition according to any one of items 1 to 32. (Item 34) 1. A method of treating abnormal accumulation or deposition of Aβ in the central nervous system in a human subject in need thereof, comprising: Administering the pharmaceutical composition according to any one of items 1 to 33 to the human subject. The method comprising: (Item 35) 1. A method of treating mild cognitive impairment in a human subject in need thereof, comprising: Administering the pharmaceutical composition according to any one of items 1 to 33 to the human subject. The method comprising: (Item 36) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising: Administering the pharmaceutical composition according to any one of items 1 to 33 to the human subject. The method comprising: (Item 37) 37. The method of any one of items 34 to 36, wherein the pharmaceutical composition is administered subcutaneously to the human subject. (Item 38) 37. The method of any one of items 34 to 36, wherein the pharmaceutical composition is administered intravenously to the human subject. (Item 39) A pharmaceutical composition comprising an anti-beta amyloid (Aβ) antibody or an Aβ-binding fragment thereof, a thiol-containing antioxidant, and arginine hydrochloride (Arg.HCl), wherein the anti-Aβ antibody or the Aβ-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise: (a) VH-CDR1 consists of the amino acid sequence shown in SEQ ID NO: 1, VH-CDR2 consists of the amino acid sequence shown in SEQ ID NO: 2, VH-CDR3 consists of the amino acid sequence shown in SEQ ID NO: 3; VH complementarity determining regions (CDRs), and (b) VL-CDR1 consists of the amino acid sequence shown in SEQ ID NO: 4, VL-CDR2 consists of the amino acid sequence shown in SEQ ID NO: 5, VL-CDR3 consists of the amino acid sequence shown in SEQ ID NO: 6; VL CDR wherein the pH of the composition is 5.2 to 6.2. (Item 40) 40. The pharmaceutical composition according to item 39, wherein the composition comprises the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50 to 250 mg / ml. (Item 41) Item 39. The pharmaceutical composition according to Item 39, wherein the composition comprises the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 75 to 165 mg / ml. (Item 42) 40. The pharmaceutical composition of item 39, wherein the composition comprises the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 150 mg / ml. (Item 43) 40. The pharmaceutical composition of item 39, wherein the composition comprises the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 100 mg / ml. (Item 44) 44. The pharmaceutical composition according to any one of items 39 to 43, wherein the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. (Item 45) 45. The pharmaceutical composition of item 44, wherein the thiol-containing antioxidant is GSH. (Item 46) 45. The pharmaceutical composition of item 44, wherein the thiol-containing antioxidant is GSSG. (Item 47) 45. The pharmaceutical composition of item 44, wherein the thiol-containing antioxidant is a combination of GSH and GSSG. (Item 48) 48. The pharmaceutical composition according to any one of items 39 to 47, wherein the concentration of the thiol-containing antioxidant is 0.02 to 4 mM. (Item 49) 48. The pharmaceutical composition according to any one of items 39 to 47, wherein the concentration of the thiol-containing antioxidant is 0.2 mM. (Item 50) 48. The pharmaceutical composition according to any one of items 39 to 47, wherein the concentration of the thiol-containing antioxidant is 0.4 mM. (Item 51) 48. The pharmaceutical composition according to any one of items 39 to 47, wherein the concentration of the thiol-containing antioxidant is 1 mM. (Item 52) 48. The pharmaceutical composition of item 47, wherein the concentration of GSH is 0.4 mM and the concentration of GSSG is 0.2 mM. (Item 53) 45. The pharmaceutical composition of claim 44, wherein the thiol-containing antioxidant is a combination of cysteine ​​and cystine, the concentration of the cysteine ​​is 0.4 mM, and the concentration of the cystine is 0.2 mM. (Item 54) 54. The pharmaceutical composition according to any one of items 39 to 53, wherein the composition comprises Arg.HCl at a concentration of 50 to 250 mM. (Item 55) 54. The pharmaceutical composition according to any one of items 39 to 53, wherein the composition comprises Arg.HCl at a concentration of 75 to 175 mM. (Item 56) 54. The pharmaceutical composition according to any one of items 39 to 53, wherein the composition comprises Arg.HCl at a concentration of 150 mM. (Item 57) 57. The pharmaceutical composition according to any one of items 39 to 56, wherein the composition comprises polysorbate 80 (PS80). (Item 58) 58. The pharmaceutical composition according to item 57, wherein the composition comprises PS80 at a concentration of 0.01 to 0.1%. (Item 59) 58. The pharmaceutical composition according to item 57, wherein the composition comprises PS80 at a concentration of 0.03 to 0.08%. (Item 60) 58. The pharmaceutical composition of item 57, wherein the composition comprises PS80 at a concentration of 0.05%. (Item 61) 61. The pharmaceutical composition according to any one of items 39 to 60, wherein the composition comprises a buffer selected from the group consisting of histidine, acetate, succinate and citrate. (Item 62) 62. The pharmaceutical composition according to item 61, wherein the composition comprises histidine, acetate, succinate or citrate at a concentration of 10 to 30 mM. (Item 63) 62. The pharmaceutical composition of claim 61, wherein the composition comprises histidine, acetate, succinate or citrate at a concentration of 20 mM. (Item 64) 62. The pharmaceutical composition of claim 61, wherein the buffering agent is histidine. (Item 65) Item 65. The pharmaceutical composition according to item 64, wherein the concentration of histidine is 10 to 30 mM. (Item 66) 65. The pharmaceutical composition according to item 64, wherein the concentration of histidine is 20 mM. (Item 67) Item 68. The pharmaceutical composition according to any one of Items 39 to 66, wherein the composition contains sucrose. 