WO2025237397A1 - 抗N3pGlu Aβ抗体及其医药用途 - Google Patents

抗N3pGlu Aβ抗体及其医药用途

Info

Publication number
WO2025237397A1
WO2025237397A1 PCT/CN2025/095336 CN2025095336W WO2025237397A1 WO 2025237397 A1 WO2025237397 A1 WO 2025237397A1 CN 2025095336 W CN2025095336 W CN 2025095336W WO 2025237397 A1 WO2025237397 A1 WO 2025237397A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
variable region
chain variable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/095336
Other languages
English (en)
French (fr)
Inventor
曾芳
赵杰
金薪盛
张聃
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Original Assignee
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Hengrui Pharmaceutical Co Ltd, Jiangsu Hengrui Pharmaceutical Co Ltd filed Critical Shanghai Hengrui Pharmaceutical Co Ltd
Publication of WO2025237397A1 publication Critical patent/WO2025237397A1/zh
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies

Definitions

  • This disclosure pertains to the field of biotechnology, and more specifically, to anti-N3pGlu A ⁇ antibodies and their pharmaceutical uses.
  • AD Alzheimer's disease
  • senile dementia is a serious neurodegenerative disease. Its main clinical manifestations are cognitive decline, mental symptoms, and behavioral disorders, with severe cases resulting in the loss of basic living abilities. It is generally believed that the deposition of ⁇ -amyloid protein (A ⁇ ) triggers neurofibrillary tangles, leading to a reduction in synapses between nerve cells, cell death, and cognitive decline (Corbett A, et al. Nature reviews. Drug discovery, 2012, 11(11):833–846). However, the causes of A ⁇ deposition and the mechanisms by which A ⁇ deposition damages nerve cells remain unclear.
  • a ⁇ ⁇ -amyloid protein
  • Brain plaques are one of the most important pathological features of Alzheimer's disease. N3pGlu A ⁇ peptides are mainly found in brain plaques, and the formation of N-terminal modified peptides may enhance ⁇ -amyloid protein aggregation and toxicity, thus worsening the occurrence and progression of the disease. (Russo C, et al. Journal of neurochemistry, 2002, 82(6):1480–1489; Piccini A, et al. The Journal of biological chemistry, 2005, 280(40):34186–34192). Anti-N3pGlu A ⁇ antibodies can specifically clear brain plaques in Alzheimer's disease patients, more efficiently and rapidly clearing A ⁇ deposits and treating Alzheimer's disease.
  • Patents such as WO2012021469A1, WO2017009459A2, WO2018194951A1, WO2018083628A1, WO2019149689A1, and WO2020193644A1 disclose anti-N3pGlu A ⁇ antibodies.
  • This disclosure provides an anti-N3pGlu A ⁇ antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein:
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 229
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 230
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 231
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 232
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6, wherein:
  • X1 is Y, K, or H;
  • X2 is M or Q;
  • X3 is A or G;
  • X 8 is D, E, Q, L, or S
  • X 9 is D, E, L, Y, or G
  • X 10 is N, Y, S, or T; X 11 is G or V; or
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 233
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 234
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16;
  • X 17 is D or E; X 18 is D or E.
  • This disclosure provides an anti-N3pGlu A ⁇ antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein:
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 17, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 18; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 119, 100, 102, 104, 122, 99, 101, 103, 117, 118, 120, 121, 123, 124, 125, 126, 127, or 128, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 97 or 98; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 19, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 20; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 141, 132, 133, 137, 134, 138, 139, or 140, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 129, 131, or 130; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 21, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 22.
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 88, 42, 45, 69, 78, 79, 80, or 91
  • the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 66, 37, 38, 39, or 65; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 17, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 18; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 119, 100, 102, 104, or 122, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 97; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 19, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 20; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 141, 132, 133, or 137, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 129 or 131; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 21, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 22.
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 88, 69, 78, 79, 80, or 91
  • the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 66; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 88 or 42, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 37; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 45, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 38; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 42 or 69
  • the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 39; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 17, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 18; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 43, 44, 45, or 46, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 37; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 42, 43, 44, or 46, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 38; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 43, 44, 45, 46, 67, 68, 70, 71, 72, 73, 74, 75, 76, or 77, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 39; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 42, 43, 44, 45, or 46, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 40; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 42, 43, 44, 45, or 46, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 41; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 45, 46, or 69, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 63; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 45, 46, or 69, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 64; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 45 or 46, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 65; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 45, 46, 81, 82, 83, 84, 85, 86, 87, 89, 90, 92, or 93, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 66; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 119, 110, 102, 104, or 122, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 97; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 19, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 20; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 99, 101, 103, 117, 118, 120, 121, 123, 124, 125, 126, 127, or 128, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 97; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 99, 100, 101, 102, 103, 104, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, or 128, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 98; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 141, 132, 133, or 137, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 129; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 133
  • the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 131; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 21, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 22; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 134, 138, 139, or 140, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 129; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 132, 133, 134, 137, 138, 139, 140, or 141, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 130; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 132, 134, 137, 138, 139, 140, or 141, and the light chain variable regions LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 131.
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 88, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 66; or
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 119, and the light chain variable regions LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2, and LCDR3 in SEQ ID NO: 97; or
  • the heavy chain variable regions HCDR1, HCDR2 and HCDR3 respectively contain the amino acid sequences of HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 141, and the light chain variable regions LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 129.
  • the HCDR1, HCDR2, and HCDR3 of the heavy chain variable regions and the LCDR1, LCDR2, and LCDR3 of the light chain variable regions are defined according to a numbering rule selected from Kabat, IMGT, Chothia, AbM, and Contact.
  • the HCDR1, HCDR2, and HCDR3 of the heavy chain variable regions and the LCDR1, LCDR2, and LCDR3 of the light chain variable regions are defined according to the Kabat numbering rule.
  • the HCDR1, HCDR2, and HCDR3 of the heavy chain variable regions and the LCDR1, LCDR2, and LCDR3 of the light chain variable regions are defined according to the IMGT numbering rule. In some embodiments, the HCDR1, HCDR2, and HCDR3 of the heavy chain variable regions and the LCDR1, LCDR2, and LCDR3 of the light chain variable regions are defined according to the Chothia numbering rule. In some embodiments, the heavy chain variable regions HCDR1, HCDR2, and HCDR3, and the light chain variable regions LCDR1, LCDR2, and LCDR3, are defined according to the AbM numbering rules. In some embodiments, the heavy chain variable regions HCDR1, HCDR2, and HCDR3, and the light chain variable regions LCDR1, LCDR2, and LCDR3, are defined according to the Contact numbering rules.
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49, 1, 35, 47 or 48
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52, 2, 36, 53, 50 or 51
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54, 3, 58, 55, 56, 57, 59, 60, 61 or 62
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32, 4, 31, 33 or 34
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6; or
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 107, 8, 94, 96, 110, 95, 105, 106, 108, 109, 111, 112, 113, 114, 115, or 116
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10; or
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 136, 13, or 135
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49 or 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52, 2, 36 or 53
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54, 3 or 58
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32, 4 or 31
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6; or
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 107, 8, 94, 96, or 110
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 136, 13 or 135
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16.
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 4
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 31
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 53
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 53
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 58
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 4
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1 or 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 4
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1 or 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 31
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 31
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36, 50, or 51
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2 or 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 47
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36, 50 or 51
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 48
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36, 50 or 51
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 55, 56, 57, 58, 59, 60, or 61
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6; or
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 50 or 51
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 58 or 62
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 53
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54 or 62
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1 or 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 33
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1 or 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 33
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1 or 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 34
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1 or 35
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 34
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 107
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 8
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 94
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 96
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 110
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 95, 105, 106, 108, 109, 111, 112, 113, 114, 115, or 116
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10; or
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 136
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 13
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 135
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16.
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52 or 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52, 36 or 53
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 53
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 58
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 4
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 31
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 136, 13 or 135
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16.
  • the anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments is a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody.
  • the anti-N3pGlu A ⁇ antibody is a murine antibody, a chimeric antibody, or a humanized antibody.
  • the anti-N3pGlu A ⁇ antibody is a chimeric antibody or a humanized antibody.
  • the anti-N3pGlu A ⁇ antibody is a chimeric antibody.
  • the anti-N3pGlu A ⁇ antibody is a humanized antibody.
  • the antibody includes the frame region (FR) of the human antibody.
  • the heavy chain variable region has FR1, FR2, FR3 derived from IGHV3-7*01 and FR4 derived from IGHJ6*01, and is unsubstituted or contains one or more amino acid substitutions selected from the group consisting of 3K, 30R, 45P, and 93V; and/or the light chain variable region has FR1, FR2, FR3 derived from IGKV2-40*01, IGKV4-1*01, IGKV3-20*01, or IGKV1-39*01 and FR4 derived from IGKJ4*01, and is unsubstituted or contains one or more amino acid substitutions selected from the group consisting of 2V, 43S, and 45K.
  • the anti-N3pGlu A ⁇ antibody wherein the heavy chain variable region HCDR1 comprises the amino acid sequence of SEQ ID NO: 49, 1, 35, 47 or 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 52, 2, 36, 53, 50 or 51, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 54, 3, 58, 55, 56, 57, 59, 60, 61 or 62, and the FR of the heavy chain variable region is unsubstituted.
  • the heavy chain variable region HCDR1 comprises the amino acid sequence of SEQ ID NO: 49, 1, 35, 47 or 48
  • HCDR2 comprises the amino acid sequence of SEQ ID NO: 52, 2, 36, 53, 50 or 51
  • HCDR3 comprises the amino acid sequence of SEQ ID NO: 54, 3, 58, 55, 56, 57, 59, 60, 61 or 62, and the FR of the heavy chain variable region is unsubstituted.
  • variable region of the light chain contains one or more amino acid substitutions selected from the group consisting of 3K, 30R, 45P, and 93V; and the LCDR1 of the light chain variable region contains the amino acid sequence of SEQ ID NO: 32, 4, 31, 33, or 34, the LCDR2 contains the amino acid sequence of SEQ ID NO: 5, and the LCDR3 contains the amino acid sequence of SEQ ID NO: 6, and the FR of the light chain variable region is unsubstituted or contains one or more amino acid substitutions selected from the group consisting of 2V, 43S, and 45K.
  • the above-mentioned variable regions and CDRs are defined according to the Kabat numbering rules.
  • the heavy chain variable region has FR1, FR2, FR3 derived from IGHV3-7*01 and FR4 derived from IGHJ6*01, and is unsubstituted or contains one or more amino acid substitutions selected from the group consisting of 28S, 45P, and 76K; and/or the light chain variable region has FR1, FR2, FR3 derived from IGKV2-29*02 and FR4 derived from IGKJ4*01, and is unsubstituted or contains one or more amino acid substitutions selected from the group consisting of 2V and 45K.
  • the anti-N3pGlu A ⁇ antibody wherein the heavy chain variable region HCDR1 comprises the amino acid sequence of SEQ ID NO: 1, HCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 107, 8, 94, 96, 110, 95, 105, 106, 108, 109, 111, 112, 113, 114, 115, or 116, and the FR of the heavy chain variable region is unsubstituted or comprises one or more amino acid substitutions selected from the group consisting of 28S, 45P, and 76K; and the light chain variable region LCDR1 comprises the amino acid sequence of SEQ ID NO: 9, LCDR2 comprises the amino acid sequence of SEQ ID NO: 5, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 10, and the FR of the light chain variable region is unsubstituted or comprises one or more amino acid substitutions selected from the group consisting of 2V and 45K.
  • the heavy chain variable region has FR1, FR2, FR3 derived from IGHV3-21*01 and FR4 derived from IGHJ6*01, and is either unsubstituted or contains one or more amino acid substitutions selected from the group consisting of 28I, 40T, 42D, 44R, 49A, and 93G; and/or the light chain variable region has FR1, FR2, FR3 derived from IGKV4-1*01 and FR4 derived from IGKJ4*01, and is either unsubstituted or contains one or more amino acid substitutions selected from the group consisting of 4L, 58I, 68R, and 85T.
  • the anti-N3pGlu A ⁇ antibody wherein the heavy chain variable region HCDR1 comprises the amino acid sequence of SEQ ID NO: 11, HCDR2 comprises the amino acid sequence of SEQ ID NO: 12, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 136, 13, or 135, and the FR of the heavy chain variable region is unsubstituted or comprises one or more amino acid substitutions selected from the group consisting of 28I, 40T, 42D, 44R, 49A, and 93G; and the light chain variable region LCDR1 comprises the amino acid sequence of SEQ ID NO: 14, LCDR2 comprises the amino acid sequence of SEQ ID NO: 15, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 16, and the FR of the light chain variable region is unsubstituted or comprises one or more amino acid substitutions selected from the group consisting of 4L, 58I, 68R, and 85T.
  • the above-mentioned variable regions and CDRs are defined according to the Kab
  • the heavy chain variable region comprises having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%) of SEQ ID NO: 88, 42, 45, 69, 78, 79, 80, 91, 43, 44, 46, 67, 68, 70, 71, 72, 73, 74, 75, 76, 77, 81, 82, 83, 84, 85, 86, 87, 89, 90, 92 or 93)
  • An amino acid sequence having at least 75% e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 66, 37, 38, 39, 65, 40, 41, 63, or 64; or
  • the heavy chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 17, and the light chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 18; or
  • the heavy chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 119, 100, 102, 104, 122, 99, 101, 103, 117, 118, 120, 121, 123, 124, 125, 126, 127, or 128) sequence identity, and the light chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 97 or 98; or
  • the heavy chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 19, and the light chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 20; or
  • the heavy chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 141, 132, 133, 137, 134, 138, 139, or 140, and the light chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 129, 131, or 130; or
  • the heavy chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 21, and the light chain variable region comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 22.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88, 42, 45, 69, 78, 79, 80, 91, 43, 44, 46, 67, 68, 70, 71, 72, 73, 74, 75, 76, 77, 81, 82, 83, 84, 85, 86, 87, 89, 90, 92 or 93, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66, 37, 38, 39, 65, 40, 41, 63 or 64; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 17, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 18; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 119, 100, 102, 104, 122, 99, 101, 103, 117, 118, 120, 121, 123, 124, 125, 126, 127 or 128, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97 or 98; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 19, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 20; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 141, 132, 133, 137, 134, 138, 139 or 140, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129, 131 or 130; or
  • the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 21, and the light chain variable region contains the amino acid sequence of SEQ ID NO: 22.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88, 42, 45, 69, 78, 79, 80 or 91, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66, 37, 38, 39 or 65; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 17, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 18; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 119, 100, 102, 104 or 122, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 19, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 20; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 141, 132, 133 or 137, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129 or 131; or
  • the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 21, and the light chain variable region contains the amino acid sequence of SEQ ID NO: 22.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 17, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 18; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 37; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 45, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 38; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 39; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 39; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 65; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 79, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 91, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 43, 44, 45 or 46, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 37; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42, 43, 44 or 46, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 38; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 43, 44, 45, 46, 67, 68, 70, 71, 72, 73, 74, 75, 76 or 77, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 39; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42, 43, 44, 45 or 46, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 40; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42, 43, 44, 45 or 46, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 41; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 45, 46, or 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 63; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 45, 46, or 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 64; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 45 or 46, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 65; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 45, 46, 81, 82, 83, 84, 85, 86, 87, 89, 90, 92 or 93, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 119, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 19, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 20; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 99, 101, 103, 117, 118, 120, 121, 123, 124, 125, 126, 127 or 128, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 99, 100, 101, 102, 103, 104, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127 or 128, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 98; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 141, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 21, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 22; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 133, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 137, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 133, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 131; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 134, 138, 139 or 140, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132, 133, 134, 137, 138, 139, 140 or 141, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 130; or
  • the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 132, 134, 137, 138, 139, 140 or 141, and the light chain variable region contains the amino acid sequence of SEQ ID NO: 131.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88, 69, 78, 79, 80 or 91, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 37; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 45, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 38; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42 or 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 39; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 65; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 17, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 18; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 119, 100, 102, 104 or 122, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 19, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 20; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 141, 132, 133 or 137, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 133, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 131; or
  • the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 21, and the light chain variable region contains the amino acid sequence of SEQ ID NO: 22.
  • the anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments is an antigen-binding fragment (antibody fragment).
  • the anti-N3pGlu A ⁇ antigen-binding fragment (antibody fragment) is selected from Fab, Fab′, F(ab′)2, Fd, Fv, scFv, and dsFv.
  • the anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments, wherein the antibody comprises a heavy chain constant region and a light chain constant region.
  • the heavy chain constant region is a heavy chain constant region of human IgG1, IgG2, IgG3, IgG4 or variants thereof, or mouse mIgG2a or variants thereof
  • the light chain constant region is a light chain constant region of human ⁇ chain, ⁇ chain or variants thereof, or mouse ⁇ chain, ⁇ chain or variants thereof.
  • the heavy chain constant region is a heavy chain constant region of human IgG1, IgG2, IgG3, IgG4 or variants thereof, and the light chain constant region is a light chain constant region of human ⁇ chain, ⁇ chain or variants thereof.
  • the heavy chain constant region is a heavy chain constant region of human IgG1 or mouse mIgG2a, and the light chain constant region is a light chain constant region of human ⁇ chain or mouse ⁇ chain.
  • the heavy chain constant region is a mouse mIgG2a heavy chain constant region, and the light chain constant region is a mouse ⁇ light chain constant region.
  • the heavy chain constant region is the human IgG1 heavy chain constant region, and the light chain constant region is the human ⁇ light chain constant region.
  • the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 23 or 225, and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 24 or 226.
  • the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 225, and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 226.
  • the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 23, and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 24.
  • the anti-N3pGlu A ⁇ antibody comprises a heavy chain and a light chain, wherein:
  • the heavy chain comprises having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 90%) of SEQ ID NO: 169, 143, 146, 150, 159, 160, 161, 172, 144, 145, 147, 148, 149, 151, 152, 153, 154, 155, 156, 157, 158, 162, 163, 164, 165, 166, 167, 168, 170, 171, 173 or 174)
  • An amino acid sequence having at least 75% e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 183, 175, 176, 177, 182, 178, 179, 180, or 181; or
  • the heavy chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 25, and the light chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 26; or
  • the heavy chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 219, and the light chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 220; or
  • the heavy chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 192, 185, 187, 189, 195, 184, 186, 188, 198, 199, 200, or 201) sequence identity, and the light chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 202 or 203; or
  • the heavy chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 27, and the light chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 28; or
  • the heavy chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 221, and the light chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 222; or
  • the heavy chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 211, 204, 205, 207, 206, 208, 209, or 210, and the light chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 212, 214, or 213; or
  • the heavy chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 29, and the light chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 30; or
  • the heavy chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 223, and the light chain comprises an amino acid sequence having at least 75% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 224;
  • the heavy chain comprises the amino acid sequence SEQ ID NO: 169, 143, 146, 150, 159, 160, 161, 172, 144, 145, 147, 148, 149, 151, 152, 153, 154, 155, 156, 157, 158, 162, 163, 164, 165, 166, 167, 168, 170, 171, 173 or 174, and the light chain comprises the amino acid sequence SEQ ID NO: 183, 175, 176, 177, 182, 178, 179, 180 or 181; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 25, and the light chain comprises the amino acid sequence of SEQ ID NO: 26; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 219, and the light chain comprises the amino acid sequence of SEQ ID NO: 220; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 192, 185, 187, 189, 195, 184, 186, 188, 190, 191, 193, 194, 196, 197, 198, 199, 200 or 201, and the light chain comprises the amino acid sequence of SEQ ID NO: 202 or 203; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 27, and the light chain comprises the amino acid sequence of SEQ ID NO: 28; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 221, and the light chain comprises the amino acid sequence of SEQ ID NO: 222; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 211, 204, 205, 207, 206, 208, 209 or 210, and the light chain comprises the amino acid sequence of SEQ ID NO: 212, 214 or 213; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 29, and the light chain comprises the amino acid sequence of SEQ ID NO: 30; or