68. The pharmaceutical composition according to item 67, wherein the composition comprises sucrose at a concentration of 0.01 to 3%. (Item 69) 68. The pharmaceutical composition according to item 67, wherein the composition comprises sucrose in a concentration of 1 to 3%. (Item 70) 68. The pharmaceutical composition of item 67, wherein the composition comprises sucrose at a concentration of 3%. (Item 71) 71. The pharmaceutical composition according to any one of items 39 to 70, wherein the pH of the composition is 5.2 to 6.0. (Item 72) 71. The pharmaceutical composition according to any one of items 39 to 70, wherein the pH of the composition is 5.3 to 5.7. (Item 73) 71. The pharmaceutical composition according to any one of items 39 to 70, wherein the pH of the composition is 5.5. (Item 74) the anti-Aβ antibody or the Aβ-binding fragment thereof at a concentration of 50 to 250 mg / ml; Arg.HCl at a concentration of 50-200 mM, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM; histidine at a concentration of 10–30 mM; PS80 at a concentration of 0.01 to 0.1%, 0-3% sucrose Item 40. The pharmaceutical composition according to item 39, wherein the pH of the composition is 5.2 to 6.0. (Item 75) the anti-Aβ antibody or the Aβ-binding fragment thereof at a concentration of 150 mg / ml; Arg.HCl at a concentration of 150 mM, a thiol-containing antioxidant at a concentration of 0.02 to 4 mM; histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05% 40. The pharmaceutical composition according to item 39, comprising: (Item 76) the anti-Aβ antibody or the Aβ-binding fragment thereof at a concentration of 100 mg / ml; Arg.HCl at a concentration of 150 mM, a thiol-containing antioxidant at a concentration of 0.02 to 2 mM; histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05% 40. The pharmaceutical composition according to item 39, comprising: (Item 77) 77. The pharmaceutical composition according to any one of items 74 to 76, wherein the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. (Item 78) 78. The pharmaceutical composition of item 77, wherein the thiol-containing antioxidant is GSH. (Item 79) 78. The pharmaceutical composition of item 77, wherein the thiol-containing antioxidant is GSSG. (Item 80) 78. The pharmaceutical composition of item 77, wherein the thiol-containing antioxidant is a combination of GSH and GSSG. (Item 81) 81. The pharmaceutical composition according to any one of items 39 to 80, further comprising methionine. (Item 82) 82. The pharmaceutical composition according to item 81, wherein the concentration of methionine is 0.01 to 150 mM. (Item 83) 82. The pharmaceutical composition according to item 81, wherein the concentration of methionine is 5 to 20 mM. (Item 84) (i) the VH consists of a sequence that is at least 80% identical to SEQ ID NO: 7 and the VL consists of a sequence that is at least 80% identical to SEQ ID NO: 8; or (ii) the VH consists of a sequence at least 90% identical to SEQ ID NO: 7 and the VL consists of a sequence at least 90% identical to SEQ ID NO: 8; or (iii) the VH consists of the amino acid sequence shown in SEQ ID NO: 7, and the VL consists of the amino acid sequence shown in SEQ ID NO: 8; The pharmaceutical composition according to any one of items 39 to 83. (Item 85) the anti-Aβ antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain; (i) the heavy chain consists of a sequence that is at least 80% identical to SEQ ID NO:9 and the light chain consists of a sequence that is at least 80% identical to SEQ ID NO:10; or (ii) the heavy chain consists of a sequence at least 90% identical to SEQ ID NO: 9 and the light chain consists of a sequence at least 90% identical to SEQ ID NO: 10; or (iii) the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 9, and the light chain consists of the amino acid sequence shown in SEQ ID NO: 10; 85. The pharmaceutical composition according to any one of items 39 to 84. (Item 86) 1. A method of treating abnormal accumulation or deposition of Aβ in the central nervous system in a human subject in need thereof, comprising: Administering the pharmaceutical composition according to any one of items 39 to 85 to the human subject. The method comprising: (Item 87) 1. A method of treating mild cognitive impairment in a human subject in need thereof, comprising: Administering the pharmaceutical composition according to any one of items 39 to 85 to the human subject. The method comprising: (Item 88) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising: Administering the pharmaceutical composition according to any one of items 39 to 85 to the human subject. The method comprising: (Item 89) 89. The method of any one of items 86 to 88, wherein the pharmaceutical composition is administered subcutaneously to the human subject. (Item 90) 89. The method of any one of items 86 to 88, wherein the pharmaceutical composition is administered intravenously to the human subject.

Claims

[Claim 1] The invention as set forth in the drawings.

Images