  • the heavy chain contains the amino acid sequence of SEQ ID NO: 223, and the light chain contains the amino acid sequence of SEQ ID NO: 224.
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 169, 143, 146, 150, 159, 160, 161 or 172, and the light chain comprises the amino acid sequence of SEQ ID NO: 183, 175, 176, 177 or 182; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 25, and the light chain comprises the amino acid sequence of SEQ ID NO: 26; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 219, and the light chain comprises the amino acid sequence of SEQ ID NO: 220; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 192, 185, 187, 189 or 195, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 27, and the light chain comprises the amino acid sequence of SEQ ID NO: 28; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 221, and the light chain comprises the amino acid sequence of SEQ ID NO: 222; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 211, 204, 205 or 207, and the light chain comprises the amino acid sequence of SEQ ID NO: 212 or 214; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 29, and the light chain comprises the amino acid sequence of SEQ ID NO: 30; or
  • the heavy chain contains the amino acid sequence of SEQ ID NO: 223, and the light chain contains the amino acid sequence of SEQ ID NO: 224.
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 169, 150, 159, 160, 161 or 172, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 25, and the light chain comprises the amino acid sequence of SEQ ID NO: 26; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 143, and the light chain comprises the amino acid sequence of SEQ ID NO: 175; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 146, and the light chain comprises the amino acid sequence of SEQ ID NO: 176; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 143 or 150, and the light chain comprises the amino acid sequence of SEQ ID NO: 177; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 150, and the light chain comprises the amino acid sequence of SEQ ID NO: 182; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 219, and the light chain comprises the amino acid sequence of SEQ ID NO: 220; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 192, 185, 187, 189 or 195, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 27, and the light chain comprises the amino acid sequence of SEQ ID NO: 28; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 221, and the light chain comprises the amino acid sequence of SEQ ID NO: 222; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 211, 204, 205 or 207, and the light chain comprises the amino acid sequence of SEQ ID NO: 212; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 29, and the light chain comprises the amino acid sequence of SEQ ID NO: 30; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 205, and the light chain comprises the amino acid sequence of SEQ ID NO: 214; or
  • this disclosure provides a multispecific antibody comprising an anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments.
  • the multispecific antibody is a bispecific antibody.
  • the multispecific antibody further comprises an antibody that binds to a blood-brain barrier receptor.
  • the multispecific antibody is a bispecific antibody that binds to both N3pGlu A ⁇ and a blood-brain barrier receptor.
  • this disclosure provides an anti-N3pGlu A ⁇ antibody that competes with the anti-N3pGlu A ⁇ antibody or the multispecific antibody as described in any of the preceding claims for binding to human N3pGlu A ⁇ .
  • this disclosure provides an anti-N3pGlu A ⁇ antibody that binds to the same N3pGlu A ⁇ antigenic epitope as the anti-N3pGlu A ⁇ antibody or the multispecific antibody as described in any of the preceding claims.
  • this disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising an anti-N3pGlu A ⁇ antibody as described in any of the preceding claims or a multispecific antibody as described in any of the preceding claims, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the pharmaceutical composition contains 0.01-99.99% of the anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments. In some embodiments, the pharmaceutical composition contains 1%-99% of the anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments. In some embodiments, the pharmaceutical composition contains 2%-98% of the anti-N3pGlu A ⁇ antibody as described in any of the preceding embodiments.
  • the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable carriers, diluents, or excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable carriers, diluents, or excipients.
  • this disclosure provides an isolated nucleic acid that encodes an anti-N3pGlu A ⁇ antibody as described in any of the preceding claims or a multispecific antibody as described in any of the preceding claims.
  • this disclosure provides a carrier containing isolated nucleic acids as described in any of the preceding claims.
  • this disclosure provides a host cell comprising the isolated nucleic acid as described in any of the preceding claims or the vector as described in any of the preceding claims.
  • the host cell comprises the isolated nucleic acid as described in any of the preceding claims.
  • the host cell comprises the vector as described in any of the preceding claims.
  • this disclosure provides a method for producing an anti-N3pGlu A ⁇ antibody or a multispecific antibody as described in any of the preceding claims, the method comprising culturing a host cell as described in any of the preceding claims in a culture medium to form and accumulate an anti-N3pGlu A ⁇ antibody or a multispecific antibody as described in any of the preceding claims, and recovering the antibody from the culture.
  • this disclosure provides the use of the anti-N3pGlu A ⁇ antibody as described in any of the preceding claims, or the multispecific antibody as described in any of the preceding claims, or the pharmaceutical composition as described in any of the preceding claims, in the preparation of a medicament for the treatment or prevention of diseases or conditions related to N3pGlu A ⁇ .
  • this disclosure provides a method for treating or preventing diseases or conditions associated with N3pGlu A ⁇ , the method comprising administering to a subject a therapeutically or preventively effective amount of an anti-N3pGlu A ⁇ antibody as described in any of the preceding claims, or a multispecific antibody as described in any of the preceding claims, or a pharmaceutical composition as described in any of the preceding claims.
  • this disclosure provides an anti-N3pGlu A ⁇ antibody as described in any of the preceding claims, or a multispecific antibody as described in any of the preceding claims, or a pharmaceutical composition as described in any of the preceding claims, for use as a medicament.
  • the medicament is a medicine for treating or preventing diseases or conditions related to N3pGlu A ⁇ .
  • the disease or condition associated with N3pGlu A ⁇ is a neurological disease, a degenerative disease, or a cerebrovascular disease.
  • the disease or condition associated with N3pGlu A ⁇ is Alzheimer's disease, cognitive impairment, or cerebral amyloid angiopathy.
  • the disease or condition associated with N3pGlu A ⁇ is Alzheimer's disease.
  • the anti-N3pGlu A ⁇ antibody provided in this disclosure binds to N3pGlu-42 A ⁇ fibers with an EC50 value of less than 15 nM (e.g., less than 12 nM, less than 10 nM, less than 8 nM, less than 6 nM, less than 4 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, less than 0.05 nM, less than 0.01 nM), said EC50 value being measured by ELISA.
  • 15 nM e.g., less than 12 nM, less than 10 nM, less than 8 nM, less than 6 nM, less than 4 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, less than 0.05 nM, less than 0.01 nM
  • said EC50 value being measured by ELISA.
  • the anti-N3pGlu A ⁇ antibody provided in this disclosure binds to the N3pGlu-40 A ⁇ monomer with an EC50 value of less than 15 nM (e.g., less than 12 nM, less than 10 nM, less than 8 nM, less than 6 nM, less than 4 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, less than 0.05 nM, less than 0.01 nM), said EC50 value being measured by ELISA.
  • nM e.g., less than 12 nM, less than 10 nM, less than 8 nM, less than 6 nM, less than 4 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, less than 0.05 nM, less than 0.01 nM
  • the anti-N3pGlu A ⁇ antibody provided in this disclosure binds to the N3pGlu-42 A ⁇ monomer with an EC50 value of less than 15 nM (e.g., less than 12 nM, less than 10 nM, less than 8 nM, less than 6 nM, less than 4 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, less than 0.05 nM, less than 0.01 nM), said EC50 value being measured by ELISA.
  • nM e.g., less than 12 nM, less than 10 nM, less than 8 nM, less than 6 nM, less than 4 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, less than 0.05 nM, less than 0.01 nM
  • the anti-N3pGlu A ⁇ antibody provided in this disclosure binds to the N3pGlu-42 A ⁇ monomer with a KD value of less than 1E-07M (e.g., less than 5E-08M, less than 1E-08M, less than 5E-09M, less than 1E-09M, less than 5E-10M, less than 1E-10M, less than 5E-11M, less than 1E-11M, less than 5E-12M, less than 1E-12nM), said KD value being measured by Biacore.
  • KD value being measured by Biacore.
  • the anti-N3pGlu A ⁇ antibody provided in this disclosure binds to N3pGlu-42 A ⁇ fibers with a KD value less than 1E-07M (e.g., less than 5E-08M, less than 1E-08M, less than 5E-09M, less than 1E-09M, less than 5E-10M, less than 1E-10M, less than 5E-11M, less than 1E-11M, less than 5E-12M, less than 1E-12nM), said KD value being measured by Biacore.
  • KD value less than 1E-07M (e.g., less than 5E-08M, less than 1E-08M, less than 5E-09M, less than 1E-09M, less than 5E-10M, less than 1E-10M, less than 5E-11M, less than 1E-11M, less than 5E-12M, less than 1E-12nM)
  • the anti-N3pGlu A ⁇ antibody provided in this disclosure is able to block the formation of fibrils from N3pGlu-42 A ⁇ monomers, and the blocking activity is stronger than that of a control antibody (e.g., Remternetug).
  • a control antibody e.g., Remternetug
  • the anti-N3pGlu A ⁇ antibody provided in this disclosure is capable of mediating the phagocytosis of N3pGlu-42A ⁇ fibers by BV2 cells, with the phagocytic activity being stronger than that of a control antibody (e.g., Donanemab).
  • a control antibody e.g., Donanemab
  • a ⁇ also known as “amyloid protein ⁇ ,” “ ⁇ -amyloid protein,” “amyloid ⁇ ,” “ ⁇ -amyloid protein,” and “Abeta,” refers to the fragments generated from amyloid precursor protein (APP) after cleavage by ⁇ -secretase 1 (BACE1), as well as its modified fragments and any functional equivalents, including but not limited to N3pGlu A ⁇ , A ⁇ 1-40, and A ⁇ 1-42.
  • a ⁇ is known to exist as monomers, as well as in combination to form oligomers, protofibrils, fibrils, or plaques.
  • N3pGlu A ⁇ refers to an A ⁇ peptide in which the glutamate at the N-terminus of the A ⁇ peptide is pyroglutamicized, and its written forms include, but are not limited to, N3pE A ⁇ , 3pE A ⁇ , 3pGlu A ⁇ , pGlu3 A ⁇ , and pE3 A ⁇ .
  • N3pGlu A ⁇ includes truncated forms of the A ⁇ peptide, including, but not limited to, N3pGlu-42 A ⁇ and N3pGlu-40 A ⁇ .
  • the N3pGlu A ⁇ used in this disclosure lacks the first two amino acid residues (aspartic acid and alanine) at the N-terminus of the A ⁇ peptide and undergoes pyroglutamicization at the glutamate at the N-terminus of the A ⁇ peptide.
  • This N3pGlu A ⁇ is more prone to aggregation and is present in Alzheimer's amyloid deposits.
  • central nervous system refers to a complex of neural tissues that control bodily functions and includes the brain and spinal cord.
  • blood-brain barrier refers to the physiological barrier between the peripheral circulation and the brain and spinal cord. It consists of tight junctions of the brain capillary endothelial plasma membranes, forming an extremely tight barrier that restricts the transport of molecules into the brain, even very small molecules such as urea (60 Da).
  • the blood-brain barrier within the brain, the blood-spinal cord barrier within the spinal cord, and the blood-retinal barrier within the retina are the continuous capillary barriers within the central nervous system, collectively known as the blood-brain barrier.
  • the blood-brain barrier also includes the blood-cerebrospinal fluid barrier (choroid plexus), which is composed of ependymal cells rather than capillary endothelial cells.
  • blood-brain barrier receptor refers to a class of extracellular membrane-linked receptor proteins expressed on brain endothelial cells that can transport molecules across the blood-brain barrier or be used to transport molecules administered exogenously.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimics that function in a manner similar to naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those that are subsequently modified, such as hydroxyproline, ⁇ -carboxyglutamic acid, and O-phosphoserine.
  • Amino acid analogs are compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., the ⁇ -carbon bound to hydrogen, carboxyl, amino, and R groups), such as homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium.
  • analogs have modified R groups (e.g., ortholeucine) or modified peptide backbones but retain the same basic chemical structure as naturally occurring amino acids.
  • Amino acid mimics are chemical compounds that have a structure different from the general chemical structure of amino acids but function in a manner similar to naturally occurring amino acids.
  • amino acid mutation includes amino acid substitution (also known as amino acid replacement), deletion, insertion, and modification. Any combination of substitution, deletion, insertion, and modification can be performed to achieve the final construct, provided that the final construct possesses the desired properties, such as reduced or absent binding to Fc receptors.
  • Amino acid sequence deletions and insertions include deletions and insertions at the amino and/or carboxyl ends of the polypeptide chain.
  • a specific amino acid mutation can be an amino acid substitution.
  • an amino acid mutation is a non-conservative amino acid substitution, i.e., replacing one amino acid with another amino acid that has a different structure and/or chemical properties.
  • Amino acid substitution includes substitution by non-naturally occurring amino acids or by derivatives of 20 naturally occurring amino acids (e.g., 4-hydroxyproline, 3-methylhistidine, ornithine, homoserine, 5-hydroxylysine).
  • Amino acid mutations can be generated using genetic or chemical methods known in the art. Genetic methods can include site-directed mutagenesis, PCR, gene synthesis, etc. Methods other than genetic engineering that alter amino acid side chain groups, such as chemical modification, are also expected to be available. Various names may be used herein to refer to the same amino acid mutation.
  • the amino acid residue at a specific site can be represented by the format "position + amino acid residue". For example, 356K indicates that the amino acid residue at position 356 is K.
  • D356K indicates that the amino acid residue at position 356 has mutated from D to K. It should be understood that when the amino acid sequence is defined by the format "position + residue" in the claims, the amino acid before the mutation at that site does not constitute a limitation on the technical solution.
  • peptide and protein are used interchangeably herein to refer to polymers of amino acid residues.
  • the term applies to amino acid polymers, where one or more amino acid residues are artificial chemical mimics of the corresponding naturally occurring amino acids, as well as to both naturally occurring and non-naturally occurring amino acid polymers. Unless otherwise stated, a particular peptide sequence also implicitly encompasses variants with conserved modifications.
  • antibody is used in the broadest sense and covers a wide range of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies); full-length antibodies and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity.
  • antigen-binding fragment encompasses full-length antibodies, Fab, modified Fab, Fab', Fab'-SH, modified Fab', F(ab')2, Fv, dsFv, Fab-Fv, Fab-dsFv, Fd, single-domain antibodies (sdAb, e.g., VH, VL, or VHH), single-chain Fab (scFab), single-chain antibodies (e.g., scFv, sc(Fv)2), biantibodies, linear antibodies, bivalent, trivalent, or tetravalent antibodies, Bis-scFv, diabody, tribody, triabody, tetrabody, and epitope-binding fragments of any of the above. Methods for generating and preparing these antigen-binding fragments are well known in the art.
  • Natural antibodies refer to naturally occurring immunoglobulin molecules.
  • natural IgG antibodies are heterotetraglycoproteins of approximately 150,000 Daltons, composed of two light chains and two heavy chains linked by disulfide bonds.
  • VH variable region
  • heavy chain constant region typically contains three constant domains (CH1, CH2, and CH3).
  • VL variable region
  • CL constant light domain
  • full-length antibody “intact antibody,” and “complete antibody” are used interchangeably in this document, referring to antibodies with a structure substantially similar to that of natural antibodies or with a heavy chain containing the Fc region as defined herein.
  • the light chain of a natural intact antibody includes a variable region (VL) and a constant region (CL), with VL located at the amino terminus of the light chain.
  • the constant region includes the ⁇ and ⁇ chains.
  • the heavy chain includes a variable region (VH) and constant regions (CH1, CH2, and CH3), with VH located at the amino terminus of the heavy chain and the constant region located at the carboxyl terminus. CH3 is closest to the carboxyl terminus of the polypeptide.
  • the heavy chain can belong to any isotype, including IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgM, and IgE.
  • IgG including IgG1, IgG2, IgG3, and IgG4 subtypes
  • IgA including IgA1 and IgA2 subtypes
  • IgM IgE.
  • Fc region or “fragment crystallizable region” is used to define the C-terminal region of an antibody heavy chain, including both native and engineered Fc regions.
  • the Fc region comprises two identical or different subunits.
  • Suitable Fc regions for the antibodies described herein include the Fc regions of human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4.
  • the boundaries of the Fc region may also vary, for example, by deleting the C-terminal lysine (residue 447 according to the EU numbering system) or by deleting both the C-terminal glycine and lysine (residues 446 and 447 according to the EU numbering system). Unless otherwise stated, the Fc region is numbered according to the EU numbering system, also known as the EU index.
  • the Fc region can be appropriately obtained by partially digesting IgG monoclonal antibodies with proteolytic enzymes such as pepsin, followed by eluting the components adsorbed on the protein A or protein G column.
  • proteolytic enzymes such as pepsin
  • any enzyme capable of restrictively digesting full-length antibodies to produce Fab and F(ab')2 by appropriately setting the enzyme reaction conditions such as pH is acceptable; there is no particular limitation, and examples include pepsin and papain.
  • variable region or “variable domain” in an antibody refers to the domain in the antibody heavy or light chain involved in antibody binding to the antigen.
  • the antibody heavy chain variable region (VH) and light chain variable region (VL) each contain four conserved frame regions (FRs) and three complementarity-determining regions (CDRs).
  • FRs conserved frame regions
  • CDRs complementarity-determining regions
  • CDR complementarity-determining region
  • the VH contains three CDR regions: HCDR1, HCDR2, and HCDR3; the VL contains three CDR regions: LCDR1, LCDR2, and LCDR3.
  • Each VH and VL consists of three CDRs and four FRs arranged in the following order from the amino terminus (also called the N-terminus) to the carboxyl terminus (also called the C-terminus): FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the amino acid sequence boundaries of CDRs can be determined using various well-known schemes, such as the "Kabat” numbering rule, the “Chothia” numbering rule, the “ABM” numbering rule, the “contact” numbering rule, and the ImMunoGenTics (IMGT) numbering rule.
  • the correspondence between various numbering systems is well known to those skilled in the art and is exemplified as shown in Table 1 below.
  • variable areas and CDRs in this disclosure embodiment are subject to the "Kabat" numbering rule.
  • antibody fragment refers to a molecule that is distinct from the intact antibody but contains a portion of the intact antibody that binds to the antigen to which the intact antibody is bound.
  • antibody fragments include, but are not limited to, Fv, dsFv, Fab, Fab′, Fab′-SH, Fd, F(ab′)2, single-domain antibodies (sdAb, such as VH, VL, or VHH), single-chain Fab (scFab, sc(Fv)2), biantibodies, linear antibodies, single-chain antibodies (such as scFv); and multispecific antibodies formed from antibody fragments.
  • chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a specific source or species, while the remaining portion of the heavy and/or light chain is derived from another different source or species.
  • humanized antibody refers to an antibody that retains the reactivity of a non-human antibody while exhibiting lower immunogenicity in humans. For example, this can be achieved by retaining the non-human CDR region and replacing the rest of the antibody with its human counterpart (i.e., the frame region portion of the constant region and the variable region).
  • human antibody refers to antibodies whose variable and constant regions are human sequences. This term encompasses antibodies derived from human genes but with sequence alterations, such as reduced potential immunogenicity, increased affinity, or the elimination of cysteine residues or glycosylation sites that might cause undesirable folding. This term also covers antibodies recombined in non-human cells (which may confer glycosylations not characteristic of human cells). The term also includes antibodies produced in transgenic mice containing some or all human immunoglobulin heavy and light chain loci. The term "human antibody” explicitly excludes humanized antibodies.
  • affinity refers to the overall strength of the non-covalent interaction between a single binding site of a molecule (e.g., an antibody) and its binding ligand (e.g., an antigen). Unless otherwise specified, as used herein, binding “affinity” refers to internal binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of molecule X for its ligand Y can typically be represented by the dissociation constant (KD). Affinity can be measured using conventional methods known in the art, including those described herein.
  • the term “kassoc” or “ka” refers to the association rate of a specific antibody-antigen interaction
  • kdis or “kd” refers to the dissociation rate of a specific antibody-antigen interaction
  • KD refers to the dissociation constant, which is derived from the ratio of kd to ka (i.e., kd/ka) and expressed as a molar concentration (M).
  • M molar concentration
  • the KD value of an antibody can be determined using methods known in the art. For example, it can be measured using a biosensing system such as a system for measuring surface plasmon resonance (e.g., Biacore), or by measuring affinity in solution using solution equilibrium titration (SET).
  • a biosensing system such as a system for measuring surface plasmon resonance (e.g., Biacore)
  • SET solution equilibrium titration
  • surface plasmon resonance refers to the analysis of optical phenomena involving real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example, using the BIAcore system (Biacore LifeSciences division of GE Healthcare, Piscataway, NJ).
  • effector function refers to biological activities attributable to the antibody's Fc region (either the native Fc region or a Fc region with amino acid sequence mutations) and that vary across antibody isotypes.
  • antibody effector functions include, but are not limited to: C1q binding and complement-dependent cytotoxicity, Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.
  • polyclonal antibody refers to a group of substantially homogeneous antibodies, meaning that the antibody molecules contained in this group have the same amino acid sequence, except for the possible presence of small amounts of naturally occurring mutations.
  • polyclonal antibodies typically comprise a variety of different antibodies with different amino acid sequences in their variable domains, and they generally specifically target different epitopes.
  • “Monoclonal” should not be construed as requiring the antibody to be produced by any particular method.
  • the antibodies provided in this disclosure are monoclonal antibodies.
  • bispecific antibody refers to an antibody (including the antibody or its antigen-binding fragment, such as a single-chain antibody) capable of specifically binding to two different antigens or at least two different antigenic epitopes of the same antigen.
  • Various structures of bispecific antibodies have been disclosed in the prior art. Based on the integrity of the IgG molecule, they can be classified into IgG-like bispecific antibodies and antibody fragment-based bispecific antibodies. Based on the number of antigen-binding regions, they can be classified into bivalent, trivalent, tetravalent, or more bispecific antibodies. Based on structural symmetry, they can be classified into symmetrical and asymmetrical bispecific antibodies.
  • bispecific antibodies based on antibody fragments form bispecific antibodies by combining two or more Fab fragments into one molecule. They exhibit lower immunogenicity, smaller molecular weight, and higher tumor tissue penetration. IgG-like bispecific antibodies (e.g., those with an Fc fragment) have a relatively larger molecular weight.
  • the Fc fragment facilitates antibody purification and improves its solubility and stability.
  • the Fc portion may also bind to the receptor FcRn, increasing the antibody's serum half-life.
  • antigen refers to a molecule or molecular part that can be selectively bound by antigen-binding proteins, including, for example, antibodies.
  • An antigen may have one or more epitopes that can interact with different antigen-binding proteins, such as antibodies.
  • epitope refers to a region on an antigen that can specifically bind to an antibody or its antigen-binding fragment.
  • Epitopes can be formed from a continuous string of amino acids (linear epitopes) or contain non-continuous amino acids (conformal epitopes), such as those spatially close due to antigen folding. The difference between conformational and linear epitopes is that antibody binding to a conformational epitope is lost in the presence of a denaturing solvent.
  • An epitope contains at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial conformation.
  • Screening for antibodies that bind to a specific epitope can be performed using methods routine in the art, such as, but not limited to, alanine scanning, Western blotting, peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of the antigen, and cross-blocking.
  • binding refers to the ability of an antibody to bind to an antigen or epitope with a higher affinity than to other antigens or epitopes.
  • antibodies bind to antigens or epitopes with an equilibrium dissociation constant (KD) of about 1 ⁇ 10 ⁇ 6 M or less (e.g., about 1 ⁇ 10 ⁇ 7 M, 1 ⁇ 10 ⁇ 8 M, 1 ⁇ 10 ⁇ 9 M, 1 ⁇ 10 ⁇ 10 M, 1 ⁇ 10 ⁇ 11 M or less).
  • the KD for antibody binding to an antigen is 10 % or less (e.g., 1%) of the KD for antibody binding to a nonspecific antigen (e.g., BSA, casein).
  • KD can be measured using known methods, such as by... The surface plasmon resonance assay is used to measure this.
  • antibodies that specifically bind to an antigen or its epitope do not preclude cross-reactivity with other related antigens, such as cross-reactivity with corresponding antigens from other species (homologous) (e.g., humans or monkeys, such as the cynomolgus (cyno), the chimpanzee (chimp), or the common marmoset (marmoset)).
  • antibody-dependent cell cytotoxicity refers to mechanisms that induce cell death that rely on the interaction between antibody-coated target cells and lytic effector cells (such as natural killer (NK) cells, monocytes, macrophages, and neutrophils) via Fc ⁇ receptors (Fc ⁇ R) expressed on the effector cells.
  • lytic effector cells such as natural killer (NK) cells, monocytes, macrophages, and neutrophils
  • Fc ⁇ R Fc ⁇ receptors
  • NK cells express Fc ⁇ RIIIa
  • monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIIIa.
  • the ADCC activity of the antibodies described herein can be assessed in vitro using cells expressing the antigen as target cells and NK cells as effector cells. Cell lysis is detected based on the release of markers (e.g., radioactive substrates, fluorescent dyes, or native intracellular proteins) from lysed cells.
  • markers e.g., radioactive substrates, fluorescent dyes, or native intracellular proteins
  • ADCP antibody-dependent phagocytosis
  • complement-dependent cytotoxicity refers to a mechanism that induces cell death in which the Fc effector domain of a target-binding antibody binds to and activates the complement component C1q. C1q then activates the complement cascade, leading to target cell death. Activation of complement can also result in the deposition of complement components on the surface of target cells, which promote CDC by binding to complement receptors (e.g., CR3) on leukocytes.
  • complement receptors e.g., CR3
  • nucleic acid is used interchangeably with the term “polynucleotide” herein and refers to deoxyribonucleotides or ribonucleotides and their polymers in single-stranded or double-stranded form.
  • the term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, or non-natural, have similar binding properties to a reference nucleic acid, and are metabolized in a manner similar to that of a reference nucleotide.
  • Examples of such analogs include, but are not limited to, phosphate thioesters, aminophosphate esters, methylphosphonates, chiral methylphosphonates, 2-O-methylribonucleotides, and peptide-nucleic acids (PNAs).
  • PNAs peptide-nucleic acids
  • “Separated” nucleic acids refer to nucleic acid molecules that have been separated from their components in their natural environment. Separated nucleic acids encoding polypeptides refer to one or more nucleic acid molecules encoding polypeptides, including one or more such nucleic acid molecules in a single vector or separate vectors, and one or more such nucleic acid molecules present at one or more locations in the host cell. Unless otherwise stated, a specific nucleic acid sequence also implicitly encompasses variants of its conserved modifications (e.g., degenerate codon substitutions) and complementary sequences, as well as explicitly stated sequences. Specifically, as detailed below, degenerate codon substitutions can be obtained by generating sequences in which the third position of one or more selected (or all) codons is substituted with a mixture of bases and/or deoxyinosine residues.
  • sequence identity refers to the degree (percentage) to which two sequences share the same amino acids/nucleic acids at equivalent positions when optimally aligned; gaps may be introduced, where necessary, to obtain the maximum percentage of sequence identity, without considering any conserved substitutions as part of sequence identity.
  • alignment can be performed using techniques known in the art, such as publicly available computer software like BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software. Those skilled in the art can determine the parameters suitable for measuring alignment, including any algorithms required to achieve maximum alignment across the full length of the sequences being compared.
  • vector refers to a polynucleotide molecule capable of transporting another polynucleotide linked to it.
  • plasmid which is a circular double-stranded DNA loop in which an additional DNA segment can be attached.
  • viral vector such as an adeno-associated virus vector (AAV or AAV2), in which an additional DNA segment can be attached to the viral genome.
  • AAV adeno-associated virus vector
  • Some vectors are capable of autonomous replication in the host cells to which they are introduced (e.g., bacterial vectors with bacterial origins of replication and attachable mammalian vectors).
  • vectors can integrate into the host cell's genome after introduction into the host cell, thereby replicating along with the host genome.
  • expression vector or "expression construct” refers to a vector capable of transforming host cells and containing a nucleic acid sequence that directs and/or controls (alongside the host cell) the expression of one or more heterologous coding regions operatively linked to it.
  • Expression constructs can include, but are not limited to, sequences that affect or control transcription, translation, and, in the presence of introns, influence RNA splicing of coding regions operatively linked to them.
  • host cell refers to cells into which exogenous nucleic acids have been introduced, including the progeny of such cells.
  • Host cells include “transformers” and “transformed cells,” which include primary transformed cells and their derived progeny, regardless of the number of passages. Progeny may not be identical to parental cells in their nucleic acid contents and may contain mutations. Mutant progeny are included herein, which have the same function or biological activity as cells screened or selected in the initial transformed cells.
  • Host cells include prokaryotic and eukaryotic host cells, wherein eukaryotic host cells include, but are not limited to, mammalian cells, insect cell lines, plant cells, and fungal cells.
  • Mammalian host cells include human, mouse, rat, dog, monkey, pig, goat, cow, horse, and hamster cells, including but not limited to Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, young hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells, and HEK-293 cells.
  • CHO Chinese hamster ovary
  • NSO Chinese hamster ovary
  • SP2 cells HeLa cells
  • BHK young hamster kidney
  • COS monkey kidney cells
  • human hepatocellular carcinoma cells e.g., Hep G2
  • A549 cells e.g., 3T3 cells
  • 3T3 cells HEK-293 cells.
  • Fungal cells include yeast and filamentous fungal cells, such as *Pichia pastoris*, *Pichia finlandica*, *Pichia trehalophila*, *Pichia koclamae*, *Pichia membranaefaciens*, *Pichia minuta* (*Ogataea minuta*, *Pichia lindneri*), *Pichia xiaopuntiae*, *Pichia thermomotolerans*, *Pichia salictaria*, *Pichia guercuum*, *Pichia pijperi*, *Pichia stiptis*, *Pichia methanolica*, *Pichia* genus, and *Saccharomyces*.
  • yeast and filamentous fungal cells such as *Pichia pastoris*, *Pichia finlandica*, *Pichia trehalophila*, *Pichia k
  • composition refers to a mixture containing one or more antibodies described herein along with other chemical components, such as physiological/pharmaceutical carriers and excipients.
  • pharmaceutically acceptable carrier refers to a component in a pharmaceutical formulation that is different from the active ingredient and is non-toxic to the subject.
  • Pharmaceutically acceptable carriers, diluents, or excipients include, but are not limited to, buffers, excipients, stabilizers, or preservatives.
  • subject or “individual” include both humans and non-human animals.
  • Non-human animals include all vertebrates (e.g., mammals and non-mammals) such as non-human primates, sheep, dogs, cattle, chickens, amphibians, and reptiles.
  • the terms “patient” or “subject” are used interchangeably herein.
  • the individual or subject is a human being.
  • administering or “giving,” when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refers to the contact between an exogenous drug, therapeutic agent, diagnostic agent, or composition and the animal, human, subject, cell, tissue, organ, or biological fluid.
  • sample refers to a collection (such as fluid, cells, or tissue) separated from a subject, as well as fluids, cells, or tissues present within a subject.
  • exemplary samples include biological fluids such as blood, serum and serous fluid, plasma, lymph, urine, saliva, cystic fluid, tears, excretions, sputum, mucosal secretions of secretory tissues or organs, vaginal secretions, ascites, pleura, pericardium, peritoneum, fluids in the abdominal cavity and other body cavities, fluids collected by bronchoalveolar lavage fluid, synovial fluid, liquid solutions in contact with the subject or biological sources, such as culture media (including conditioned media), lavage fluids, tissue biopsy samples, fine-needle aspiration, surgically removed tissue, organ cultures, or cell cultures.
  • biological fluids such as blood, serum and serous fluid, plasma, lymph, urine, saliva, cystic fluid, tears, excretions, sputum, mucosal secretions of secretory tissues or organs,
  • Treatment refers to a clinical intervention on the individual being treated, and may be administered for prevention or during a clinicopathological process.
  • the desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing/decreasing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and resolving or improving prognosis.
  • the antibodies disclosed herein are used to delay the onset of disease or slow its progression.
  • an "effective amount” is generally an amount sufficient to reduce the severity and/or frequency of symptoms, eliminate these symptoms and/or underlying causes, prevent the occurrence of symptoms and/or underlying causes, and/or improve or mitigate damage caused by or associated with a disease state (e.g., lung disease).
  • a disease state e.g., lung disease
  • an effective amount is a therapeutically effective amount or a preventatively effective amount.
  • a “therapeutic effective dose” is a dose sufficient to treat a disease state or symptom, especially a state or symptom associated with that disease state, or otherwise prevent, inhibit, delay, or reverse the progression of the disease state or any other undesirable symptom associated with that disease.
  • a “preventive effective dose” is a dose that, when administered to a subject, will have a predetermined preventive effect, such as preventing or delaying the onset (or recurrence) of the disease state, or reducing the likelihood of the onset (or recurrence) of the disease state or associated symptoms. Complete treatment or prevention may not occur after a single dose, but may occur after a series of doses. Therefore, a therapeutic or preventive effective dose may be administered in a single or multiple-dose manner.
  • Both “therapeutic effective doses” and “preventive effective doses” can vary depending on a variety of factors, such as an individual’s disease state, age, sex, and weight, and the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual.
  • Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved health status in the patient.
  • This disclosure provides an anti-N3pGlu A ⁇ antibody with many advantageous properties, such as good therapeutic activity, safety, pharmacokinetic properties, and drug-likeness (e.g., solubility, viscosity, purity, and stability).
  • an anti-N3pGlu A ⁇ antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein:
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 229
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 230
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 231
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 232
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6, wherein:
  • X 10 represents N, Y, or S; X 11 represents G; or
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 233
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 234
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16;
  • X 17 is D or E; X 18 is D or E.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein:
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 4
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 31
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 2
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 36
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 53
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 3
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 53
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 58
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 107
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 8
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 94
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 96
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 110
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 136
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 13
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 135
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein:
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 52
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 54
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 1
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 7
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 107
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 9
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 5
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 11
  • HCDR2 contains the amino acid sequence of SEQ ID NO: 12
  • HCDR3 contains the amino acid sequence of SEQ ID NO: 136
  • the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 14
  • LCDR2 contains the amino acid sequence of SEQ ID NO: 15
  • LCDR3 contains the amino acid sequence of SEQ ID NO: 16.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein:
  • the heavy chain variable region HCDR1 has the amino acid sequence shown in SEQ ID NO: 49
  • HCDR2 has the amino acid sequence shown in SEQ ID NO: 52
  • HCDR3 has the amino acid sequence shown in SEQ ID NO: 54
  • the light chain variable region LCDR1 has the amino acid sequence shown in SEQ ID NO: 32
  • LCDR2 has the amino acid sequence shown in SEQ ID NO: 5
  • LCDR3 has the amino acid sequence shown in SEQ ID NO: 6;
  • the heavy chain variable region HCDR1 has the amino acid sequence shown in SEQ ID NO: 1
  • HCDR2 has the amino acid sequence shown in SEQ ID NO: 7
  • HCDR3 has the amino acid sequence shown in SEQ ID NO: 107
  • the light chain variable region LCDR1 has the amino acid sequence shown in SEQ ID NO: 9
  • LCDR2 has the amino acid sequence shown in SEQ ID NO: 5
  • LCDR3 has the amino acid sequence shown in SEQ ID NO: 10;
  • the heavy chain variable region HCDR1 has the amino acid sequence shown in SEQ ID NO: 11
  • HCDR2 has the amino acid sequence shown in SEQ ID NO: 12
  • HCDR3 has the amino acid sequence shown in SEQ ID NO: 136
  • the light chain variable region LCDR1 has the amino acid sequence shown in SEQ ID NO: 14
  • LCDR2 has the amino acid sequence shown in SEQ ID NO: 15
  • LCDR3 has the amino acid sequence shown in SEQ ID NO: 16.
  • the heavy chain variable regions HCDR1, HCDR2, and HCDR3 and the light chain variable regions LCDR1, LCDR2, and LCDR3 are defined according to the Kabat numbering rules.
  • Exemplary examples include the anti-N3pGlu A ⁇ antibody disclosed herein, wherein the anti-N3pGlu A ⁇ antibody is a murine antibody, a chimeric antibody, or a humanized antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody.
  • the anti-N3pGlu A ⁇ antibody disclosed herein includes the frame region (FR) of a human antibody.
  • the anti-N3pGlu A ⁇ antibody disclosed herein has a heavy chain variable region having FR1, FR2, FR3 derived from IGHV3-7*01 and FR4 derived from IGHJ6*01, and containing one or more amino acid substitutions selected from the group consisting of 3K, 30R, 45P, and 93V; and/or the light chain variable region has FR1, FR2, FR3 derived from IGKV2-40*01, IGKV3-20*01, or IGKV1-39*01 and FR4 derived from IGKJ4*01, and containing one or more amino acid substitutions selected from the group consisting of 2V, 43S, and 45K.
  • the anti-N3pGlu A ⁇ antibody comprises, wherein the heavy chain variable region HCDR1 contains the amino acid sequence of SEQ ID NO: 49 or 1, HCDR2 contains the amino acid sequence of SEQ ID NO: 52, 2, 36 or 53, and HCDR3 contains the amino acid sequence of SEQ ID NO: 54, 3 or 58, and the FR of the heavy chain variable region contains one or more amino acid substitutions selected from the group consisting of 3K, 30R, 45P and 93V; and the light chain variable region LCDR1 contains the amino acid sequence of SEQ ID NO: 32, 4 or 31, LCDR2 contains the amino acid sequence of SEQ ID NO: 5, and LCDR3 contains the amino acid sequence of SEQ ID NO: 6, and the FR of the light chain variable region contains one or more amino acid substitutions selected from the group consisting of 2V, 43S and 45K.
  • the above-mentioned variable regions and CDRs are defined according to the Kabat numbering rules.
  • the anti-N3pGlu A ⁇ antibody disclosed herein has heavy chain variable regions having FR1, FR2, FR3 derived from IGHV3-7*01 and FR4 derived from IGHJ6*01, and containing one or more amino acid substitutions selected from the group consisting of 28S, 45P, and 76K; and/or the light chain variable region has FR1, FR2, FR3 derived from IGKV2-29*02 and FR4 derived from IGKJ4*01, and is unsubstituted.
  • the anti-N3pGlu A ⁇ antibody wherein the heavy chain variable region HCDR1 comprises the amino acid sequence of SEQ ID NO: 1, HCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 107, 8, 94, 96, or 110, and the FR of the heavy chain variable region comprises one or more amino acid substitutions selected from the group consisting of 28S, 45P, and 76K; and the light chain variable region LCDR1 comprises the amino acid sequence of SEQ ID NO: 9, LCDR2 comprises the amino acid sequence of SEQ ID NO: 5, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 10, and the FR of the light chain variable region is unsubstituted.
  • the above-mentioned variable regions and CDRs are defined according to the Kabat numbering rules.
  • the anti-N3pGlu A ⁇ antibody disclosed herein has a heavy chain variable region having FR1, FR2, FR3 derived from IGHV3-21*01 and FR4 derived from IGHJ6*01, and containing one or more amino acid substitutions selected from the group consisting of 28I, 44R, 49A, and 93G; and/or the light chain variable region has FR1, FR2, FR3 derived from IGKV4-1*01 and FR4 derived from IGKJ4*01, and is either unsubstituted or contains one or more amino acid substitutions selected from the group consisting of 4L, 58I, 68R, and 85T.
  • the anti-N3pGlu A ⁇ antibody wherein the heavy chain variable region HCDR1 comprises the amino acid sequence of SEQ ID NO: 11, HCDR2 comprises the amino acid sequence of SEQ ID NO: 12, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 136, 13, or 135, and the FR of the heavy chain variable region comprises one or more amino acid substitutions selected from the group consisting of 28I, 44R, 49A, and 93G; and the light chain variable region LCDR1 comprises the amino acid sequence of SEQ ID NO: 14, LCDR2 comprises the amino acid sequence of SEQ ID NO: 15, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 16, and the FR of the light chain variable region is unsubstituted or comprises one or more amino acid substitutions selected from the group consisting of 4L, 58I, 68R, and 85T.
  • the above-mentioned variable regions and CDRs are defined according to the Kabat numbering rules.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein,
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 17, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 18; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 37; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 45, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 38; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 42, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 39; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 39; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 65; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 79, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 91, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 119, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 19, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 20; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 141, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 21, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 22; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 133, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 137, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; or
  • the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 133, and the light chain variable region contains the amino acid sequence of SEQ ID NO: 131.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein,
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 66; or
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 119, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97; or
  • the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 141, and the light chain variable region contains the amino acid sequence of SEQ ID NO: 129.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein,
  • the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 88, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 66; or
  • the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 119, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 97; or
  • the heavy chain variable region is an amino acid sequence as shown in SEQ ID NO: 141, and the light chain variable region is an amino acid sequence as shown in SEQ ID NO: 129.
  • the anti-N3pGlu A ⁇ antibody disclosed herein comprises a heavy chain and a light chain, wherein,
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 169, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 25, and the light chain comprises the amino acid sequence of SEQ ID NO: 26; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 143, and the light chain comprises the amino acid sequence of SEQ ID NO: 175; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 146, and the light chain comprises the amino acid sequence of SEQ ID NO: 176; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 143, and the light chain comprises the amino acid sequence of SEQ ID NO: 177; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 150, and the light chain comprises the amino acid sequence of SEQ ID NO: 177; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 150, and the light chain comprises the amino acid sequence of SEQ ID NO: 182; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 150, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 159, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 160, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 161, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 172, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 219, and the light chain comprises the amino acid sequence of SEQ ID NO: 220; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 144, 145, 146 or 147, and the light chain comprises the amino acid sequence of SEQ ID NO: 175; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 143, 144, 145 or 147, and the light chain comprises the amino acid sequence of SEQ ID NO: 176; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 144, 145, 146, 147, 148, 149, 151, 152, 153, 154, 155, 156, 157 or 158, and the light chain comprises the amino acid sequence of SEQ ID NO: 177; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 143, 144, 145, 146 or 147, and the light chain comprises the amino acid sequence of SEQ ID NO: 178; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 143, 144, 145, 146 or 147, and the light chain comprises the amino acid sequence of SEQ ID NO: 179; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 146, 147, or 150, and the light chain comprises the amino acid sequence of SEQ ID NO: 180; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 146, 147 or 150, and the light chain comprises the amino acid sequence of SEQ ID NO: 181; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 146 or 147, and the light chain comprises the amino acid sequence of SEQ ID NO: 182; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 146, 147, 162, 163, 164, 165, 166, 167, 168, 170, 171, 173 or 174, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 192, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 27, and the light chain comprises the amino acid sequence of SEQ ID NO: 28; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 185, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 187, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 189, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 195, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 221, and the light chain comprises the amino acid sequence of SEQ ID NO: 222; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 184, 186, 188, 190, 191, 193, 194, 196, 197, 198, 199, 200 or 201, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200 or 201, and the light chain comprises the amino acid sequence of SEQ ID NO: 203; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 211, and the light chain comprises the amino acid sequence of SEQ ID NO: 212; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 29, and the light chain comprises the amino acid sequence of SEQ ID NO: 30; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 204, and the light chain comprises the amino acid sequence of SEQ ID NO: 212; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 205, and the light chain comprises the amino acid sequence of SEQ ID NO: 212; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 207, and the light chain comprises the amino acid sequence of SEQ ID NO: 212; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 205, and the light chain comprises the amino acid sequence of SEQ ID NO: 214; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 223, and the light chain comprises the amino acid sequence of SEQ ID NO: 224; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 206, 208, 209 or 210, and the light chain comprises the amino acid sequence of SEQ ID NO: 212; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 204, 205, 206, 207, 208, 209, 210 or 211, and the light chain comprises the amino acid sequence of SEQ ID NO: 213; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 204, 206, 207, 208, 209, 210 or 211, and the light chain comprises the amino acid sequence of SEQ ID NO: 214.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein,
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 169, and the light chain comprises the amino acid sequence of SEQ ID NO: 183; or
  • the heavy chain comprises the amino acid sequence of SEQ ID NO: 192, and the light chain comprises the amino acid sequence of SEQ ID NO: 202; or
  • the heavy chain contains the amino acid sequence of SEQ ID NO: 211, and the light chain contains the amino acid sequence of SEQ ID NO: 212.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein,
  • the heavy chain has the amino acid sequence shown in SEQ ID NO: 169, and the light chain has the amino acid sequence shown in SEQ ID NO: 183; or
  • amino acid sequence of the heavy chain is shown as amino acid residues 1 to 451 of SEQ ID NO: 169, and the amino acid sequence of the light chain is shown as amino acid residues 1 to 219 of SEQ ID NO: 183; or
  • the heavy chain has the amino acid sequence shown in SEQ ID NO: 192, and the light chain has the amino acid sequence shown in SEQ ID NO: 202; or
  • amino acid sequence of the heavy chain is shown as amino acid residues 1 to 451 of SEQ ID NO: 192, and the amino acid sequence of the light chain is shown as amino acid residues 1 to 219 of SEQ ID NO: 202; or
  • the heavy chain has the amino acid sequence shown in SEQ ID NO: 211, and the light chain has the amino acid sequence shown in SEQ ID NO: 212; or
  • amino acid sequence of the heavy chain is shown as amino acid residues 1 to 451 of SEQ ID NO: 211, and the amino acid sequence of the light chain is shown as amino acid residues 1 to 218 of SEQ ID NO: 212.
  • anti-N3pGlu A ⁇ antibody disclosed herein, wherein,
  • the heavy chain has the amino acid sequence shown in SEQ ID NO: 169, and the light chain has the amino acid sequence shown in SEQ ID NO: 183; or
  • the heavy chain has the amino acid sequence shown in SEQ ID NO: 192, and the light chain has the amino acid sequence shown in SEQ ID NO: 202; or
  • the heavy chain has an amino acid sequence as shown in SEQ ID NO: 211, and the light chain has an amino acid sequence as shown in SEQ ID NO: 212.
  • the antibodies provided herein are full-length antibodies.
  • the antibodies provided herein are antibody fragments.
  • the antibody fragment is a Fab, Fab′, Fab′-SH, or F(ab′)2 fragment, particularly a Fab fragment.
  • Fab is a monovalent fragment consisting of VL, VH, CL, and CH1 domains.
  • a “Fab fragment” can be generated by cleavage of an antibody with papain.
  • Fab′ contains VL, CL, VH, and CH1, and also contains a region between the CH1 and CH2 domains, allowing interchain disulfide bonds to form between the two heavy chains of two Fab′ fragments to form an F(ab′)2 molecule.
  • Fab′-SH is a Fab′ fragment in which the cysteine residues in the constant region have free thiol groups.
  • F(ab′)2 is a divalent fragment comprising two Fab fragments linked by disulfide bonds in the hinge region.
  • the antibody fragment is a biantibody, triantibody, or tetraantibody.
  • a biantibody is an antibody fragment with two antigen-binding sites, containing linked VH and VL domains within the same polypeptide chain (VH-VL). By using a short linker that prevents pairing between two domains on the same chain, these domains are forced to pair with complementary domains on another chain, thereby creating two antigen-binding sites.
  • the two antigens can be the same or different.
  • the antibody fragment is a single-chain Fab fragment.
  • a “single-chain Fab fragment” or “scFab” is a polypeptide consisting of VH, CH1, VL, CL, and a linker, wherein the antibody domain and the linker have one of the following sequences in the N-terminal to C-terminal direction: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1, or d) VL-CH1-linker-VH-CL.
  • the linker is a polypeptide having at least 30 amino acids.
  • the linker is a polypeptide having between 32 and 50 amino acids.
  • the single-chain Fab fragment is stabilized via a native disulfide bond between CL and CH1. Additionally, these single-chain Fab molecules can be further stabilized by inserting cysteine residues (e.g., at position 44 in the heavy chain variable region and position 100 in the light chain variable region, according to Kabat numbering) to create interchain disulfide bonds.
  • the antibody fragment is an Fv fragment composed of the VH and VL domains of a single arm of the antibody.
  • the antibody fragment is a single-chain variable fragment (scFv).
  • scFv is a fusion protein comprising at least one antibody fragment containing a light chain variable region and at least one antibody fragment containing a heavy chain variable region, wherein the light and heavy chain variable regions are sequentially linked by a short, flexible peptide linker, capable of being expressed as a single-chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived.
  • the scFv may have VL and VH variable regions in any order herein; for example, relative to the N-terminus and C-terminus of the polypeptide, the scFv may contain VL-linker-VH or may contain VH-linker-VL.
  • the antibody fragment is dsFv, which is obtained by linking polypeptides in which one amino acid residue in each VH and VL is replaced by a cysteine residue via disulfide bonds between cysteine residues.
  • the amino acid residues to be replaced by cysteine residues can be selected based on known methods according to predictions of the antibody's three-dimensional structure.
  • the antibody fragment is a single-domain antibody (dAb).
  • dAb single-domain antibody
  • a single-domain antibody is an antibody fragment containing all or part of the heavy chain variable domain or all or part of the light chain variable domain.
  • the antibodies provided herein are chimeric antibodies.
  • a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region.
  • a chimeric antibody is a "class-switched" antibody, wherein the class or subclass has been changed from the class or subclass of the parent antibody.
  • the antibody is a humanized antibody.
  • a non-human antibody is humanized to reduce its immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody.
  • a humanized antibody contains one or more variable regions, wherein the CDR or a portion thereof is derived from the non-human antibody, and the FR or a portion thereof is derived from the human antibody.
  • the humanized antibody may also contain a portion of a human constant region.
  • some FR residues in the humanized antibody may be replaced with corresponding residues from the non-human antibody (e.g., an antibody providing the CDR sequence).
  • amino acid sequence variants of the anti-N3pGlu A ⁇ antibody provided herein are included.
  • improved binding affinity and/or other biological properties of the antibody may be desired.
  • Amino acid sequence variants of the antibody can be prepared by introducing suitable modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletion, and/or insertion, and/or substitution of residues within the amino acid sequence of the anti-N3pGlu A ⁇ antibody. Any combination of deletions, insertions, and substitutions may be performed to obtain the final construct, provided that the final construct possesses the desired characteristics, such as antigen-binding properties.
  • antibody variants with one or more amino acid substitutions are provided.
  • Substitution mutagenesis sites of interest include CDR and FR.
  • conserved substitutions are shown in Table 2 under the heading “Preferred Substitutions.” More substantial variations are provided in Table 2 under the heading “Exemplary Substitutions” and are further described below with reference to the amino acid side chain categories.
  • Amino acid substitutions can be introduced into the antibody of interest, and the product can be screened for desired activities, such as retained/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC.
  • amino acids can be grouped as follows:
  • Non-conservative replacement would require replacing a member of one of these categories with a member of another category.
  • substitution variants involves replacing one or more CDR residues of a parent antibody (e.g., a humanized or human antibody).
  • a parent antibody e.g., a humanized or human antibody
  • the resulting variants selected for further research will have alterations (e.g., improvements) to certain biological properties (e.g., increased affinity, decreased immunogenicity) relative to the parent antibody, and/or will substantially retain certain biological properties of the parent antibody.
  • An exemplary substitution variant is an affinity-matured antibody, which can be conveniently generated, for example, using phage display-based affinity maturation techniques (such as those described herein).
  • one or more CDR residues are mutated, and the variant antibody is displayed on a phage and screened for specific biological activities (e.g., binding affinity).
  • CDRs can be altered (e.g., substituted), for example, to improve antibody affinity. Such alterations can be made to CDR “hotspots,” residues encoded by codons that undergo mutations at a high frequency during somatic maturation, and/or residues that contact the antigen, while testing the binding affinity of the resulting variant VH or VL.
  • affinity maturation diversity is introduced into the selected variant gene for maturation using any of a variety of methods, such as error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis.
  • a secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity.
  • CDR-directed approaches where several CDR residues (e.g., 4-6 residues at a time) are randomized.
  • CDR residues involved in antigen binding can be specifically identified, for example, using alanine scan mutagenesis or modeling.
  • HCDR3 and LCDR3 are frequently targeted.
  • substitution, insertion, or deletion may occur within one or more CDRs, provided that such changes do not materially reduce the antibody's ability to bind to the antigen.
  • conserved changes e.g., conserved substitutions, as provided herein
  • Such changes may, for example, be external to the antigen-contacting residues in the CDR.
  • each CDR is unchanged or contains no more than one, two, or three amino acid substitutions.
  • alanine scan mutagenesis One method for identifying residues or regions in an antibody that can serve as mutagenic targets is called “alanine scan mutagenesis.”
  • a residue or target group of residues e.g., charged residues such as Arg, Asp, His, Lys, and Glu
  • a neutral or negatively charged amino acid e.g., Ala or polyalanine
  • Further substitutions can be introduced at amino acid positions that show functional sensitivity to the initial substitution.
  • the contact points between the antibody and antigen can be identified by studying the crystal structure of the antigen-antibody complex. These contact residues and adjacent residues can be targeted or eliminated as substitution candidates.
  • Variants can be screened to determine if they contain the desired properties.
  • Amino acid sequence insertions include fusion of the amino and/or carboxyl ends of peptides ranging in length from 1 residue to 100 or more residues, and intra-sequence insertions of single or multiple amino acid residues.
  • terminal insertions include antibodies having an N-terminal methionyl residue.
  • Other insertion variants of antibody molecules include fusions of the N- or C-terminus of the antibody with an enzyme or a peptide that extends the serum half-life of the antibody.
  • Anti-N3pGlu A ⁇ antibodies can be produced using recombinant methods. For these methods, one or more isolated nucleic acids encoding the anti-N3pGlu A ⁇ antibody are provided.
  • this disclosure provides isolated nucleic acids encoding the anti-N3pGlu A ⁇ antibody as described above. Such nucleic acids can be derived from independently encoding any of the aforementioned polypeptide chains.
  • this disclosure provides one or more vectors (e.g., expression vectors) comprising such nucleic acids.
  • this disclosure provides host cells comprising such nucleic acids.
  • a method for preparing a polypeptide or fusion protein is provided, wherein the method comprises culturing host cells comprising nucleic acids encoding said polypeptide or fusion protein, as provided above, under conditions suitable for expression, and optionally recovering said anti-N3pGlu A ⁇ antibody from the host cells (or host cell culture medium).
  • nucleic acid encoding the protein is isolated and inserted into one or more vectors for further cloning and/or expression in host cells.
  • nucleic acids can be readily isolated and sequenced using standard procedures, or generated via recombinant methods or obtained through chemical synthesis.
  • Suitable host cells for cloning or expressing vectors encoding anti-N3pGlu A ⁇ antibodies include prokaryotic or eukaryotic cells as described herein. For example, they can be produced in bacteria, particularly when glycosylation and Fc effector function are not required. Following expression, the expression can be separated from the bacterial cell paste in a soluble fraction and further purified.
  • eukaryotic microorganisms such as filamentous fungi or yeast are also suitable cloning or expression hosts for vectors encoding fusion proteins, including fungal and yeast strains.
  • Suitable host cells for expressing fusion proteins can also be derived from multicellular organisms (invertebrates and vertebrates); examples of invertebrate cells include plant and insect cells.
  • baculovirus strains have been identified that can be used in conjunction with insect cells, particularly for transfection of fall armyworm (Spodoptera frugiperda) cells; plant cell cultures can also be used as hosts, such as US5959177, US6040498, US6420548, US7125978, and US6417429; and vertebrate cells, such as mammalian cell lines adapted for growth in suspension, can also be used as hosts.
  • insect cells particularly for transfection of fall armyworm (Spodoptera frugiperda) cells
  • plant cell cultures can also be used as hosts, such as US5959177, US6040498, US6420548, US7125978, and US6417429
  • vertebrate cells such as mammalian cell lines adapted for growth in suspension, can also be used as hosts.
  • suitable mammalian host cell lines include SV40-transformed monkey kidney CV1 line (COS-7); human embryonic kidney line (293 or 293T cells); young hamster kidney cells (BHK); mouse seltoli cells (TM4 cells); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); buffalo rat hepatocytes (BRL3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumors (MMT 060562); TRI cells; MRC 5 cells; and FS4 cells.
  • Other suitable mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells; and myeloma cell lines such as Y0, NSO, and Sp2/0.
  • the anti-N3pGlu A ⁇ antibody provided herein can be identified, screened, or characterized by its physical/chemical properties and/or biological activity using a variety of assays known in the art.
  • the activity of the disclosed anti-N3pGlu A ⁇ antibody can be tested, for example, by known methods such as ELISA, Western blotting, etc.
  • any anti-N3pGlu A ⁇ antibody provided in this disclosure may be used for therapeutic purposes.
  • the anti-N3pGlu A ⁇ antibody provided in this disclosure may be used in the manufacture or preparation of a medicament.
  • the disease is a disease or condition related to N3pGlu A ⁇ .
  • the disease or condition related to N3pGlu A ⁇ is a neurological disorder, a degenerative disease, or a cerebrovascular disease.
  • compositions comprising the aforementioned anti-N3pGlu A ⁇ antibody are provided, for example, for any of the pharmaceutical uses or therapeutic methods described above.
  • the pharmaceutical composition comprises any anti-N3pGlu A ⁇ antibody provided herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises at least one additional therapeutic agent.
  • the disclosed anti-N3pGlu A ⁇ antibody can be used alone or in combination with other agents for treatment.
  • the disclosed antibody can be administered co-administered with at least one other therapeutic agent.
  • the anti-N3pGlu A ⁇ antibody (and any other therapeutic agents) disclosed herein may be administered by any suitable means, including parenteral, intrapulmonary, and intranasal administration, and, if local treatment is required, intralesional administration.
  • Parenteral infusion includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Administration may be by any suitable route, such as by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is short-term or long-term.
  • Various dosing schedules are considered herein, including, but not limited to, single or multiple administrations at multiple time points, bolus administration, and pulsatile infusion.
  • the anti-N3pGlu A ⁇ antibody disclosed herein will be formulated, administered, and applied in accordance with good medical practice. Factors considered in this context include the specific condition being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the condition, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to a medical practitioner.
  • the anti-N3pGlu A ⁇ antibody may be formulated with or without one or more agents currently used for the prevention or treatment of the stated condition. The effective amount of such other agents depends on the amount present in the pharmaceutical composition, the type of condition or treatment, and other factors. These are generally used at the same dosage and route of administration as described herein, or at approximately 1% to 99% of the dosage described herein, or at other dosages, and in any route determined empirically/clinically as appropriate.
  • the appropriate dosage of the disclosed anti-N3pGlu A ⁇ antibody (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of therapeutic molecule, the severity and duration of the disease, whether it is administered for prophylactic or therapeutic purposes, prior treatment, the patient's clinical history and response to the therapeutic molecule, and the judgment of the attending physician.
  • the therapeutic molecule is appropriately administered to the patient either as a single dose or after a series of treatments.
  • an article of manufacture comprising materials that can be used to treat, prevent, and/or diagnose the aforementioned conditions.
  • the article of manufacture comprises a container and a label or package insert on or in conjunction with the container.
  • Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc.
  • the container can be formed from various materials such as glass or plastic.
  • the container contains a composition, alone or in combination with another composition, that is effective in treating, preventing, and/or diagnosing the condition, and may have a sterile access port (e.g., the container may be an intravenous solution bag or vial with a stopper puncturable by a hypodermic needle).
  • At least one active agent in the composition is the anti-N3pGlu A ⁇ antibody of this disclosure.
  • the label or package insert indicates that the use of the composition is for the treatment of the selected condition.
  • the article of manufacture may comprise: (a) a first container containing the composition, wherein the composition comprises the anti-N3pGlu A ⁇ antibody of this disclosure; and (b) a second container containing the composition, wherein the composition contains additional cytotoxic agents or other therapeutic agents.
  • the article of manufacture in this embodiment of the present disclosure may further include a packaging insert indicating that the composition can be used to treat a specific condition.
  • the article of manufacture may further include a second (or third) container containing a pharmaceutically acceptable buffer solution. From a commercial and user perspective, it may further include other materials as desired, including other buffers, diluents, filters, needles, and syringes.
  • the synthesized peptide human N3pGlu-42 A ⁇ (Gil Biochemical) was dissolved in PBS and then incubated overnight at 37°C to obtain human N3pGlu-42 A ⁇ fibril. After LC-MS identification, it was dispensed for use.
  • SEQ ID NO: 142 Note: X stands for pyroglutamic acid.
  • the synthesized human N3pGlu-42 A ⁇ peptide (Gil Biochemicals) was dissolved in PBS and then incubated overnight at 37°C to obtain human N3pGlu-42 A ⁇ fibers. After LC-MS confirmation, the fibers were dispensed for use.
  • the human N3pGlu-42 A ⁇ peptide powder synthesized by Gil Biochemicals was dissolved in 100% DMSO to prepare human N3pGlu-42 A ⁇ monomers. These monomers were also confirmed to be correct by LC-MS before dispensing for use.
  • Anti-human N3pGlu A ⁇ antibodies were produced by immunizing mice. Balb/c and SJL mice, female, 6-8 weeks old (Beijing Vital River Laboratory Animal Technology Co., Ltd., Animal Production License No.: SCXK( ⁇ )2012-0001). Housing environment: SPF grade. After purchase, mice were housed in a laboratory environment for one week with a 12/12-hour light/dark cycle, temperature 20-25°C, and humidity 40%-60%. The acclimatized mice were then immunized according to the following protocol.
  • mice and SJL mice were immunized with human N3pGlu-42 A ⁇ fibrin, alternating between the two treatments.
  • Gold Adjuvant Sigma Cat No.T2684
  • Thermo Alum Thermo Cat No. 77161
  • Antigen and The Gold Adjuvant adjuvant ratio is 1:1, and the antigen is mixed with Thermo...
  • the Alum adjuvant ratio was 3:1, 50 ⁇ g/mouse/dose.
  • Human N3pGlu-42 A ⁇ fibrin antigen was emulsified and inoculated on days 0, 14, 28, 42, and 56. Blood samples were collected on days 21, 35, and 49, and serum antibody titers were determined by ELISA. Mice with high serum antibody titers that tended to plateau were selected, and their spleen cells were used for hybridoma fusion.
  • the supernatant of the fusion hybridoma was used to screen for positive murine antibodies by detecting their binding activity with human N3pGlu-42 A ⁇ . Finally, three murine antibodies with human N3pGlu-42 A ⁇ binding activity were obtained.
  • the heavy and light chain CDR sequences of each murine antibody are shown in Table 3 below.
  • the CDRs in the table are CDRs determined according to the Kabat numbering system.
  • variable region sequence of the murine antibody is as follows:
  • the underlined part is the CDR sequence determined according to the Kabat numbering system
  • the non-underlined part is the FR sequence.
  • the C-terminus of the heavy chain variable region of the three previously screened murine antibodies was linked to the N-terminus of the human IgG1 heavy chain constant region, and the C-terminus of the light chain variable region of the murine antibody was linked to the N-terminus of the human ⁇ light chain constant region to obtain their corresponding chimeric antibodies.
  • the constant region and the light/heavy chain sequence of the chimeric antibody are as follows:
  • germline genes of heavy and light chain variable regions with high homology to mAb81, mAb84, and mAb89 were selected as templates.
  • the CDRs of these three murine antibodies were transplanted into the corresponding human templates to form variable region sequences in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • the CDR amino acid residues were determined and annotated using the Kabat numbering system.
  • FR1, FR2, and FR3 of IGKV2-40*01 and FR4 of IGKJ4*01 were selected as templates for the light chain framework region.
  • FR1, FR2, and FR3 of IGHV3-7*01 and FR4 of IGHJ6*01 were selected as templates for the heavy chain framework region.
  • the CDR of the mouse antibody mAb81 was transplanted into its human template.
  • amino acid residues at positions 2, 28, 29, and/or 45 on the variable region of the light chain of the humanized antibody were substituted; and amino acid residues at positions 3, 30, 35, 45, 60, and/or 93 on the variable region of the heavy chain of the humanized antibody were substituted (the positions of the amino acids were determined according to the Kabat numbering rules).
  • the humanized antibody design of the mouse antibody mAb81 is shown in Table 4 below:
  • Graft represents the insertion of a murine antibody CDR into the human FR region; "I2V” indicates that, according to the Kabat numbering system, the second I is mutated to V, and so on.
  • the CDR mutation sequence of the mAb81 humanized antibody is shown in Table 5 below:
  • the light chain variable region/heavy chain variable region sequences of the mAb81 humanized antibody are as follows:
  • the underlined part is the CDR sequence determined according to the Kabat numbering system
  • the non-underlined part is the FR sequence.
  • amino acid residues at positions 2, 28, and/or 43 on the light chain variable region of the humanized antibody are substituted; and amino acid residues at positions 3, 30, 32, 34, 45, 51, 52a, 60, 61, 93, 98, and/or 100b on the heavy chain variable region of the humanized antibody are substituted (the amino acid positions are determined according to the Kabat numbering rules).
  • the humanized light chain templates are FR1, FR2, and FR3 selected from IGKV2-40*01, IGKV4-1*01, IGKV3-20*01, and IGKV1-39*01, and FR4 selected from IGKJ4*01.
  • the humanized heavy chain templates are FR1, FR2, and FR3 selected from IGHV3-7*01, and FR4 selected from IGHJ6*01.
  • the humanized antibody design for the mouse antibody mAb81 is shown in Table 6 below.
  • Graft represents the insertion of a murine antibody CDR into the human FR region; "I2V” indicates that the second I is mutated to V according to the Kabat numbering system, and so on.
  • the modified CDR sequence of the mAb81 humanized antibody is shown in Table 7 below:
  • modified mAb81 humanized antibody light chain variable region/heavy chain variable region sequences are as follows:
  • the humanized light chain templates for the mouse antibody mAb84 were FR1, FR2, and FR3 of IGKV2-29*02 and FR4 of IGKJ4*01, respectively.
  • the humanized heavy chain templates were FR1, FR2, and FR3 of IGHV3-7*01 and FR4 of IGHJ6*01, respectively.
  • the CDRs of the mouse antibody mAb84 were transplanted into their respective humanized templates.
  • amino acid residues at positions 2 and 45 of the variable region of the light chain of the humanized antibody were substituted; and amino acid residues at positions 28, 45, 76, 98, 99, and/or 100 of the variable region of the heavy chain of the humanized antibody were substituted (the mutation sites were determined according to the Kabat numbering rules).
  • the humanized antibody design for mAb84 is shown in Table 8 below.
  • Graft represents the insertion of a murine antibody CDR into the human FR region; "I2V” indicates that the second I is mutated to V according to the Kabat numbering system, and so on.
  • the modified CDR sequence of the mAb84 humanized antibody is shown in Table 9 below:
  • the light chain variable region/heavy chain variable region sequences of the mAb84 humanized antibody are as follows:
  • amino acids at positions 96, 98, and/or 100b of the heavy chain variable region (CDR) of Hu84VH6 were modified.
  • the modified CDR sequences of the mAb84 humanized antibody are shown in Table 10 below:
  • modified mAb84 humanized antibody light chain variable region/heavy chain variable region sequences are as follows:
  • FR1, FR2, and FR3 of IGKV4-1*01 and FR4 of IGKJ4*01 were selected as light chain framework region templates.
  • FR1, FR2, and FR3 of IGHV3-21*01 and FR4 of IGHJ6*01 were selected as heavy chain framework region templates.
  • the CDR of the mouse antibody mAb89 was transplanted into its humanized template.
  • amino acid residues at positions 4, 58, 68, and/or 85 on the variable region of the light chain of the humanized antibody were substituted; and amino acid residues at positions 28, 40, 42, 44, 49, and/or 93 on the variable region of the heavy chain of the humanized antibody were substituted (the mutation sites were determined according to the Kabat numbering rules).
  • the humanized antibody design of mAb89 is shown in Table 11 below:
  • Graft represents the insertion of a murine antibody CDR into the human FR region; "M4L” indicates that the fourth M is mutated to L according to the Kabat numbering system, and so on.
  • the light chain variable region/heavy chain variable region sequences of the mAb89 humanized antibody are as follows:
  • the underlined part is the CDR sequence determined according to the Kabat numbering system
  • the non-underlined part is the FR sequence.
  • the heavy chain variable region sequence of the mAb89 humanized antibody is as follows:
  • the heavy chain constant region of the antibody can be selected from the heavy chain constant regions of human IgG1, IgG2, IgG3, IgG4, or their variants, and the light chain constant region can be selected from the light chain constant regions of human ⁇ , ⁇ chains, or their variants.
  • the antibody heavy chain constant region is the human IgG1 heavy chain constant region
  • the light chain constant region is the human ⁇ light chain constant region.
  • Human81001 indicates that the heavy chain variable region is Hu81VH1 (SEQ ID NO: 42), the light chain variable region is Hu81VL1 (SEQ ID NO: 37), and the heavy chain constant region is as shown in SEQ ID NO: 23, the light chain constant region is as shown in SEQ ID NO: 24, and so on for other humanized antibodies.
  • Human84001 indicates that the heavy chain variable region is Hu84VH1 (SEQ ID NO: 99), the light chain variable region is Hu84VL1 (SEQ ID NO: 97), and the heavy chain constant region is as shown in SEQ ID NO: 23, and the light chain constant region is as shown in SEQ ID NO: 24, and so on for other humanized antibodies.
  • Human89001 indicates that the heavy chain variable region is Hu89VH1 (SEQ ID NO: 132), the light chain variable region is Hu89VL1 (SEQ ID NO: 129), and the heavy chain constant region is as shown in SEQ ID NO: 23, and the light chain constant region is as shown in SEQ ID NO: 24, and so on for other humanized antibodies.
  • Heavy chain sequences Hu81003, Hu81035, Hu81067, Hu81099, Hu81131
  • Heavy chain sequences Hu81004, Hu81036, Hu81068, Hu81100, Hu81132, Hu81164, Hu81196, Hu81228, Hu81260
  • Heavy chain sequences Hu81005, Hu81037, Hu81069, Hu81101, Hu81133, Hu81165, Hu81197, Hu81229, Hu81261
  • Heavy chain sequences Hu81072, Hu81168, Hu81200, Hu81232, Hu81264
  • Light chain sequence Hu81065, Hu81066, Hu81067, Hu81068, Hu81069, Hu81070, Hu81071, Hu81072, Hu81073, Hu81074, Hu81075, Hu81076, Hu81077, Hu81078, Hu81079, Hu81080
  • Hu81260 Hu81261, Hu81264, Hu81273, Hu81274, Hu81275, Hu81276, Hu81277, Hu81278, Hu81279, Hu81280, Hu81281, Hu81282, Hu81283, Hu81284, Hu81285, Hu81286, Hu81287, Hu81288
  • the underlined portion is the variable region sequence
  • the ununderlined portion is the constant region sequence
  • this disclosure uses the fusion of the mouse mIgG2a heavy chain constant region and the mouse m ⁇ light chain constant region with a humanized variable region to obtain a chimeric antibody in the form of mIgG2a.
  • the relevant sequence of the chimeric antibody in the form of mIgG2a is as follows:
  • Underlined regions represent variable regions, while non-underlined regions represent constant regions.
  • this disclosure uses an hIgG1 antibody as an isotype antibody control (whose VH/VL is derived from the C25 antibody of patent US6114143A), and the relevant sequence is as follows:
  • human N3pGlu-40 A ⁇ is used as the antigen for detection in this disclosure, and the relevant sequence is as follows:
  • Test Example 1 ELISA Affinity Assay for Anti-N3pGlu A ⁇ Antibody
  • N3pGlu A ⁇ monomers The synthesized N3pGlu-40 A ⁇ (Jier Biochemical) and N3pGlu-42 A ⁇ (medium peptide) polypeptide powders were dissolved in 100% DMSO and dispensed at a concentration of 1 mg/mL for use.
  • N3pGlu A ⁇ Fibers The synthesized N3pGlu-42 A ⁇ (medium peptide) polypeptide powder was dissolved in DMSO (10 ⁇ L DMSO for 0.5 mg peptide), and then deionized water was added to prepare a solution (434 ⁇ L deionized water for 0.5 mg peptide). The solution was incubated at 37°C for 11 days to obtain N3pGlu-42 A ⁇ fibers, which were then dispensed for use.
  • N3pGlu-40 A ⁇ monomer, N3pGlu-42 A ⁇ monomer, and N3pGlu-42 A ⁇ fiber were each 2 ⁇ g/mL and 50 ⁇ L/well coated in an ELISA plate (corning, 3590), and incubated overnight at 4°C. Discard the liquid, then block the plate with 200 ⁇ L/well of 1% BSA at room temperature for 1 hour. Discard the blocking solution, then wash the plate three times with PBST (PBS solution containing 0.1% Tween 20).
  • PBST PBS solution containing 0.1% Tween 20
  • Test Example 2 Biacore Affinity Assay for Anti-N3pGlu A ⁇ Antibody
  • Antibodies were affinity-captured using a Protein A biosensor chip (GE, 29127556), and then the antigen-human N3pGlu-42 A ⁇ monomer was flowed onto the chip surface. The reaction signal was monitored in real time using a Biacore T200 (GE) instrument to obtain binding and dissociation curves. After dissociation in each experimental cycle, the biosensor chip was washed and regenerated with 10 mM Glycine-HCl (pH 1.5) (GE, BR-1003-54). A 1:1 model was used for data fitting. The experimental results are shown in Table 17 below.
  • N3pGlu-42 A ⁇ fibers were coupled to a CM5 biosensor chip via amino-coupling. Antibody molecules were then flowed through the chip surface, and the reaction signal was monitored in real-time using a Biacore 8K instrument to obtain binding and dissociation curves. After dissociation in each experimental cycle, the biosensor chip was washed and regenerated with NaOH 50 and Glycine 1.5. The data fitting model employed either a kinetic 1:1 binding or a Steady State model. The experimental results are shown in Table 18 below.
  • Test Example 3 Experiment on blocking N3pGlu-42 A ⁇ monomers to form fibrils using anti-N3pGlu A ⁇ antibody
  • This experiment used thioflavin T (ThT) (sigma, T3516) to detect the content of N3pGlu-42 A ⁇ fibers in the reaction system, thereby determining the ability of the test antibody to block the aggregation of N3pGlu-42 A ⁇ monomers to form N3pGlu-42 A ⁇ fibers.
  • Thioflavin T can rapidly and specifically bind to antiparallel ⁇ -sheet N3pGlu-42 A ⁇ fibers, but it does not bind to N3pGlu-42 A ⁇ monomers or oligomers. After binding to N3pGlu-42 A ⁇ fibers, thioflavin T produces a characteristic 120nm red excitation spectral transfer, which can be used for the quantitative detection of N3pGlu-42 A ⁇ fibers.
  • N3pGlu-42 A ⁇ polypeptide was monomerized with sodium hydroxide (Sigma, G19852D), dissolved in a buffer system with ThT, and 3.4 ⁇ M of antibody was added. The mixture was incubated at 37 °C in a 384-well plate (corning, 4514) for 24 hours. Fluorescence absorbance was measured on a FlexStation3 (Molecular Devices) with excitation wavelength of 440 nm and emission wavelength of 485 nm. The effect of different antibody concentrations on the aggregation of N3pGlu-42 A ⁇ monomers to form N3pGlu-42 A ⁇ fibers was analyzed by fluorescence intensity. The inhibition rate of the antibody against the aggregation of N3pGlu-42 A ⁇ monomers to form N3pGlu-42 A ⁇ fibers was calculated using the detected fluorescence signals, as shown in the following formula:
  • Inhibition rate % (Negative control wells with fluorescent signals - Antibody wells with fluorescent signals) / Negative control wells with fluorescent signals ⁇ 100%
  • Test Example 4 N3pGlu A ⁇ antibody promotes BV2 phagocytosis of N3pGlu-42 A ⁇ fibrils
  • BV2 mouse microglia
  • N3pGlu A ⁇ antibodies against N3pGlu A ⁇ fibrils The experimental method is as follows:
  • Log-phase BV2 cells (China Center for Type Culture Collection, 3142C0001000000337) were passaged in F12-K (Gibco, 21127022) complete medium and plated in 96-well flat-bottomed plates (Corning, 3599), 3 ⁇ 104 cells per well. N3pGlu A ⁇ antibodies were serially diluted with F12-K complete medium. To 100 ⁇ L of culture from overnight-platened BV2 cells, 80 ⁇ L of medium was aspirated, and 20 ⁇ L of antibody was added to each well. The mixture was incubated at room temperature for 5 minutes.
  • N3pGlu-42 A ⁇ cellulose Zhongtai Biochemical labeled with Alexa Fluor 488 (Thermo, A30006) was added to each well, mixed, and incubated at 37°C for 80 minutes. Cells were pipetted 5-10 times using a pipette tip. Adherent cells were observed to detach under a microscope (OLYNPUS, CKX53). Cells were transferred to a 96-well U-plate (Corning, 3795), centrifuged at 1000g for 1 minute, and the supernatant was discarded.
  • Normalization calculation formula (test antibody MFI value - antibody-free MFI background value) / (hIgG1 antibody MFI value - antibody-free MFI background value), where the antibody-free MFI background value is 3253.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Urology & Nephrology (AREA)
  • Neurosurgery (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Pathology (AREA)
  • Cell Biology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

提供抗N3pGlu Aβ抗体及其医药用途；及抗N3pGlu Aβ抗体在制备治疗或预防与N3pGlu Aβ相关的疾病或病症的药物中的用途。

Description

抗N3pGlu Aβ抗体及其医药用途
本申请要求2024年5月16日提交的中国专利申请CN202410608148.7的优先权。
技术领域
本披露属于生物技术领域，更具体地，本披露涉及抗N3pGlu Aβ抗体及其医药用途。
背景技术
这里的陈述仅提供与本披露有关的背景信息，而不必然地构成现有技术。
阿尔茨海默病(Alzheimer's disease，简称AD)，又称老年痴呆，是一种严重的神经系统退行性疾病，其主要临床表现为认知功能减退、精神症状、行为障碍，严重者丧失基本生活能力。目前普遍认为，β-淀粉样蛋白(amyloidβ-protein，简称Aβ)沉积的发生，触发神经纤维缠结，造成神经细胞间突触减少、细胞死亡和认知能力的减退(Corbett A,et al.Nature reviews.Drug discovery,2012,11(11):833–846)。但造成Aβ沉积的原因，以及Aβ沉积对神经细胞造成损伤的机制仍旧模糊。近年，FDA连续获批Aducanumab和Lecanemab两种Aβ抗体药物用于阿尔茨海默病早期治疗，说明Aβ清除与临床收益存在量效关系，但其应用仍受限于Aβ中枢清除效率不足和脑出血、脑水肿等不良反应(Karran E,et al.Nature reviews.Drug discovery,2022,21(4):306–318)。
脑内斑块是阿尔茨海默病的最主要病理之一，N3pGlu Aβ肽主要存在于脑内斑块中，N端修饰肽的形成可能增强β-淀粉样蛋白聚集和毒性，恶化疾病的发生和进展。(Russo C,et al.Journal of neurochemistry,2002,82(6):1480–1489；Piccini A,et al.The Journal of biological chemistry,2005,280(40):34186–34192)。抗N3pGlu Aβ抗体可以特异性清除阿尔茨海默病患者脑内斑块，更高效、快速地清除Aβ沉积，治疗阿尔茨海默病。WO2012021469A1、WO2017009459A2、WO2018194951A1、WO2018083628A1、WO2019149689A1、WO2020193644A1等专利公开了抗N3pGlu Aβ抗体。
发明内容
本披露提供一种抗N3pGlu Aβ抗体，其包含重链可变区和轻链可变区，其中，所述重链可变区包含HCDR1、HCDR2和HCDR3，和所述轻链可变区包含LCDR1、LCDR2和LCDR3，其中：
(1)所述重链可变区的HCDR1包含SEQ ID NO：229的氨基酸序列，HCDR2包含SEQ ID NO：230的氨基酸序列，和HCDR3包含SEQ ID NO：231的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：232的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列，其中：
DX1GX2X3       SEQ ID NO：229；
FX4SX5LAYNIYYX6X7TVTG       SEQ ID NO：230；
YIFX8GYYX9YAMDY            SEQ ID NO：231；
RSSQSLVHSX10X11NTYFH        SEQ ID NO：232；
X1为Y、K或H；X2为M或Q；X3为A或G；
X4为I或P；X5为N或L；X6为A或G；X7为D、E或Q；
X8为D、E、Q、L或S；X9为D、E、L、Y或G；
X10为N、Y、S或T；X11为G或V；或
(2)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：233的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；其中：
YX12YX13X14X15IX16YVMDY    SEQ ID NO：233；
X12为D、Q或E；X13为D、E、N、Q或T；X14为D或E；X15为V或G；X16为D、T或E；或
(3)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：234的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；其中：
EVIYX17GYYYAMX18Y    SEQ ID NO：234；
X17为D或E；X18为D或E。
本披露提供一种抗N3pGlu Aβ抗体，其包含重链可变区和轻链可变区，其中，所述重链可变区包含HCDR1、HCDR2和HCDR3，和所述轻链可变区包含LCDR1、LCDR2和LCDR3，其中：
(1)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：88、42、45、69、78、79、80、91、43、44、46、67、68、70、71、72、73、74、75、76、77、81、82、83、84、85、86、87、89、90、92或93中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：66、37、38、39、65、40、41、63或64中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：17中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：18中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
(2)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：119、100、102、104、122、99、101、103、117、118、120、121、123、124、125、126、127或128中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：97或98中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：19中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：20中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
(3)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：141、132、133、137、134、138、139或140中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：129、131或130中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：21中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：22中的LCDR1、LCDR2和LCDR3的氨基酸序列；
优选地，
(1)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：88、42、45、69、78、79、80或91中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：66、37、38、39或65中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：17中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：18中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
(2)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：119、100、102、104或122中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：97中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：19中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：20中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
(3)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：141、132、133或137中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：129或131中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：21中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：22中的LCDR1、LCDR2和LCDR3的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：88、69、78、79、80或91中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：66中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：88或42中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：37中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：45中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：38中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：42或69中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：39中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：17中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：18中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：43、44、45或46中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：37中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：42、43、44或46中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：38中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：43、44、45、46、67、68、70、71、72、73、74、75、76或77中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：39中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：42、43、44、45或46中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：40中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：42、43、44、45或46中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：41中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：45、46或69中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：63中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：45、46或69中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：64中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：45或46中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：65中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：45、46、81、82、83、84、85、86、87、89、90、92或93中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：66中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
(2)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：119、110、102、104或122中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：97中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：19中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：20中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：99、101、103、117、118、120、121、123、124、125、126、127或128中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：97中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：99、100、101、102、103、104、117、118、119、120、121、122、123、124、125、126、127或128中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：98中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
(3)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：141、132、133或137中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：129中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：133中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：131中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：21中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：22中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：134、138、139或140中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：129中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：132、133、134、137、138、139、140或141中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：130中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：132、134、137、138、139、140或141中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3包含SEQ ID NO：131中的LCDR1、LCDR2和LCDR3的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：88中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：66中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
(2)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：119中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：97中的LCDR1、LCDR2和LCDR3的氨基酸序列；或
(3)所述重链可变区的HCDR1、HCDR2和HCDR3分别包含SEQ ID NO：141中的HCDR1、HCDR2和HCDR3的氨基酸序列，和所述轻链可变区的LCDR1、LCDR2和LCDR3分别包含SEQ ID NO：129中的LCDR1、LCDR2和LCDR3的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，所述重链可变区的HCDR1、HCDR2和HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3是根据选自Kabat、IMGT、Chothia、AbM和Contact编号规则定义的。在一些实施方案中，所述重链可变区的HCDR1、HCDR2和HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3是根据Kabat编号规则定义的。在一些实施方案中，所述重链可变区的HCDR1、HCDR2和HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3是根据IMGT编号规则定义的。在一些实施方案中，所述重链可变区的HCDR1、HCDR2和HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3是根据Chothia编号规则定义的。在一些实施方案中，所述重链可变区的HCDR1、HCDR2和HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3是根据AbM编号规则定义的。在一些实施方案中，所述重链可变区的HCDR1、HCDR2和HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3是根据Contact编号规则定义的。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区的HCDR1包含SEQ ID NO：49、1、35、47或48的氨基酸序列，HCDR2包含SEQ ID NO：52、2、36、53、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：54、3、58、55、56、57、59、60、61或62的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32、4、31、33或34的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
(2)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107、8、94、96、110、95、105、106、108、109、111、112、113、114、115或116的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
(3)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136、13或135的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；
优选地，
(1)所述重链可变区的HCDR1包含SEQ ID NO：49或1的氨基酸序列，HCDR2包含SEQ ID NO：52、2、36或53的氨基酸序列，和HCDR3包含SEQ ID NO：54、3或58的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32、4或31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
(2)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107、8、94、96或110的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
(3)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136、13或135的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：4的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：58的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：35的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：4的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：4的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：35的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：36、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：35的氨基酸序列，HCDR2包含SEQ ID NO：2或36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：47的氨基酸序列，HCDR2包含SEQ ID NO：36、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：48的氨基酸序列，HCDR2包含SEQ ID NO：36、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：55、56、57、58、59、60或61的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：50或51的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：58或62的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：54或62的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：33的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：33的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：34的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：34的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
(2)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：8的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：94的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：96的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：110的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：95、105、106、108、109、111、112、113、114、115或116的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
(3)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：13的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：135的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中，
(1)所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52或36的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52、36或53的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：58的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：4的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
(2)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107、8、94、96或110的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
(3)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136、13或135的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，所述重链可变区的HCDR1、HCDR2和HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3是根据Kabat编号规则定义的。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中，所述的抗N3pGlu Aβ抗体为鼠源抗体、嵌合抗体、人源化抗体或全人源抗体。在一些实施方案中，所述抗N3pGlu Aβ抗体为鼠源抗体、嵌合抗体或人源化抗体。在一些实施方案中，所述抗N3pGlu Aβ抗体是嵌合抗体或人源化抗体。在一些实施方案中，所述抗N3pGlu Aβ抗体是嵌合抗体。在一些实施方案中，所述抗N3pGlu Aβ抗体是人源化抗体。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中所述抗N3pGlu Aβ抗体为人源化、回复突变、亲和力成熟、去除T细胞表位、降低抗体脱酰胺和/或降低抗体异构化改造的。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其包含人抗体的框架区(FR)。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，所述重链可变区具有来源于IGHV3-7*01的FR1、FR2、FR3和来源于IGHJ6*01的FR4，并且其是未被取代的或包含选自3K、30R、45P和93V组成的组中的一个或多个氨基酸取代；和/或所述轻链可变区具有来源于IGKV2-40*01、IGKV4-1*01、IGKV3-20*01或IGKV1-39*01的FR1、FR2、FR3和来源于IGKJ4*01的FR4，并且其是未被取代的或包含选自2V、43S和45K组成的组中的一个或多个氨基酸取代。在一些实施方案中，所述的抗N3pGlu Aβ抗体，其中，所述重链可变区的HCDR1包含SEQ ID NO：49、1、35、47或48的氨基酸序列，HCDR2包含SEQ ID NO：52、2、36、53、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：54、3、58、55、56、57、59、60、61或62的氨基酸序列，且所述重链可变区的FR是未被取代的或包含选自3K、30R、45P和93V组成的组中的一个或多个氨基酸取代；和所述轻链可变区的LCDR1包含SEQ ID NO：32、4、31、33或34的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列，且所述轻链可变区的FR是未被取代的或包含选自2V、43S和45K组成的组中的一个或多个氨基酸取代。在一些实施方案中，上述可变区和CDR是根据Kabat编号规则定义的。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，所述重链可变区具有来源于IGHV3-7*01的FR1、FR2、FR3和来源于IGHJ6*01的FR4，并且其是未被取代的或包含选自28S、45P和76K组成的组中的一个或多个氨基酸取代；和/或所述轻链可变区具有来源于IGKV2-29*02的FR1、FR2、FR3和来源于IGKJ4*01的FR4，并且其是未被取代的或包含选自2V和45K组成的组中的一个或多个氨基酸取代。在一些实施方案中，所述的抗N3pGlu Aβ抗体，其中，所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107、8、94、96、110、95、105、106、108、109、111、112、113、114、115或116的氨基酸序列，且所述重链可变区的FR是未被取代的或包含选自28S、45P和76K组成的组中的一个或多个氨基酸取代；和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列，且所述轻链可变区的FR是未被取代的或包含选自2V和45K组成的组中的一个或多个氨基酸取代。在一些实施方案中，上述可变区和CDR是根据Kabat编号规则定义的。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，所述重链可变区具有来源于IGHV3-21*01的FR1、FR2、FR3和来源于IGHJ6*01的FR4，并且其是未被取代的或包含选自28I、40T、42D、44R、49A和93G组成的组中的一个或多个氨基酸取代；和/或所述轻链可变区具有来源于IGKV4-1*01的FR1、FR2、FR3和来源于IGKJ4*01的FR4，并且其是未被取代的或具有包含4L、58I、68R和85T组成的组中的一个或多个氨基酸取代。在一些实施方案中，所述的抗N3pGlu Aβ抗体，其中，所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136、13或135的氨基酸序列，且所述重链可变区的FR是未被取代的或包含选自28I、40T、42D、44R、49A和93G组成的组中的一个或多个氨基酸取代；和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列，且所述轻链可变区的FR是未被取代的或包含选自4L、58I、68R和85T组成的组中的一个或多个氨基酸取代。在一些实施方案中，上述可变区和CDR是根据Kabat编号规则定义的。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区包含与SEQ ID NO：88、42、45、69、78、79、80、91、43、44、46、67、68、70、71、72、73、74、75、76、77、81、82、83、84、85、86、87、89、90、92或93具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：66、37、38、39、65、40、41、63或64具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链可变区包含与SEQ ID NO：17具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：18具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
(2)所述重链可变区包含与SEQ ID NO：119、100、102、104、122、99、101、103、117、118、120、121、123、124、125、126、127或128具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：97或98具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链可变区包含与SEQ ID NO：19具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：20具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
(3)所述重链可变区包含与SEQ ID NO：141、132、133、137、134、138、139或140具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：129、131或130具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链可变区包含与SEQ ID NO：21具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：22具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区包含SEQ ID NO：88、42、45、69、78、79、80、91、43、44、46、67、68、70、71、72、73、74、75、76、77、81、82、83、84、85、86、87、89、90、92或93的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66、37、38、39、65、40、41、63或64的氨基酸序列；或
所述重链可变区包含SEQ ID NO：17的氨基酸序列，和所述轻链可变区包含SEQ ID NO：18的氨基酸序列；或
(2)所述重链可变区包含SEQ ID NO：119、100、102、104、122、99、101、103、117、118、120、121、123、124、125、126、127或128的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97或98的氨基酸序列；或
所述重链可变区包含SEQ ID NO：19的氨基酸序列，和所述轻链可变区包含SEQ ID NO：20的氨基酸序列；或
(3)所述重链可变区包含SEQ ID NO：141、132、133、137、134、138、139或140的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129、131或130的氨基酸序列；或
所述重链可变区包含SEQ ID NO：21的氨基酸序列，和所述轻链可变区包含SEQ ID NO：22的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区包含SEQ ID NO：88、42、45、69、78、79、80或91的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66、37、38、39或65的氨基酸序列；或
所述重链可变区包含SEQ ID NO：17的氨基酸序列，和所述轻链可变区包含SEQ ID NO：18的氨基酸序列；或
(2)所述重链可变区包含SEQ ID NO：119、100、102、104或122的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：19的氨基酸序列，和所述轻链可变区包含SEQ ID NO：20的氨基酸序列；或
(3)所述重链可变区包含SEQ ID NO：141、132、133或137的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129或131的氨基酸序列；或
所述重链可变区包含SEQ ID NO：21的氨基酸序列，和所述轻链可变区包含SEQ ID NO：22的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区包含SEQ ID NO：88的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：17的氨基酸序列，和所述轻链可变区包含SEQ ID NO：18的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42的氨基酸序列，和所述轻链可变区包含SEQ ID NO：37的氨基酸序列；或
所述重链可变区包含SEQ ID NO：45的氨基酸序列，和所述轻链可变区包含SEQ ID NO：38的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42的氨基酸序列，和所述轻链可变区包含SEQ ID NO：39的氨基酸序列；或
所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：39的氨基酸序列；或
所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：65的氨基酸序列；或
所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：78的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：79的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：80的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：91的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：43、44、45或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：37的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42、43、44或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：38的氨基酸序列；或
所述重链可变区包含SEQ ID NO：43、44、45、46、67、68、70、71、72、73、74、75、76或77的氨基酸序列，和所述轻链可变区包含SEQ ID NO：39的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42、43、44、45或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：40的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42、43、44、45或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：41的氨基酸序列；或
所述重链可变区包含SEQ ID NO：45、46或69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：63的氨基酸序列；或
所述重链可变区包含SEQ ID NO：45、46或69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：64的氨基酸序列；或
所述重链可变区包含SEQ ID NO：45或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：65的氨基酸序列；或
所述重链可变区包含SEQ ID NO：45、46、81、82、83、84、85、86、87、89、90、92或93的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
(2)所述重链可变区包含SEQ ID NO：119的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：19的氨基酸序列，和所述轻链可变区包含SEQ ID NO：20的氨基酸序列；或
所述重链可变区包含SEQ ID NO：100的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：102的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：104的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：122的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：99、101、103、117、118、120、121、123、124、125、126、127或128的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：99、100、101、102、103、104、117、118、119、120、121、122、123、124、125、126、127或128的氨基酸序列，和所述轻链可变区包含SEQ ID NO：98的氨基酸序列；或
(3)所述重链可变区包含SEQ ID NO：141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：21的氨基酸序列，和所述轻链可变区包含SEQ ID NO：22的氨基酸序列；或
所述重链可变区包含SEQ ID NO：132的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：133的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：137的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：133的氨基酸序列，和所述轻链可变区包含SEQ ID NO：131的氨基酸序列；或
所述重链可变区包含SEQ ID NO：134、138、139或140的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：132、133、134、137、138、139、140或141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：130的氨基酸序列；或
所述重链可变区包含SEQ ID NO：132、134、137、138、139、140或141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：131的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区包含SEQ ID NO：88、69、78、79、80或91的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42的氨基酸序列，和所述轻链可变区包含SEQ ID NO：37的氨基酸序列；或
所述重链可变区包含SEQ ID NO：45的氨基酸序列，和所述轻链可变区包含SEQ ID NO：38的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42或69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：39的氨基酸序列；或
所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：65的氨基酸序列；或
所述重链可变区包含SEQ ID NO：17的氨基酸序列，和所述轻链可变区包含SEQ ID NO：18的氨基酸序列；或
(2)所述重链可变区包含SEQ ID NO：119、100、102、104或122的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：19的氨基酸序列，和所述轻链可变区包含SEQ ID NO：20的氨基酸序列；或
(3)所述重链可变区包含SEQ ID NO：141、132、133或137的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：133的氨基酸序列，和所述轻链可变区包含SEQ ID NO：131的氨基酸序列；或
所述重链可变区包含SEQ ID NO：21的氨基酸序列，和所述轻链可变区包含SEQ ID NO：22的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中所述抗N3pGlu Aβ抗体是抗原结合片段(抗体片段)。在一些实施方案中，所述的抗N3pGlu Aβ抗原结合片段(抗体片段)选自Fab、Fab′、F(ab′)2、Fd、Fv、scFv和dsFv。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中所述抗体包含重链恒定区和轻链恒定区。在一些实施方案中，所述重链恒定区为人IgG1、IgG2、IgG3、IgG4或其变体、或鼠mIgG2a或其变体的重链恒定区，和所述轻链恒定区为人κ链、λ链或其变体、或鼠κ链、λ链或其变体的轻链恒定区。在一些实施方案中，所述重链恒定区为人IgG1、IgG2、IgG3、IgG4或其变体的重链恒定区，和所述轻链恒定区为人κ链、λ链或其变体的轻链恒定区。在一些实施方案中，所述重链恒定区为人IgG1或鼠mIgG2a的重链恒定区，和所述轻链恒定区为人κ链或鼠κ链的轻链恒定区。在一些实施方案中，所述重链恒定区为鼠mIgG2a重链恒定区，和所述轻链恒定区为鼠κ轻链恒定区。在一些实施方案中，所述重链恒定区为人IgG1重链恒定区，和所述轻链恒定区为人κ轻链恒定区。在一些实施方案中，所述重链恒定区包含SEQ ID NO：23或225的氨基酸序列，和所述轻链恒定区包含SEQ ID NO：24或226的氨基酸序列。在一些实施方案中，所述重链恒定区包含SEQ ID NO：225的氨基酸序列，和所述轻链恒定区包含SEQ ID NO：226的氨基酸序列。在一些实施方案中，所述重链恒定区包含SEQ ID NO：23的氨基酸序列，和所述轻链恒定区包含SEQ ID NO：24的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中所述的抗N3pGlu Aβ抗体包含重链和轻链，其中：
(1)所述重链包含与SEQ ID NO：169、143、146、150、159、160、161、172、144、145、147、148、149、151、152、153、154、155、156、157、158、162、163、164、165、166、167、168、170、171、173或174具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：183、175、176、177、182、178、179、180或181具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链包含与SEQ ID NO：25具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：26具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链包含与SEQ ID NO：219具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：220具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
(2)所述重链包含与SEQ ID NO：192、185、187、189、195、184、186、188、190、191、193、194、196、197、198、199、200或201具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：202或203具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链包含与SEQ ID NO：27具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：28具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链包含与SEQ ID NO：221具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：222具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
(3)所述重链包含与SEQ ID NO：211、204、205、207、206、208、209或210具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：212、214或213具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链包含与SEQ ID NO：29具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：30具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；或
所述重链包含与SEQ ID NO：223具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：224具有至少75％(例如至少75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％)序列同一性的氨基酸序列；
优选地，
(1)所述重链包含SEQ ID NO：169、143、146、150、159、160、161、172、144、145、147、148、149、151、152、153、154、155、156、157、158、162、163、164、165、166、167、168、170、171、173或174的氨基酸序列，和所述轻链包含SEQ ID NO：183、175、176、177、182、178、179、180或181的氨基酸序列；或
所述重链包含SEQ ID NO：25的氨基酸序列，和所述轻链包含SEQ ID NO：26的氨基酸序列；或
所述重链包含SEQ ID NO：219的氨基酸序列，和所述轻链包含SEQ ID NO：220的氨基酸序列；或
(2)所述重链包含SEQ ID NO：192、185、187、189、195、184、186、188、190、191、193、194、196、197、198、199、200或201的氨基酸序列，和所述轻链包含SEQ ID NO：202或203的氨基酸序列；或
所述重链包含SEQ ID NO：27的氨基酸序列，和所述轻链包含SEQ ID NO：28的氨基酸序列；或
所述重链包含SEQ ID NO：221的氨基酸序列，和所述轻链包含SEQ ID NO：222的氨基酸序列；或
(3)所述重链包含SEQ ID NO：211、204、205、207、206、208、209或210的氨基酸序列，和所述轻链包含SEQ ID NO：212、214或213的氨基酸序列；或
所述重链包含SEQ ID NO：29的氨基酸序列，和所述轻链包含SEQ ID NO：30的氨基酸序列；或
所述重链包含SEQ ID NO：223的氨基酸序列，和所述轻链包含SEQ ID NO：224的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链包含SEQ ID NO：169、143、146、150、159、160、161或172的氨基酸序列，和所述轻链包含SEQ ID NO：183、175、176、177或182的氨基酸序列；或
所述重链包含SEQ ID NO：25的氨基酸序列，和所述轻链包含SEQ ID NO：26的氨基酸序列；或
所述重链包含SEQ ID NO：219的氨基酸序列，和所述轻链包含SEQ ID NO：220的氨基酸序列；或
(2)所述重链包含SEQ ID NO：192、185、187、189或195的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
所述重链包含SEQ ID NO：27的氨基酸序列，和所述轻链包含SEQ ID NO：28的氨基酸序列；或
所述重链包含SEQ ID NO：221的氨基酸序列，和所述轻链包含SEQ ID NO：222的氨基酸序列；或
(3)所述重链包含SEQ ID NO：211、204、205或207的氨基酸序列，和所述轻链包含SEQ ID NO：212或214的氨基酸序列；或
所述重链包含SEQ ID NO：29的氨基酸序列，和所述轻链包含SEQ ID NO：30的氨基酸序列；或
所述重链包含SEQ ID NO：223的氨基酸序列，和所述轻链包含SEQ ID NO：224的氨基酸序列。
在一些实施方案中，如上任一项所述的抗N3pGlu Aβ抗体，其中：
(1)所述重链包含SEQ ID NO：169、150、159、160、161或172的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
所述重链包含SEQ ID NO：25的氨基酸序列，和所述轻链包含SEQ ID NO：26的氨基酸序列；或
所述重链包含SEQ ID NO：143的氨基酸序列，和所述轻链包含SEQ ID NO：175的氨基酸序列；或
所述重链包含SEQ ID NO：146的氨基酸序列，和所述轻链包含SEQ ID NO：176的氨基酸序列；或
所述重链包含SEQ ID NO：143或150的氨基酸序列，和所述轻链包含SEQ ID NO：177的氨基酸序列；或
所述重链包含SEQ ID NO：150的氨基酸序列，和所述轻链包含SEQ ID NO：182的氨基酸序列；或
所述重链包含SEQ ID NO：219的氨基酸序列，和所述轻链包含SEQ ID NO：220的氨基酸序列；或
(2)所述重链包含SEQ ID NO：192、185、187、189或195的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
所述重链包含SEQ ID NO：27的氨基酸序列，和所述轻链包含SEQ ID NO：28的氨基酸序列；或
所述重链包含SEQ ID NO：221的氨基酸序列，和所述轻链包含SEQ ID NO：222的氨基酸序列；或
(3)所述重链包含SEQ ID NO：211、204、205或207的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
所述重链包含SEQ ID NO：29的氨基酸序列，和所述轻链包含SEQ ID NO：30的氨基酸序列；或
所述重链包含SEQ ID NO：205的氨基酸序列，和所述轻链包含SEQ ID NO：214的氨基酸序列；或
所述重链包含SEQ ID NO：223的氨基酸序列，和所述轻链包含SEQ ID NO：224的氨基酸序列。
另一方面，本披露提供一种多特异性抗体，其包含如上任一项所述的抗N3pGlu Aβ抗体。在一些实施方案中，所述多特异性抗体是双特异性抗体。在一些实施方案中，所述多特异性抗体还包含结合血脑屏障受体的抗体。在一些实施方案中，所述多特异性抗体是结合N3pGlu Aβ和血脑屏障受体的双特异性抗体。
另一方面，本披露提供一种抗N3pGlu Aβ抗体，与如上任一项所述的抗N3pGlu Aβ抗体或如上任一项所述的多特异性抗体竞争结合人N3pGlu Aβ。
另一方面，本披露提供一种抗N3pGlu Aβ抗体，与与如上任一项所述的抗N3pGlu Aβ抗体或如上任一项所述的多特异性抗体结合相同的N3pGlu Aβ抗原表位。
另一方面，本披露提供一种药物组合物，其包含如上任一项所述的抗N3pGlu Aβ抗体或如上任一项所述的多特异性抗体，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
在一些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的如前任一项所述的抗N3pGlu Aβ抗体。在一些实施方案中，所述的药物组合物含有0.1-99.9％的如前任一项所述的抗N3pGlu Aβ抗体。在一些实施方案中，所述的药物组合物含有0.5％-99.5％的如前任一项所述的抗N3pGlu Aβ抗体。在一些实施方案中，所述的药物组合物含有1％-99％的如前任一项所述的抗N3pGlu Aβ抗体。在一些实施方案中，所述的药物组合物含有2％-98％的如前任一项所述的抗N3pGlu Aβ抗体。
在一些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的载体、稀释剂或赋形剂。在一些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的载体、稀释剂或赋形剂。在一些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的载体、稀释剂或赋形剂。在一些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的载体、稀释剂或赋形剂。在一些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的载体、稀释剂或赋形剂。
另一方面，本披露提供一种分离的核酸，其编码如上任一项所述的抗N3pGlu Aβ抗体或如上任一项所述的多特异性抗体。
另一方面，本披露提供一种载体，其包含如上任一项所述的分离的核酸。
另一方面，本披露提供一种宿主细胞，其包含如上任一项所述的分离的核酸或如上任一项所述的载体。在一些实施方案中，所述宿主细胞包含如上任一项所述的分离的核酸。在一些实施方案中，所述宿主细胞包含如上任一项所述的载体。
另一方面，本披露提供一种用于生产如上任一项所述的抗N3pGlu Aβ抗体或如上任一项所述的多特异性抗体的方法，所述方法包括将如上任一项所述的宿主细胞在培养基中进行培养以形成并积累如上任一项所述的抗N3pGlu Aβ抗体或如上任一项所述的多特异性抗体，以及从培养物回收所述抗体的步骤。
另一方面，本披露提供如上任一项所述的抗N3pGlu Aβ抗体，或如上任一项所述的多特异性抗体，或如上任一项所述的药物组合物在制备治疗或预防与N3pGlu Aβ相关的疾病或病症的药物中的用途。
另一方面，本披露提供一种治疗或预防与N3pGlu Aβ相关的疾病或病症的方法，所述方法包括向受试者施用治疗或预防有效量的如上任一项所述的抗N3pGlu Aβ抗体，或如上任一项所述的多特异性抗体，或如上任一项所述的药物组合物。
另一方面，本披露提供一种用作药物的如上任一项所述的抗N3pGlu Aβ抗体，或如上任一项所述的多特异性抗体，或如上任一项所述的药物组合物。在一些实施方案中，所述药物为治疗或预防与N3pGlu Aβ相关的疾病或病症的药物。
在一些实施方案中，如上任一项所述的与N3pGlu Aβ相关的疾病或病症为神经系统疾病、退行性疾病或脑血管病。
在一些实施方案中，如上任一项所述的与N3pGlu Aβ相关的疾病或病症为阿尔茨海默病、认知障碍或脑淀粉样蛋白血管病。
在一些实施方案中，如上任一项所述的与N3pGlu Aβ相关的疾病或病症为阿尔茨海默病。
在一些实施方案中，本披露提供的抗N3pGlu Aβ抗体，以小于15nM(例如小于12nM、小于10nM、小于8nM、小于6nM、小于4nM、小于2nM、小于1nM、小于0.5nM、小于0.1nM、小于0.05nM、小于0.01nM)的EC50值与N3pGlu-42 Aβ纤维结合，所述EC50值是通过ELISA测量的。
在一些实施方案中，本披露提供的抗N3pGlu Aβ抗体，以小于15nM(例如小于12nM、小于10nM、小于8nM、小于6nM、小于4nM、小于2nM、小于1nM、小于0.5nM、小于0.1nM、小于0.05nM、小于0.01nM)的EC50值与N3pGlu-40 Aβ单体结合，所述EC50值是通过ELISA测量的。
在一些实施方案中，本披露提供的抗N3pGlu Aβ抗体，以小于15nM(例如小于12nM、小于10nM、小于8nM、小于6nM、小于4nM、小于2nM、小于1nM、小于0.5nM、小于0.1nM、小于0.05nM、小于0.01nM)的EC50值与N3pGlu-42 Aβ单体结合，所述EC50值是通过ELISA测量的。
在一些实施方案中，本披露提供的抗N3pGlu Aβ抗体，以小于1E-07M(例如小于5E-08M、小于1E-08M、小于5E-09M、小于1E-09M、小于5E-10M、小于1E-10M、小于5E-11M、小于1E-11M、小于5E-12M、小于1E-12nM)的KD值与N3pGlu-42 Aβ单体结合，所述KD值是通过Biacore测量的。
在一些实施方案中，本披露提供的抗N3pGlu Aβ抗体，以小于1E-07M(例如小于5E-08M、小于1E-08M、小于5E-09M、小于1E-09M、小于5E-10M、小于1E-10M、小于5E-11M、小于1E-11M、小于5E-12M、小于1E-12nM)的KD值与N3pGlu-42 Aβ纤维结合，所述KD值是通过Biacore测量的。
在一些实施方案中，本披露提供的抗N3pGlu Aβ抗体，能够阻断N3pGlu-42 Aβ单体形成纤维，所述阻断活性相较于对照抗体(例如Remternetug)更强。
在一些实施方案中，本披露提供的抗N3pGlu Aβ抗体，能够介导BV2细胞对N3pGlu-42Aβ纤维的吞噬，所述吞噬活性相较于对照抗体(例如Donanemab)更强。
具体实施方式
术语
为了更容易理解本披露，以下对某些技术和科学术语进行了描述。除非在本文中另有明确定义，本文使用的全部技术和科学术语具有与本领域的普通技术人员通常所理解的相同含义。
说明书和权利要求书中所用的单数形式“一个”、“一种”和“所述”包括复数指代，除非上下文清楚表明并非如此。
除非上下文另外清楚要求，否则在专利说明书和权利要求书中，应将词语“包含”、“具有”、“包括”等理解为“包括但不仅限于”的意义，而不是排他性或穷举性意义。
术语“和/或”，意指包含“和”与“或”两种含义。例如短语“A、B和/或C”旨在涵盖以下方面中的每一个：A、B和C；A、B或C；A或C；A或B；B或C；A和C；A和B；B和C；A(单独)；B(单独)；和C(单独)。
术语“Aβ”，其别称包括但不限于“淀粉状蛋白β”、“β-淀粉状蛋白”、“淀粉样蛋白β”、“β-淀粉样蛋白”和“Abeta”，指淀粉样前体蛋白(amyloid precursor protein，APP)在β-分泌酶1(BACE1)切割APP后生成的片段，及其修饰片段和任何功能等同物，包括但不限于N3pGlu Aβ、Aβ1-40和Aβ1-42。已知Aβ以单体(mononer)形式存在，以及联合而形成寡聚体(oligomer)、原纤维(protofibril)、纤维(fibril)或斑块(plaque)。
术语“N3pGlu Aβ”指的是Aβ肽的N端第3位谷氨酸发生焦谷氨酸化的Aβ肽，其书写形式包括但不限于N3pE Aβ、3pE Aβ、3pGlu Aβ、pGlu3 Aβ、pE3 Aβ。N3pGlu Aβ包含Aβ肽的截短形式，包括但不限于N3pGlu-42 Aβ、N3pGlu-40 Aβ。示例性地，本披露中使用的N3pGlu Aβ缺乏Aβ肽的N端开头的2个氨基酸残基(天冬氨酸和丙氨酸)，并在Aβ肽的N端第3位谷氨酸发生焦谷氨酸化。这种N3pGlu Aβ更容易聚集，存在于阿尔茨海默病淀粉样蛋白沉积物中。
术语“中枢神经系统(central nervous system，CNS)”表示控制身体功能的神经组织的复合物，并且包括脑和脊髓。
术语“血脑屏障(blood brain barrier，BBB)”表示在外周循环与脑和脊髓之间的生理学屏障，其由脑毛细血管内皮质膜(brain capillary endothelial plasma membranes)的紧密连接组成，形成一个极其紧密的屏障，限制分子进入大脑的运输，即使是非常小的分子，如尿素(60Da)。脑内的血脑屏障、脊髓内的血液-脊髓屏障和视网膜内的血液-视网膜屏障是中枢神经系统内连续的毛细血管屏障，统称血脑屏障。血脑屏障还包括血液-脑脊液屏障(脉络丛)，所述屏障由室管膜细胞而非毛细管内皮细胞组成。
术语“血脑屏障受体(blood brain barrier receptor，BBBR)”是一类在脑内皮细胞上表达的细胞外膜连接受体蛋白(extracellular membrane-linked receptor protein)，其能够转运分子穿过血脑屏障，或用于转运外源施用的分子。
本披露所用氨基酸三字母代码和单字母代码如J.biol.chem，243，p3558(1968)中所述。
术语“氨基酸”是指天然存在的和合成的氨基酸，以及以与天然存在的氨基酸类似的方式起作用的氨基酸类似物和氨基酸模拟物。天然存在的氨基酸是由遗传密码编码的那些氨基酸，以及后来修饰的那些氨基酸，例如羟脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。氨基酸类似物是指与天然存在的氨基酸具有相同基本化学结构(即与氢、羧基、氨基和R基团结合的α碳)的化合物，例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜、甲硫氨酸甲基锍。此类类似物具有修饰的R基团(例如，正亮氨酸)或修饰的肽骨架，但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指具有与氨基酸的一般化学结构不同的结构，但是以与天然存在的氨基酸类似的方式起作用的化学化合物。
术语“氨基酸突变”包括氨基酸取代(也称氨基酸替换)、缺失、插入和修饰。可以进行取代、缺失、插入和修饰的任意组合来实现最终构建体，只要最终构建体拥有期望的特性，例如降低或对Fc受体的结合。氨基酸序列缺失和插入包括在多肽链的氨基端和/或羧基端的缺失和插入。具体的氨基酸突变可以是氨基酸取代。在一些实施方式中，氨基酸突变是非保守性的氨基酸取代，即将一个氨基酸用具有不同结构和/或化学特性的另一种氨基酸替换。氨基酸取代包括由非天然存在的氨基酸或由20种天然氨基酸的衍生物(例如4-羟脯氨酸、3-甲基组氨酸、鸟氨酸、高丝氨酸、5-羟赖氨酸)替换。可以使用本领域中公知的遗传或化学方法生成氨基酸突变。遗传方法可以包括定点诱变、PCR，基因合成等。预计基因工程以外的改变氨基酸侧链基团的方法，如化学修饰也可能是可用的。本文中可使用各种名称来指示同一氨基酸突变。本文中，可采用位置+氨基酸残基的方式表示特定位点的氨基酸残基，例如356K，表示在356位点上的氨基酸残基为K。D356K则表示第356位点上的氨基酸残基由原来的D突变为了K。应当理解，当权利要求中以位置+残基的方式限定氨基酸序列时，该位点突变前的氨基酸不对技术方案构成限制。
术语“多肽”和“蛋白质”在本文中可互换使用，指氨基酸残基的聚合物。该术语适用于氨基酸聚合物，其中一个或多个氨基酸残基是相应天然存在的氨基酸的人工化学模拟物，以及适用于天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。除非另外说明，否则特定的多肽序列还隐含地涵盖其保守修饰的变体。
术语“抗体”以最广义使用，并且涵盖各种抗体结构，包括但不限于单克隆抗体，多克隆抗体；单特异性抗体，多特异性抗体(例如双特异性抗体)；全长抗体和抗体片段(或抗原结合片段，或抗原结合部分)，只要它们展现出期望的抗原结合活性。
术语“抗原结合片段”涵盖全长抗体、Fab、修饰的Fab、Fab’、Fab′-SH、修饰的Fab’、F(ab’)2、Fv、dsFv、Fab-Fv、Fab-dsFv、Fd、单结构域抗体(sdAb，例如VH或VL或VHH)、单链Fab(scFab)、单链抗体(例如scFv，sc(Fv)2)、双抗体、线性抗体、二价或三价或四价抗体、Bis-scFv、diabody、tribody、triabody、tetrabody和上述任意一种的表位结合片段。产生和制备这些抗原结合片段的方法在本领域是公知的。
“天然抗体”指天然存在的免疫球蛋白分子。例如，天然IgG抗体是约150,000道尔顿的异四聚糖蛋白，由二硫键结合的两条轻链和两条重链构成。从N至C端，每条重链具有一个可变区(VH)，又称作可变重域、重链可变区，接着是重链恒定区，天然IgG重链恒定区通常含三个恒定域(CH1、CH2和CH3)。类似地，从N至C端，每条轻链具有一个可变区(VL)，又称作可变轻域，或轻链可变域，接着是一个恒定轻域(轻链恒定区、CL)。
术语“全长抗体”、“完整抗体”和“全抗体”在本文可互换使用，指具有与天然抗体结构基本类似的结构或具有如本文所限定的Fc区的重链的抗体。天然完整抗体轻链包括轻链可变区VL及恒定区CL，VL处于轻链的氨基末端，轻链恒定区包括κ链及λ链；重链包括可变区VH及恒定区(CH1、CH2及CH3)，VH处于重链的氨基末端，恒定区处于羧基末端，其中CH3最接近多肽的羧基末端，重链可属于任何同种型，包括IgG(包括IgG1、IgG2、IgG3及IgG4亚型)、IgA(包括IgA1及IgA2亚型)、IgM及IgE。
术语“Fc区”或“片段可结晶区”用于定义抗体重链的C末端区域，包括天然Fc区和改造的Fc区。在一些实施方式中，Fc区包含了相同或不同的两个亚基。用于本文所述抗体的合适Fc区包括人IgG1、IgG2(IgG2A、IgG2B)、IgG3和IgG4的Fc区。在一些实施方式中，Fc区的边界还可以变化，例如缺失Fc区的C末端赖氨酸(根据EU编号系统的残基447)或缺失Fc区的C末端甘氨酸和赖氨酸(根据EU编号系统的残基446和447)。除非另有说明，Fc区的编号规则为EU编号系统，又称作EU索引。
Fc区可通过用胃蛋白酶等蛋白水解酶部分消化IgG单克隆抗体等之后，再洗脱吸附于蛋白A或蛋白G柱上的组分而适当地获取。作为所述蛋白水解酶，通过适当设定pH值等的酶的反应条件，能够限制性地消化全长抗体以产生Fab、F(ab')2的酶即可，没有特别限定，例如可以示例胃蛋白酶、木瓜蛋白酶等。
术语抗体“可变区”或“可变域”指抗体重链或轻链中涉及抗体结合抗原的域。本文中，抗体重链可变区(VH)和轻链可变区(VL)各包含四个保守的框架区(FR)和三个互补决定区(CDR)。其中，术语“互补决定区”或“CDR”指可变结构域内主要促成与抗原结合的区域；“框架”或“FR”是指除CDR残基之外的可变结构域残基。VH包含3个CDR区：HCDR1、HCDR2和HCDR3；VL包含3个CDR区：LCDR1、LCDR2和LCDR3。每个VH和VL由从氨基末端(也称N末端)排到羧基末端(也称C末端)按以下顺序排列的三个CDR和四个FR构成：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。
可以通过各种公知方案来确定CDR的氨基酸序列边界，例如：“Kabat”编号规则、“Chothia”编号规则、“ABM”编号规则、“contact”编号规则和ImMunoGenTics(IMGT)编号规则等；各种编号系统之间的对应关系是本领域技术人员熟知的，示例性的，如下表1中所示。
表1.CDR编号系统之间的关系
除非另有说明，本披露实施例中的可变区和CDR均适用“Kabat”编号规则。
术语“抗体片段”指不同于完整抗体的分子，其包含完整抗体的部分，所述部分与完整抗体所结合的抗原相结合。抗体片段的实例包括但不限于Fv、dsFv、Fab、Fab′、Fab′-SH、Fd、F(ab′)2、单域抗体(sdAb，例如VH、VL或VHH)、单链Fab(scFab、sc(Fv)2)、双抗体、线性抗体、单链抗体(例如scFv)；以及由抗体片段形成的多特异性抗体。
术语“嵌合”抗体指抗体中的重和/或轻链的一部分自特定的来源或物种衍生，而重和/或轻链的剩余部分自另外的不同来源或物种衍生的抗体。
术语“人源化”抗体是保留非人抗体的反应性同时在人中具有较低免疫原性的抗体。例如，可以通过保留非人CDR区并用其人对应物(即，恒定区以及可变区的框架区部分)替换抗体的其余部分来实现。
术语“人抗体”、“人源抗体”、“全人抗体”、“完全人抗体”可以互换使用，意指可变区及恒定区是人序列的抗体。该术语涵盖源自人基因但具有，例如，降低可能的免疫原性、增加亲和力、消除可能会引起不期望的折叠的半胱氨酸或糖基化位点等序列已发生改变的抗体。该术语涵盖这些在非人细胞(其可能会赋予不具人细胞特征的糖基化)中重组产生的抗体。该术语亦涵盖已在含有一些或所有人免疫球蛋白重链及轻链基因座的转基因小鼠中产生的抗体。人抗体的含义明确排除人源化抗体。
术语“亲和力”是指分子(例如，抗体)的单个结合部位与其结合配体(例如，抗原)之间非共价相互作用的总体的强度。除非另外指明，如本文所用，结合“亲和力”是指内部结合亲和力，其反映出结合对(例如，抗体与抗原)的成员之间1:1相互作用。分子X对其配体Y的亲和力通常可以由解离常数(KD)表示。亲和力可以通过本领域已知的常规方法(包括本文所述的那些方法)测量。
如本文所使用的，术语“kassoc”或“ka”指特定抗体-抗原相互作用的缔合速率，术语“kdis”或“kd”指特定抗体-抗原相互作用的解离速率。术语“KD”指解离常数，其获得自kd与ka的比率(即kd/ka)并且表示为摩尔浓度(M)。可以使用本领域公知的方法测定抗体的KD值。例如，使用生物传感系统例如系统测量表面等离子体共振(例如Biacore)，或通过溶液平衡滴定法(SET)测量溶液中的亲和力。
术语“表面等离子共振”指的是通过检测生物传感器基质内的蛋白质浓度的变化而分析实时相互作用的光学现象，例如，使用BIAcore系统(Biacore LifeSciences division of GE Healthcare，Piscataway，NJ)。
术语“效应子功能”指那些可归于抗体Fc区(天然序列Fc区或氨基酸序列突变的Fc区)且随抗体同种型而变化的生物学活性。抗体效应子功能的例子包括但不限于：C1q结合和补体依赖性细胞毒性、Fc受体结合、抗体依赖性细胞介导的细胞毒性(ADCC)、吞噬作用、细胞表面受体(例如B细胞受体)下调；和B细胞活化。
术语“单克隆抗体”指基本上均质的抗体的群，即在该群中包含的抗体分子的氨基酸序列是相同的，除了可能少量存在的天然突变以外。相比之下，多克隆抗体通常包含在其可变结构域具有不同氨基酸序列的多种不同抗体，其通常特异性针对不同表位。“单克隆”不应解释为要求通过任何特定方法来生产抗体。在一些实施方式中，本披露提供的抗体是单克隆抗体。
术语“双特异性抗体”指能够与两个不同抗原或同一抗原的至少两个不同抗原表位特异性结合的抗体(包括抗体或其抗原结合片段，如单链抗体)。现有技术已公开了各种结构的双特异性抗体，根据IgG分子的完整性可分为IgG样双特异性抗体和抗体片段型双特异性抗体，根据抗原结合区域的数量可分为二价、三价、四价或更多价的双特异性抗体，根据结构是否对称可分为对称结构双特异性抗体和不对称结构双特异性抗体。其中，基于抗体片段的双特异性抗体，例如缺乏Fc片段的Fab片段，其通过将2个或多个Fab片段结合在一个分子中形成双特异性抗体，其具有较低的免疫原性，且分子量小，具有较高的肿瘤组织渗透性；IgG样双特异性抗体(例如具有Fc片段)，这类抗体相对分子量较大，Fc片段有助于抗体的纯化，并提高其溶解性、稳定性，Fc部分还可能会与受体FcRn结合，增加抗体血清半衰期。
术语“抗原”是指能够由诸如抗原结合蛋白(包括例如抗体)选择性结合的分子或分子部分。抗原可具有一个或多个能够与不同的抗原结合蛋白(例如抗体)相互作用的表位。
术语“表位”指能够与抗体或其抗原结合片段特异性结合的抗原上的区域(area或region)。表位可以由连续氨基酸串(线性表位)形成或包含非连续氨基酸(构象表位)，例如因抗原的折叠而变成空间接近。构象表位和线性表位的差别在于：在变性溶剂的存在下，抗体对构象表位的结合丧失。表位包含处于独特空间构象的至少3，至少4，至少5，至少6，至少7，或8-10个氨基酸。筛选结合特定表位的抗体(即那些结合相同表位的)可以使用本领域例行方法来进行，例如但不限于丙氨酸扫描，肽印迹，肽切割分析，表位切除，表位提取，抗原的化学修饰，和交叉阻断。
术语“能够特异性结合”、“特异性结合”或“结合”是指相比其他抗原或表位，抗体能够以更高的亲和力结合至某个抗原或其表位。通常地，抗体以约1×10-6M或更小(例如约1×10-7M、1×10-8M、1×10-9M、1×10-10M、1×10-11M或更小)的平衡解离常数(KD)结合抗原或其表位。在一些实施方式中，抗体与抗原结合的KD为该抗体结合至非特异性抗原(例如BSA、酪蛋白)的KD的10％或更低(例如1％)。可使用已知的方法来测量KD，例如通过表面等离子体共振测定法所测量的。然而，特异性结合至抗原或其表位的抗体不排除对其它相关的抗原具有交叉反应性，例如，对来自其它物种(同源)(诸如人或猴，例如食蟹猕猴(Macaca fascicularis)(cynomolgus，cyno)、黑猩猩(Pan troglodytes)(chimpanzee，chimp)或狨猴(Callithrix jacchus)(commonmarmoset，marmoset))的相应抗原具有交叉反应性。
术语“抗体依赖性细胞的细胞毒性”、“抗体依赖性细胞介导的细胞毒性”或“ADCC”是诱导细胞死亡的机制，该机制依赖于抗体包被靶细胞与具有裂解活性的效应细胞(诸如自然杀伤细胞(NK)、单核细胞、巨噬细胞和中性粒细胞)经由效应细胞上表达的Fcγ受体(FcγR)发生的相互作用。例如，NK细胞表达FcγRIIIa，而单核细胞表达FcγRI、FcγRII和FcγRIIIa。本文提供的抗体的ADCC活性可使用体外测定，使用表达抗原的细胞作为靶细胞和NK细胞作为效应细胞进行评定。根据从裂解的细胞中释放的标记物(例如放射性底物、荧光染料或天然胞内蛋白)来检测细胞裂解。
术语“抗体依赖性细胞吞噬作用(ADCP)”是指通过吞噬细胞(诸如巨噬细胞或树突状细胞)的内化作用消除抗体包被的靶细胞的机制。
术语“补体依赖性细胞毒性”或“CDC”是指诱导细胞死亡的机制，其中靶结合抗体的Fc效应域结合并激活补体成分C1q，C1q继而激活补体级联，从而导致靶细胞死亡。补体的激活也可导致补体成分沉积在靶细胞表面上，这些补体成分通过结合白细胞上的补体受体(例如，CR3)来促进CDC。
术语“核酸”在本文中可与术语“多核苷酸”互换使用，并且是指呈单链或双链形式的脱氧核糖核苷酸或核糖核苷酸及其聚合物。所述术语涵盖含有已知核苷酸类似物或修饰的骨架残基或连接的核酸，所述核酸是合成的、天然存在的和非天然存在的，具有与参考核酸相似的结合特性，并且以类似于参考核苷酸的方式代谢。此类类似物的实例包括但不限于硫代磷酸酯、氨基磷酸酯、甲基膦酸酯、手性-甲基膦酸酯、2-O-甲基核糖核苷酸、肽-核酸(PNA)。
“分离的”核酸指已经与其天然环境的组分分开的核酸分子。编码多肽的分离的核酸指编码多肽的一个或更多个核酸分子，包括在单一载体或分开的载体中的这样的一个或更多个核酸分子，和存在于宿主细胞中一个或更多个位置的这样的一个或更多个核酸分子。除非另有说明，否则特定的核酸序列还隐含地涵盖其保守修饰的变体(例如，简并密码子取代)和互补序列以及明确指明的序列。具体地，如下详述，简并密码子取代可以通过产生如下序列而获得，在这些序列中，一个或多个所选的(或全部)密码子的第三位被混合碱基和/或脱氧肌苷残基取代。
术语序列“同一性”指，当对两条序列进行最佳比对时，两条序列的氨基酸/核酸在等价位置相同的程度(百分比)；必要时，引入间隙，以获取最大序列同一性百分比，且不将任何保守性取代视为序列同一性的一部分。为测定序列同一性百分比，比对可以通过本领域技术已知的技术来实现，例如使用公开可得到的计算机软件，诸如BLAST、BLAST-2、ALIGN、ALIGN-2或Megalign(DNASTAR)软件。本领域技术人员可确定适用于测量比对的参数，包括在所比较的序列全长上达成最大比对所需的任何算法。
术语“载体”意指能够转运与其连接的另一多核苷酸的多核苷酸分子。一种类型的载体是“质粒”，其是指环状双链DNA环，其中可以连接附加的DNA区段。另一种类型的载体是病毒载体，例如腺相关病毒载体(AAV或AAV2)，其中另外的DNA区段可以连接到病毒基因组中。某些载体能够在引入它们的宿主细胞中自主复制(例如，具有细菌复制起点的细菌载体和附加型哺乳动物载体)。其他载体(例如，非附加型哺乳动物载体)可以在引入宿主细胞中后整合到宿主细胞的基因组中，从而与宿主基因组一起复制。术语“表达载体”或“表达构建体”是指可对宿主细胞进行转化，且含有指导和/或控制(连同宿主细胞一起)与其可操作地连接的一个或多个异源编码区的表达的核酸序列的载体。表达构建体可以包括但不限于影响或控制转录、翻译且在存在内含子时影响与其可操作地连接的编码区的RNA剪接的序列。
术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可互换使用，并且指已经导入外源核酸的细胞，包括此类细胞的后代。宿主细胞包括“转化体”和“经转化的细胞”，其包括原代的经转化的细胞及自其衍生的后代，而不考虑传代的次数。后代在核酸内容物上可以与亲本细胞不完全相同，而是可以含有突变。本文中包括突变体后代，其具有与在初始转化细胞中所筛选或选择的细胞相同的功能或生物学活性。宿主细胞包括原核和真核宿主细胞，其中真核宿主细胞包括但不限于哺乳动物细胞、昆虫细胞系植物细胞和真菌细胞。哺乳动物宿主细胞包括人、小鼠、大鼠、犬、猴、猪、山羊、牛、马和仓鼠细胞，包括但不限于中国仓鼠卵巢(CHO)细胞、NSO、SP2细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人肝细胞癌细胞(例如，Hep G2)、A549细胞、3T3细胞和HEK-293细胞。真菌细胞包括酵母和丝状真菌细胞，包括例如巴氏毕赤酵母(Pichiapastoris)、芬兰毕赤酵母(Pichia finlandica)、海藻毕赤酵母(Pichia trehalophila)、科克拉马毕赤酵母(Pichia koclamae)、膜状毕赤酵母(Pichia membranaefaciens)、小毕赤酵母(Pichia minuta)(Ogataea minuta、Pichia lindneri)、仙人掌毕赤酵母(Pichiaopuntiae)、耐热毕赤酵母(Pichia thermotolerans)、柳毕赤酵母(Pichia salictaria)、Pichia guercuum、皮杰普毕赤酵母(Pichia pijperi)、具柄毕赤酵母(Pichia stiptis)、甲醇毕赤酵母(Pichia methanolica)、毕赤酵母属、酿酒酵母(Saccharomycescerevisiae)、酿酒酵母属、多形汉逊酵母(Hansenula polymorpha)、克鲁维酵母属、乳酸克鲁维酵母(Kluyveromyces lactis)、白色念珠菌(Candida albicans)、曲霉属、构巢曲霉(Aspergillus nidulans)、黑曲霉(Aspergillus niger)、米曲霉(Aspergillus oryzae)、里氏木霉(Trichoderma reesei)、勒克氏菌(Chrysosporium lucknowense)、镰刀菌属(Fusarium sp.)、禾谷镰刀菌(Fusarium gramineum)、菜镰刀菌(Fusarium venenatum)、小立碗藓(Physcomitrella patens)和粗糙脉孢菌(Neurospora crassa)和解脂耶氏酵母(Yarrowia lipolytica)。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。
术语“药物组合物”表示含有一种或多种本文所述的抗体与其他化学组分的混合物，所述其他组分例如生理学/可药用的载体和赋形剂。
术语“药学上可接受的载体、稀释剂或赋形剂”指药学配制剂中与活性成分不同的,且对受试者无毒的成分。药学上可接受的载体、稀释剂或赋形剂包括但不限于缓冲剂、赋形剂、稳定剂或防腐剂。
术语“受试者”或“个体”包括人类和非人类动物。非人动物包括所有脊椎动物(例如哺乳动物和非哺乳动物)例如非人灵长类、绵羊、狗、牛、鸡、两栖动物和爬行动物。除非指出时，否则所述术语“患者”或“受试者”在本文中可互换地使用。在某些实施方案中，个体或受试者是人。
“施用”或“给予”，当其应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。
术语“样本”是指从受试者分离的采集物(如流体、细胞、或组织)，以及存在于受试者体内的流体、细胞或组织。示例性样本为生物流体，诸如血液、血清和浆膜液、血浆、淋巴液、尿液、唾液、囊液、泪液、排泄物、痰、分泌组织或器官的粘膜分泌物、阴道分泌物、腹水、胸膜、心包、腹膜、腹腔和其它体腔的流体、由支气管灌洗液收集的流体、滑液、与受试者或生物来源接触的液体溶液，例如培养基(包括条件培养基)、灌洗液等，组织活检样本、细针穿刺、手术切除的组织、器官培养物或细胞培养物。
“治疗(treatment或treat)”和“处理”(及其语法变型)指对所治疗个体的临床干预，并且可以为了预防或者在临床病理学的过程期间实施。治疗的期望效果包括但不限于预防疾病的发生或再发生，减轻症状，减轻/减少疾病的任何直接或间接病理后果，预防转移，降低疾病进展速率，改善或减轻疾病状态，和消退或改善的预后。在一些实施方案中，使用本披露的抗体来延迟疾病的形成或减缓疾病的进展。
“有效量”一般是足以降低症状的严重程度和/或频率、消除这些症状和/或潜在病因、预防症状和/或其潜在病因出现和/或改良或改善由疾病状态引起或与其相关的损伤(例如肺病)的量。在一些实施例中，有效量是治疗有效量或预防有效量。
“治疗有效量”是足以治疗疾病状态或症状、尤其与该疾病状态相关的状态或症状，或者以其他方式预防、阻碍、延迟或逆转该疾病状态或以任何方式与该疾病相关的任何其他不理想症状的进展的量。“预防有效量”是当给予受试者时将具有预定预防效应，例如预防或延迟该疾病状态的发作(或复发)，或者降低该疾病状态或相关症状的发作(或复发)可能性的量。完全治疗或预防未必在给予一个剂量之后便发生，可能在给予一系列剂量之后发生。因而，治疗或预防有效量可以一次或多次给予的方式给予。“治疗有效量”和“预防有效量”可取决于多种因素变化：诸如个体的疾病状态、年龄、性别和体重，以及治疗剂或治疗剂组合在个体中引发期望的应答的能力。有效治疗剂或治疗剂组合的示例性指标包括例如患者改善的健康状况。
本披露的抗N3pGlu Aβ抗体
本披露提供了抗N3pGlu Aβ抗体，其具有诸多有利的特性，例如良好的治疗活性、安全性、药物代谢动力学特性和成药性(如溶解度、粘度、纯度和稳定性等)。
示例性的抗N3pGlu Aβ抗体
本披露的实施例提供一种抗N3pGlu Aβ抗体，其包含重链可变区和轻链可变区，其中，所述重链可变区包含HCDR1、HCDR2和HCDR3，和所述轻链可变区包含LCDR1、LCDR2和LCDR3，其中：
(1)所述重链可变区的HCDR1包含SEQ ID NO：229的氨基酸序列，HCDR2包含SEQ ID NO：230的氨基酸序列，和HCDR3包含SEQ ID NO：231的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：232的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列，其中：
DX1GX2X3       SEQ ID NO：229；
FX4SX5LAYNIYYX6X7TVTG      SEQ ID NO：230；
YIFX8GYYX9YAMDY            SEQ ID NO：231；
RSSQSLVHSX10X11NTYFH        SEQ ID NO：232；
X1为Y或K；X2为M；X3为A；
X4为I；X5为N；X6为A或G；X7为D、E或Q；
X8为D或E；X9为D或E；
X10为N、Y或S；X11为G；或
(2)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：233的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；其中：
YX12YX13X14X15IX16YVMDY     SEQ ID NO：233；
X12为D、Q或E；X13为D或E；X14为D或E；X15为V或G；X16为D；或
(3)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：234的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；其中：
EVIYX17GYYYAMX18Y     SEQ ID NO：234；
X17为D或E；X18为D或E。
示例性地，本披露的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：4的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：58的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
(2)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：8的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：94的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：96的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：110的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
(3)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：13的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：135的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列。
示例性地，本披露的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
(2)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
(3)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列。
示例性地，本披露的抗N3pGlu Aβ抗体，其中：
(1)所述重链可变区的HCDR1为如SEQ ID NO：49所示的氨基酸序列，HCDR2为如SEQ ID NO：52所示的氨基酸序列，和HCDR3为如SEQ ID NO：54所示的氨基酸序列，和所述轻链可变区的LCDR1为如SEQ ID NO：32所示的氨基酸序列，LCDR2为如SEQ ID NO：5所示的氨基酸序列，和LCDR3为如SEQ ID NO：6所示的氨基酸序列；或
(2)所述重链可变区的HCDR1为如SEQ ID NO：1所示的氨基酸序列，HCDR2为如SEQ ID NO：7所示的氨基酸序列，和HCDR3为如SEQ ID NO：107所示的氨基酸序列，和所述轻链可变区的LCDR1为如SEQ ID NO：9所示的氨基酸序列，LCDR2为如SEQ ID NO：5所示的氨基酸序列，和LCDR3为如SEQ ID NO：10所示的氨基酸序列；或
(3)所述重链可变区的HCDR1为如SEQ ID NO：11所示的氨基酸序列，HCDR2为如SEQ ID NO：12所示的氨基酸序列，和HCDR3为如SEQ ID NO：136所示的氨基酸序列，和所述轻链可变区的LCDR1为如SEQ ID NO：14所示的氨基酸序列，LCDR2为如SEQ ID NO：15所示的氨基酸序列，和LCDR3为如SEQ ID NO：16所示的氨基酸序列。
示例性地，本披露的抗N3pGlu Aβ抗体，所述重链可变区的HCDR1、HCDR2和HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3是根据Kabat编号规则定义的。
示例性地，本披露的抗N3pGlu Aβ抗体，其中，所述的抗N3pGlu Aβ抗体为鼠源抗体、嵌合抗体或人源化抗体。在一些实施方案中，所述抗体是嵌合抗体。在一些实施方案中，所述抗体是人源化抗体。
示例性地，本披露的抗N3pGlu Aβ抗体，其包含人抗体的框架区(FR)。
示例性地，本披露的抗N3pGlu Aβ抗体，所述重链可变区具有来源于IGHV3-7*01的FR1、FR2、FR3和来源于IGHJ6*01的FR4，并且其包含选自3K、30R、45P和93V组成的组中的一个或多个氨基酸取代；和/或所述轻链可变区具有来源于IGKV2-40*01、IGKV3-20*01或IGKV1-39*01的FR1、FR2、FR3和来源于IGKJ4*01的FR4，并且其包含选自2V、43S和45K组成的组中的一个或多个氨基酸取代。在一些实施方案中，所述的抗N3pGlu Aβ抗体，其中，所述重链可变区的HCDR1包含SEQ ID NO：49或1的氨基酸序列，HCDR2包含SEQ ID NO：52、2、36或53的氨基酸序列，和HCDR3包含SEQ ID NO：54、3或58的氨基酸序列，且所述重链可变区的FR包含选自3K、30R、45P和93V组成的组中的一个或多个氨基酸取代；和所述轻链可变区的LCDR1包含SEQ ID NO：32、4或31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列，且所述轻链可变区的FR包含选自2V、43S和45K组成的组中的一个或多个氨基酸取代。在一些实施方案中，上述可变区和CDR是根据Kabat编号规则定义的。
示例性地，本披露的抗N3pGlu Aβ抗体，所述重链可变区具有来源于IGHV3-7*01的FR1、FR2、FR3和来源于IGHJ6*01的FR4，并且其包含选自28S、45P和76K组成的组中的一个或多个氨基酸取代；和/或所述轻链可变区具有来源于IGKV2-29*02的FR1、FR2、FR3和来源于IGKJ4*01的FR4，并且其是未被取代的。在一些实施方案中，所述的抗N3pGlu Aβ抗体，其中，所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107、8、94、96或110的氨基酸序列，且所述重链可变区的FR包含选自28S、45P和76K组成的组中的一个或多个氨基酸取代；和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列，且所述轻链可变区的FR是未被取代的。在一些实施方案中，上述可变区和CDR是根据Kabat编号规则定义的。
示例性地，本披露的抗N3pGlu Aβ抗体，所述重链可变区具有来源于IGHV3-21*01的FR1、FR2、FR3和来源于IGHJ6*01的FR4，并且其包含选自28I、44R、49A和93G组成的组中的一个或多个氨基酸取代；和/或所述轻链可变区具有来源于IGKV4-1*01的FR1、FR2、FR3和来源于IGKJ4*01的FR4，并且其是未被取代的或包含选自4L、58I、68R和85T组成的组中的一个或多个氨基酸取代。在一些实施方案中，所述的抗N3pGlu Aβ抗体，其中，所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136、13或135的氨基酸序列，且所述重链可变区的FR包含选自28I、44R、49A和93G组成的组中的一个或多个氨基酸取代；和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列，且所述轻链可变区的FR是未被取代的或包含选自4L、58I、68R和85T组成的组中的一个或多个氨基酸取代。在一些实施方案中，上述可变区和CDR是根据Kabat编号规则定义的。
示例性地，本披露的抗N3pGlu Aβ抗体，其中，
(1)所述重链可变区包含SEQ ID NO：88的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：17的氨基酸序列，和所述轻链可变区包含SEQ ID NO：18的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42的氨基酸序列，和所述轻链可变区包含SEQ ID NO：37的氨基酸序列；或
所述重链可变区包含SEQ ID NO：45的氨基酸序列，和所述轻链可变区包含SEQ IDNO：38的氨基酸序列；或
所述重链可变区包含SEQ ID NO：42的氨基酸序列，和所述轻链可变区包含SEQ ID NO：39的氨基酸序列；或
所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：39的氨基酸序列；或
所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：65的氨基酸序列；或
所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：78的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：79的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：80的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
所述重链可变区包含SEQ ID NO：91的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
(2)所述重链可变区包含SEQ ID NO：119的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：19的氨基酸序列，和所述轻链可变区包含SEQ ID NO：20的氨基酸序列；或
所述重链可变区包含SEQ ID NO：100的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：102的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：104的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
所述重链可变区包含SEQ ID NO：122的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
(3)所述重链可变区包含SEQ ID NO：141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：21的氨基酸序列，和所述轻链可变区包含SEQ ID NO：22的氨基酸序列；或
所述重链可变区包含SEQ ID NO：132的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：133的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：137的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
所述重链可变区包含SEQ ID NO：133的氨基酸序列，和所述轻链可变区包含SEQ ID NO：131的氨基酸序列。
示例性地，本披露的抗N3pGlu Aβ抗体，其中，
(1)所述重链可变区包含SEQ ID NO：88的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
(2)所述重链可变区包含SEQ ID NO：119的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
(3)所述重链可变区包含SEQ ID NO：141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列。
示例性的，本披露的抗N3pGlu Aβ抗体，其中，
(1)所述重链可变区为如SEQ ID NO：88所示的氨基酸序列，和所述轻链可变区为如SEQ ID NO：66所示的氨基酸序列；或
(2)所述重链可变区为如SEQ ID NO：119所示的氨基酸序列，和所述轻链可变区为如SEQ ID NO：97所示的氨基酸序列；或
(3)所述重链可变区为如SEQ ID NO：141所示的氨基酸序列，和所述轻链可变区为如SEQ ID NO：129所示的氨基酸序列。
示例性地，本披露的抗N3pGlu Aβ抗体，其中所述的抗N3pGlu Aβ抗体包含重链和轻链，其中，
(1)所述重链包含SEQ ID NO：169的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
所述重链包含SEQ ID NO：25的氨基酸序列，和所述轻链包含SEQ ID NO：26的氨基酸序列；或
所述重链包含SEQ ID NO：143的氨基酸序列，和所述轻链包含SEQ ID NO：175的氨基酸序列；或
所述重链包含SEQ ID NO：146的氨基酸序列，和所述轻链包含SEQ ID NO：176的氨基酸序列；或
所述重链包含SEQ ID NO：143的氨基酸序列，和所述轻链包含SEQ ID NO：177的氨基酸序列；或
所述重链包含SEQ ID NO：150的氨基酸序列，和所述轻链包含SEQ ID NO：177的氨基酸序列；或
所述重链包含SEQ ID NO：150的氨基酸序列，和所述轻链包含SEQ ID NO：182的氨基酸序列；或
所述重链包含SEQ ID NO：150的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
所述重链包含SEQ ID NO：159的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
所述重链包含SEQ ID NO：160的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
所述重链包含SEQ ID NO：161的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
所述重链包含SEQ ID NO：172的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
所述重链包含SEQ ID NO：219的氨基酸序列，和所述轻链包含SEQ ID NO：220的氨基酸序列；或
所述重链包含SEQ ID NO：144、145、146或147的氨基酸序列，和所述轻链包含SEQ ID NO：175的氨基酸序列；或
所述重链包含SEQ ID NO：143、144、145或147的氨基酸序列，和所述轻链包含SEQ ID NO：176的氨基酸序列；或
所述重链包含SEQ ID NO：144、145、146、147、148、149、151、152、153、154、155、156、157或158的氨基酸序列，和所述轻链包含SEQ ID NO：177的氨基酸序列；或
所述重链包含SEQ ID NO：143、144、145、146或147的氨基酸序列，和所述轻链包含SEQ ID NO：178的氨基酸序列；或
所述重链包含SEQ ID NO：143、144、145、146或147的氨基酸序列，和所述轻链包含SEQ ID NO：179的氨基酸序列；或
所述重链包含SEQ ID NO：146、147或150的氨基酸序列，和所述轻链包含SEQ ID NO：180的氨基酸序列；或
所述重链包含SEQ ID NO：146、147或150的氨基酸序列，和所述轻链包含SEQ ID NO：181的氨基酸序列；或
所述重链包含SEQ ID NO：146或147的氨基酸序列，和所述轻链包含SEQ ID NO：182的氨基酸序列；或
所述重链包含SEQ ID NO：146、147、162、163、164、165、166、167、168、170、171、173或174的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
(2)所述重链包含SEQ ID NO：192的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
所述重链包含SEQ ID NO：27的氨基酸序列，和所述轻链包含SEQ ID NO：28的氨基酸序列；或
所述重链包含SEQ ID NO：185的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
所述重链包含SEQ ID NO：187的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
所述重链包含SEQ ID NO：189的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
所述重链包含SEQ ID NO：195的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
所述重链包含SEQ ID NO：221的氨基酸序列，和所述轻链包含SEQ ID NO：222的氨基酸序列；或
所述重链包含SEQ ID NO：184、186、188、190、191、193、194、196、197、198、199、200或201的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
所述重链包含SEQ ID NO：184、185、186、187、188、189、190、191、192、193、194、195、196、197、198、199、200或201的氨基酸序列，和所述轻链包含SEQ ID NO：203的氨基酸序列；或
(3)所述重链包含SEQ ID NO：211的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
所述重链包含SEQ ID NO：29的氨基酸序列，和所述轻链包含SEQ ID NO：30的氨基酸序列；或
所述重链包含SEQ ID NO：204的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
所述重链包含SEQ ID NO：205的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
所述重链包含SEQ ID NO：207的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
所述重链包含SEQ ID NO：205的氨基酸序列，和所述轻链包含SEQ ID NO：214的氨基酸序列；或
所述重链包含SEQ ID NO：223的氨基酸序列，和所述轻链包含SEQ ID NO：224的氨基酸序列；或
所述重链包含SEQ ID NO：206、208、209或210的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
所述重链包含SEQ ID NO：204、205、206、207、208、209、210或211的氨基酸序列，和所述轻链包含SEQ ID NO：213的氨基酸序列；或
所述重链包含SEQ ID NO：204、206、207、208、209、210或211的氨基酸序列，和所述轻链包含SEQ ID NO：214的氨基酸序列。
示例性地，本披露的抗N3pGlu Aβ抗体，其中，
(1)所述重链包含SEQ ID NO：169的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
(2)所述重链包含SEQ ID NO：192的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
(3)所述重链包含SEQ ID NO：211的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列。
示例性地，本披露的抗N3pGlu Aβ抗体，其中，
(1)所述重链为如SEQ ID NO：169所示的氨基酸序列，和所述轻链为如SEQ ID NO：183所示的氨基酸序列；或
所述重链的氨基酸序列如SEQ ID NO：169的第1至451位氨基酸残基所示，和所述轻链的氨基酸序列如SEQ ID NO：183的第1至219位氨基酸残基所示；或
(2)所述重链为如SEQ ID NO：192所示的氨基酸序列，和所述轻链为如SEQ ID NO：202所示的氨基酸序列；或
所述重链的氨基酸序列如SEQ ID NO：192的第1至451位氨基酸残基所示，和所述轻链的氨基酸序列如SEQ ID NO：202的第1至219位氨基酸残基所示；或
(3)所述重链为如SEQ ID NO：211所示的氨基酸序列，和所述轻链为如SEQ ID NO：212所示的氨基酸序列；或
所述重链的氨基酸序列如SEQ ID NO：211的第1至451位氨基酸残基所示，和所述轻链的氨基酸序列如SEQ ID NO：212的第1至218位氨基酸残基所示。
示例性地，本披露的抗N3pGlu Aβ抗体，其中，
(1)所述重链为如SEQ ID NO：169所示的氨基酸序列，和所述轻链为如SEQ ID NO：183所示的氨基酸序列；或
(2)所述重链为如SEQ ID NO：192所示的氨基酸序列，和所述轻链为如SEQ ID NO：202所示的氨基酸序列；或
(3)所述重链为如SEQ ID NO：211所示的氨基酸序列，和所述轻链为如SEQ ID NO：212所示的氨基酸序列。
抗体结构
在某些实施方案中，本文中提供的抗体是全长抗体。
在某些实施方案中，本文中提供的抗体是抗体片段。
在一些实施方案中，抗体片段是Fab、Fab′、Fab′-SH或F(ab′)2片段，特别是Fab片段。“Fab”，其是由VL、VH、CL和CH1结构域组成的单价片段。“Fab片段”可以是抗体经木瓜蛋白酶裂解产生的。“Fab′”含有VL、CL以及VH和CH1，还含有CH1和CH2结构域之间的区域，以使得在两个Fab′片段的两条重链之间可以形成链间二硫键，以形成F(ab′)2分子。“Fab′-SH”是其中恒定区的半胱氨酸残基具有游离巯基的Fab′片段。“F(ab′)2”包含在铰链区通过二硫键连接的两个Fab片段的二价片段。
在一些实施方案中，抗体片段是双抗体，三抗体或四抗体。双抗体是具有两个抗原结合位点的抗体片段，该片段在同一条多肽链(VH-VL)中包含相连的VH和VL。通过使用过短的接头使得同一条链上的两个结构域之间不能配对，迫使这些结构域与另一条链的互补结构域配对，从而产生两个抗原结合位点，两个抗原可以是相同或不同的
在一些实施方案中，抗体片段是单链Fab片段。“单链Fab片段”或“scFab”是由VH，CH1，VL，CL和接头组成的多肽，其中所述抗体域和所述接头在N端至C端方向具有以下顺序之一：a)VH-CH1-接头-VL-CL，b)VL-CL-接头-VH-CH1，c)VH-CL-接头-VL-CH1或d)VL-CH1-接头-VH-CL。在一些实施方式中，所述接头是具有至少30个氨基酸的多肽。在一些实施方式中，所述接头是具有32至50个氨基酸之间的多肽。所述单链Fab片段经由CL和CH1之间的天然二硫键而被稳定化。另外，通过插入半胱氨酸残基(例如在重链可变区中的位置44和轻链可变区中的位置100，根据Kabat编号)产生链间二硫键，这些单链Fab分子可以进一步被稳定化。
在一些实施方案中，抗体片段是由抗体的单臂的VH和VL结构域组成的Fv片段。
在一些实施方案中，抗体片段是单链可变片段(scFv)。“scFv”是包含至少一个含有轻链可变区的抗体片段和至少一个含有重链可变区的抗体片段的融合蛋白，其中轻链可变区和重链可变区通过短的柔性肽接头连续连接，能够表达为单链多肽，并且其中scFv保持其所源自的完整抗体的特异性。除非特别指出，否则在本文中scFv可以以任何一种顺序具有VL和VH可变区，例如相对于多肽的N端和C端，scFv可以包含VL-接头-VH或可以包含VH-接头-VL。
在一些实施方案中，抗体片段是dsFv，dsFv是通过将其中每个VH和VL中的一个氨基酸残基被半胱氨酸残基取代的多肽经由半胱氨酸残基之间的二硫键相连而获得的。可以按照已知方法基于抗体的三维结构预测来选择被半胱氨酸残基取代的氨基酸残基。
在一些实施方案中，抗体片段是单域抗体(dAb)。单域抗体是包含抗体的整个或部分重链可变域或整个或部分轻链可变域的抗体片段。
在某些实施方案中，本文中提供的抗体是嵌合抗体。在一个例子中，嵌合抗体包含非人可变区(例如自小鼠、大鼠、仓鼠、家兔、或非人灵长类，诸如猴衍生的可变区)和人恒定区。在又一个例子中，嵌合抗体是“类转换的”抗体，其中类或亚类已经自亲本抗体的类或亚类改变。
在某些实施方案中，抗体是人源化抗体。通常，将非人抗体通过人源化以降低对人的免疫原性，同时保留亲本非人抗体的特异性和亲和力。一般地，人源化抗体包含一个或多个可变区，其中CDR或其部分衍生自非人抗体，而FR或其部分衍生自人抗体。任选地，人源化抗体还会包含人恒定区的一部分。在一些实施方案中，可将人源化抗体中的一些FR残基用来自非人抗体(例如提供CDR序列的抗体)的相应残基替代。
抗N3pGlu Aβ抗体的变体
在某些实施方案中，涵盖本文中提供的抗N3pGlu Aβ抗体的氨基酸序列变体。例如，可以期望改善抗体的结合亲和力和/或其它生物学特性。可以通过将合适的修饰引入编码抗体的核苷酸序列中，或者通过肽合成来制备抗体的氨基酸序列变体。此类修饰包括例如对抗N3pGlu Aβ抗体的氨基酸序列内的残基的删除、和/或插入、和/或取代。可以进行删除、插入、和取代的任何组合以得到最终的构建体，只要最终的构建体拥有期望的特征，例如抗原结合特性。
取代、插入、和删除变体
在某些实施方案中，提供了具有一处或多处氨基酸取代的抗体变体。取代诱变感兴趣的位点包括CDR和FR。保守取代在表2中在“优选的取代”的标题下显示。更实质的变化在表2中在“示例性取代”的标题下提供，并且如下文参照氨基酸侧链类别进一步描述的。可以将氨基酸取代引入感兴趣的抗体中，并且对产物筛选期望的活性，例如保留/改善的抗原结合，降低的免疫原性，或改善的ADCC或CDC。
表2.氨基酸的取代
依照常见的侧链特性，氨基酸可以如下分组:
(1)疏水性的：正亮氨酸，Met，Ala，Val，Leu，Ile；
(2)中性，亲水性的：Cys，Ser，Thr，Asn，Gln；
(3)酸性的：Asp，Glu；
(4)碱性的：His，Lys，Arg；
(5)影响链取向的残基：Gly，Pro；
(6)芳香族的：Trp，Tyr，Phe。
非保守取代会需要用这些类别之一的成员替换另一个类别的成员。
一类取代变体涉及取代亲本抗体(例如人源化或人抗体)的一个或多个CDR残基。一般地，经选择用于进一步研究的所得变体相对于亲本抗体会具有某些生物学特性(例如升高的亲和力，降低的免疫原性)的改变(例如改善)，和/或会基本上保留亲本抗体的某些生物学特性。一种例示性的取代变体是亲和力成熟的抗体，可以例如使用基于噬菌体展示的亲和力成熟技术(如本文所述的那些技术)，便利地产生所述抗体。简言之，将一个或多个CDR残基突变，并将变体抗体在噬菌体上展示，并对其筛选特定的生物学活性(例如结合亲和力)。可以对CDR做出改变(例如取代)，例如以改善抗体亲和力。可以对CDR“热点”，即在体细胞成熟过程期间以高频率经历突变的密码子所编码的残基，和/或接触抗原的残基做出此类改变，同时对所得的变体VH或VL测试结合亲和力。在亲和力成熟的一些实施方案中，通过多种方法(例如易错PCR、链改组、或寡核苷酸指导的诱变)的任一种，将多样性引入所选择用于成熟的可变基因中。然后，创建次级文库。然后，筛选文库以鉴定具有期望的亲和力的任何抗体变体。另一种引入多样性的方法涉及CDR定向的方法，其中将几个CDR残基(例如一次4-6个残基)随机化。可以例如使用丙氨酸扫描诱变或建模来特异性鉴定涉及抗原结合的CDR残基。特别地，经常靶向HCDR3和LCDR3。
在某些实施方案中，取代、插入或缺失可以在一个或多个CDR内发生，只要此类变化不实质性降低抗体结合抗原的能力。例如，可以对CDR做出保守变化(例如保守取代，如本文中提供的)，其不实质性降低结合亲和力。此类变化可以例如在CDR中的抗原接触残基外部。在上文提供的变体VH和VL序列的某些实施方案中，每个CDR是未改变的，或者含有不超过1、2或3处氨基酸取代。
一种可用于鉴定抗体中可以作为诱变靶位的残基或区域的方法称作“丙氨酸扫描诱变”。在这种方法中，鉴定一个残基或靶残基组(例如带电荷的残基，诸如Arg、Asp、His、Lys和Glu)，并且用中性或带负电荷的氨基酸(例如，Ala或聚丙氨酸)替换以确定该抗体与抗原的相互作用是否受影响。可以在对初始取代显示功能敏感性的氨基酸位置引入进一步的取代。此外，可通过研究抗原-抗体复合物的晶体结构来鉴定抗体与抗原间的接触点。这些接触残基及邻近残基可以作为取代候选物被打靶或消除。可以筛选变体以确定它们是否含有期望的特性。
氨基酸序列插入包括长度范围为1个残基至含有100或更多个残基的多肽的氨基和/或羧基端融合，和单个或多个氨基酸残基的序列内插入。末端插入的例子包括具有N端甲硫氨酰基残基的抗体。抗体分子的其它插入变体包括抗体的N或C端与酶或延长抗体的血清半衰期的多肽的融合物。
重组方法
抗N3pGlu Aβ抗体可以使用重组方法来产生。对于这些方法，提供编码抗N3pGlu Aβ抗体的一个或更多个分离的核酸。
在一些实施方案中，本披露提供了编码如前所述的抗N3pGlu Aβ抗体的分离的核酸。此类核酸可以给自独立的编码前述的任一多肽链。在另一方面中，本披露提供了包含此类核酸的一种或多种载体(例如表达载体)。在另一方面中，本披露提供了包含此类核酸的宿主细胞。在一些实施方案中，提供制备多肽或融合蛋白的方法，其中所述方法包括，在适合表达的条件下，培养包含编码所述多肽或融合蛋白的核酸的宿主细胞，如上文所提供的，和任选地从宿主细胞(或宿主细胞培养基)回收所述抗N3pGlu Aβ抗体。
为了重组产生抗N3pGlu Aβ抗体，将编码蛋白的核酸分离并插入一个或更多个载体中，用于在宿主细胞中进一步克隆和/或表达。此类核酸可以使用常规程序容易地分离和测序，或者通过重组方法产生或通过化学合成获得。
用于克隆或表达编码抗N3pGlu Aβ抗体的载体的适当宿主细胞包括本文描述的原核或真核细胞。例如，可在细菌中产生，特别是当不需要糖基化和Fc效应子功能时。在表达后，可以在可溶级分中从细菌细胞糊状物分离，并且可进一步纯化。
除了原核生物以外，真核微生物诸如丝状真菌或酵母也是用于编码融合蛋白的载体的合适的克隆或表达宿主，包括真菌和酵母菌株。适于表达融合蛋白的合适的宿主细胞也可源自多细胞生物体(无脊椎动物和脊椎动物)；无脊椎动物细胞的例子包括植物和昆虫细胞。已经鉴定了许多杆状病毒株，其可与昆虫细胞联合使用，特别是用于草地贪夜蛾(Spodoptera frugiperda)细胞的转染；还可利用植物细胞培养物作为宿主，例如US5959177、US6040498、US6420548、US7125978和US6417429；也可将脊椎动物细胞用作宿主，例如适应于在悬浮液中生长的哺乳动物细胞系。适宜的哺乳动物宿主细胞系的其它例子是经SV40转化的猴肾CVl系(COS-7)；人胚肾系(293或293T细胞)；幼仓鼠肾细胞(BHK)；小鼠塞托利(sertoli)细胞(TM4细胞)；猴肾细胞(CV1)；非洲绿猴肾细胞(VERO-76)；人宫颈癌细胞(HELA)；犬肾细胞(MDCK)；水牛鼠(buffalo rat)肝细胞(BRL3A)；人肺细胞(W138)；人肝细胞(Hep G2)；小鼠乳房肿瘤(MMT 060562)；TRI细胞；MRC 5细胞；和FS4细胞。其它适宜的哺乳动物宿主细胞系包括中国仓鼠卵巢(CHO)细胞，包括DHFR-CHO细胞；以及骨髓瘤细胞系，如Y0、NS0和Sp2/0。
测定
本文提供的抗N3pGlu Aβ抗体可以通过本领域已知的多种测定法对其物理/化学特征和/或生物学活性进行鉴定、筛选或表征。在一个方面中，例如通过已知方法如ELISA、蛋白印迹法等，测试本披露的抗N3pGlu Aβ抗体的活性。
治疗方法与施用途径
本披露提供的任何抗N3pGlu Aβ抗体可用于治疗方法。在又一个方面，本披露提供的抗N3pGlu Aβ抗体在药物的制造或制备中的用途。在一些实施方案中，所述疾病是与N3pGlu Aβ相关的疾病或病症。在一些实施方案中，所述与N3pGlu Aβ相关的疾病或病症为神经系统疾病、退行性疾病或脑血管病。
在又一个的方面，提供包含所述抗N3pGlu Aβ抗体的药物组合物，例如，其用于以上任何制药用途或治疗方法。在一些实施方案中，药物组合物包含本文提供的任何抗N3pGlu Aβ抗体和药学上可接受的载体。在一些实施方案中，药物组合物还包含至少一种另外的治疗剂。
本披露的抗N3pGlu Aβ抗体可单独使用或与其他试剂联合用于治疗。例如，本披露的抗体可与至少一种另外的治疗剂共同施用。
本披露的抗N3pGlu Aβ抗体(和任何另外的治疗剂)可通过任何合适的手段施用，包括肠胃外、肺内和鼻内，并且如果需要局部治疗，则病灶内施用。肠胃外输注包括肌肉内、静脉内、动脉内、腹膜内或皮下施用。给药可以通过任何适当的途径，例如，通过注射，诸如静脉内或皮下注射，这部分取决于施用是短期的还是长期的。本文考虑多种给药时间方案，包括但不限于，单次或在多个时间点多次施用，推注施用和脉冲输注。
本披露的抗N3pGlu Aβ抗体将以符合良好医疗实践的方式配制、给药和施用。在此背景下考虑的因素包括所治疗的具体病症、所治疗的具体哺乳动物、个体患者的临床状况、病症的起因、试剂的递送部位、施用方法、施用时间安排以及医学从业者已知的其他因素。抗N3pGlu Aβ抗体可以与或不与目前用于预防或治疗所述病症的一种或更多种试剂一起配制。此类其它试剂的有效量取决于药物组合物中存在的量、病症或治疗的类型以及其它因素。这些通常以与本文所述相同的剂量和施用路径使用，或以本文所述剂量的约1％至99％使用，或以其它剂量使用，并通过经验/临床确定为合适的任何途径使用。
为了预防或治疗疾病，本披露的抗N3pGlu Aβ抗体(当单独使用或与一种或更多种其他另外的治疗剂组合使用时)的适当的剂量将取决于待治疗的疾病的类型，治疗分子的类型，疾病的严重性和病程，是为预防还是治疗目的施用，之前的治疗，患者的临床病史和对治疗分子的响应，和主治医师的判断。治疗分子恰当地以一次或经过一系列治疗施用于患者。
制品
在本披露的另一方面中，提供一种制品，所述制品包含可用于治疗、预防和/或诊断上述病症的材料。该制品包含容器和在容器上或与容器联合的标签或包装插页(package insert)。合适的容器包括，例如，瓶子、管形瓶、注射器、IV溶液袋等。容器可以自各种材料诸如玻璃或塑料形成。容器装有单独或与另一种组合物组合有效治疗，预防和/或诊断疾患的组合物，并且可具有无菌的存取口(例如，容器可以是具有由皮下注射针可刺穿的塞子的静脉内溶液袋或管形瓶)。组合物中的至少一种活性试剂是本披露的抗N3pGlu Aβ抗体。标签或包装插页指示使用该组合物是来治疗选择的病况。此外，制品可以包含：(a)其中装有组合物的第一容器，其中所述组合物包含本披露的抗N3pGlu Aβ抗体；和(b)其中装有组合物的第二容器，其中所述组合物包含另外的细胞毒性剂或其他方面的治疗剂。本披露的该实施方案中的制品可进一步包含包装插页，所述包装插页指示所述组合物可以用于治疗特定病况。备选地，或另外地，制品可进一步包含第二(或第三)容器，所述第二(或第三)容器包含药学上可接受的缓冲液。从商业和用户立场，它可进一步包括所需的其他材料，包括其他缓冲剂、稀释剂、滤器、针头和注射器。
实施例
以下结合实施例和测试例进一步描述本披露，但这些实施例和测试例并非限制着本披露的范围。本披露实施例和测试例中未注明具体条件的实验方法，通常按照常规条件，如冷泉港的抗体技术实验手册，分子克隆手册；或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1：N3pGlu Aβ抗原的制备
1.免疫用抗原制备
将合成的多肽人N3pGlu-42 Aβ(吉尔生化)溶解于PBS中，然后于37℃孵育过夜获得人N3pGlu-42 Aβ纤维(fibril)，LC-MS鉴定为正确后分装备用。
>人N3pGlu-42 Aβ多肽序列
XFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
SEQ ID NO：142注：X为焦谷氨酸(pyroglutamic acid)。
2.筛选检测用抗原制备
将合成的多肽人N3pGlu-42 Aβ(吉尔生化)溶解于PBS中，然后于37℃孵育过夜获得人N3pGlu-42 Aβ纤维，LC-MS鉴定为正确后分装备用。将上述吉尔生化合成的人N3pGlu-42Aβ多肽粉末溶解于100％ DMSO中制备人N3pGlu-42 Aβ单体(mononer)，该N3pGlu-42Aβ单体经LC-MS鉴定为正确后分装备用。
实施例2：N3pGlu Aβ杂交瘤抗体的筛选
1.小鼠免疫：
抗人N3pGlu Aβ抗体通过免疫小鼠产生。实验用Balb/c小鼠和SJL小鼠，雌性，6-8周龄(北京维通利华实验动物技术有限公司，动物生产许可证号：SCXK(京)2012-0001)。饲养环境：SPF级。小鼠购进后，实验室环境饲养1周，12/12小时光/暗周期调节，温度20-25℃；湿度40％-60％。将已适应环境的小鼠按以下方案免疫。
用人N3pGlu-42 Aβ纤维免疫Balb/c小鼠和SJL小鼠，交替使用Gold Adjuvant(Sigma Cat No.T2684)与ThermoAlum(Thermo Cat No.77161)佐剂。抗原与Gold Adjuvant佐剂比例为1:1，抗原与ThermoAlum佐剂比例为3:1，50μg/只/次。人N3pGlu-42 Aβ纤维抗原乳化后进行接种，接种时间为第0、14、28、42和56天，于第21，35和49天取血，用ELISA方法确定小鼠血清中的抗体滴度。选择血清中抗体滴度高并且滴度趋于平台的小鼠，取其脾细胞用于杂交瘤融合。
2.鼠源抗体筛选：
取融合的杂交瘤上清检测与人N3pGlu-42 Aβ的结合活性来筛选阳性鼠源抗体，最终获得3个具有人N3pGlu-42 Aβ结合活性的鼠源抗体。
用Trizol(Invitrogen Cat No.15596-018)提取3个鼠源抗体对应的杂交瘤细胞RNA，用PrimeScriptTMII 1st Strand cDNA Synthesis Kit试剂盒(Takara Cat No.6210A)进行反转录获得cDNA，再将cDNA产物测序得到抗体的可变区序列。各鼠源抗体的重链及轻链CDR序列如下表3所示：
表3.鼠源抗体CDR序列
注：表中CDR为依照Kabat编号系统确定的CDR。
鼠源抗体可变区序列如下：

注：上述序列中，下划线部分为依照Kabat编号系统确定的CDR序列，非下划线部分为FR序列。
3.嵌合抗体设计：
根据测序结果，将前面筛选的3个鼠源抗体的重链可变区C端与人IgG1重链恒定区N端连接，同时将鼠源抗体轻链可变区C端与人κ轻链恒定区N端连接，可获得其对应的嵌合抗体。
恒定区与嵌合抗体的轻链/重链序列如下：
>人IgG1重链恒定区序列
>人κ轻链恒定区序列
>CH81重链序列
>CH81轻链序列
>CH84重链序列
>CH84轻链序列
>CH89重链序列

>CH89轻链序列
实施例3：抗N3pGlu Aβ鼠源抗体的人源化
通过比对IMGT人类抗体重轻链可变区种系基因数据库和MOE软件，分别挑选与mAb81、mAb84和mAb89同源性高的重轻链可变区种系基因作为模板，将这三个鼠源抗体的CDR分别移植到相应的人源模板中，形成次序为FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4的可变区序列。示例性地，以下具体实施例中CDR氨基酸残基由Kabat编号系统确定并注释。
1.鼠源抗体mAb81的人源化
鼠源抗体mAb81的人源化轻链选择IGKV2-40*01的FR1、FR2、FR3，和IGKJ4*01的FR4作为轻链框架区模板，人源化重链选择模板为IGHV3-7*01的FR1、FR2、FR3，和IGHJ6*01的FR4作为重链框架区模板，将鼠源抗体mAb81的CDR分别移植到其人源模板中，任选地，对人源化抗体的轻链可变区上第2，28，29和/或45位的氨基酸残基进行取代；和对人源化抗体的重链可变区上第3，30，35，45，60和/或93位的氨基酸残基进行取代(其中的氨基酸位置根据Kabat编号规则确定)，鼠源抗体mAb81的人源化抗体设计见下表4：
表4.mAb81人源化抗体设计

注：Graft代表鼠源抗体CDR植入人种系FR区；“I2V”表示依照Kabat编号系统，将第2位I突变为V，其他以此类推。
mAb81人源化抗体CDR突变序列如下表5：
表5.mAb81人源化抗体CDR序列
mAb81人源化抗体轻链可变区/重链可变区序列如下：

注：上述序列中，下划线部分为依照Kabat编号系统确定的CDR序列，非下划线部分为FR序列。
另外，为提高mAb81人源化分子的表达量，以及去除翻译后修饰高风险位点和T细胞表位(TCE)，任选地，对人源化抗体的轻链可变区上第2，28和/或43位的氨基酸残基进行取代；和对人源化抗体的重链可变区上第3，30，32，34，45，51，52a，60，61，93，98和/或100b位的氨基酸残基进行取代(其中的氨基酸位置根据Kabat编号规则确定)。其中，人源化轻链模板为选自IGKV2-40*01、IGKV4-1*01、IGKV3-20*01和IGKV1-39*01的FR1、FR2、FR3，和IGKJ4*01的FR4，人源化重链模板为IGHV3-7*01的FR1、FR2、FR3，和IGHJ6*01的FR4。鼠源抗体mAb81的人源化抗体设计见下表6：
表6.mAb81人源化抗体设计

注：Graft代表鼠源抗体CDR植入人种系FR区；“I2V”表示依照Kabat编号系统，将第2位I突变为V，其他以此类推。mAb81人源化抗体CDR改造序列如下表7：
表7.mAb81人源化抗体的CDR改造

改造后mAb81人源化抗体轻链可变区/重链可变区序列如下：





注：序列中斜体为FR序列，下划线为依照Kabat编号系统确定的CDR序列。
2.鼠源抗体mAb84的人源化
鼠源抗体mAb84的人源化轻链模板为IGKV2-29*02的FR1、FR2、FR3，和IGKJ4*01的FR4作为轻链框架区模板，人源化重链选择IGHV3-7*01的FR1、FR2、FR3，和IGHJ6*01的FR4作为重链框架区模板，将鼠源抗体mAb84的CDR分别移植到其人源模板中，任选地，对人源化抗体的轻链可变区上第2和45位的氨基酸残基进行取代；和对人源化抗体的重链可变区上第28，45，76，98，99和/或100位的氨基酸残基进行取代(其中的突变位点位置根据Kabat编号规则确定)，抗体mAb84的人源化抗体设计见下表8：
表8.mAb84人源化抗体设计
注：Graft代表鼠源抗体CDR植入人种系FR区；“I2V”表示依照Kabat编号系统，将第2位I突变为V，其他以此类推。mAb84人源化抗体CDR改造序列如下表9：
表9.mAb84人源化抗体CDR改造
mAb84人源化抗体轻链可变区/重链可变区序列如下：

另外，为去除翻译后修饰高风险位点，对Hu84VH6的重链可变区CDR上96，98和/或100b位氨基酸进行改造，mAb84人源化抗体CDR改造序列如下表10：
表10.mAb84人源化抗体CDR改造
改造后mAb84人源化抗体轻链可变区/重链可变区序列如下：


注：序列中斜体为FR序列，下划线为依照Kabat编号系统确定的CDR序列。
3.鼠源抗体mAb89的人源化
鼠源抗体mAb89的人源化轻链模板选择IGKV4-1*01的FR1、FR2、FR3，和IGKJ4*01的FR4作为轻链框架区模板，人源化重链选择IGHV3-21*01的FR1、FR2、FR3，和IGHJ6*01的FR4作为重链框架区模板，将鼠源抗体mAb89的CDR分别移植到其人源模板中，任选地，对人源化抗体的轻链可变区上第4，58，68和/或85位的氨基酸残基进行取代；和对人源化抗体的重链可变区上第28，40，42，44，49和/或93位的氨基酸残基进行取代(其中的突变位点位置根据Kabat编号规则确定)，抗体mAb89的人源化抗体设计见下表11：
表11.mAb89人源化抗体设计
注：Graft代表鼠源抗体CDR植入人种系FR区；“M4L”表示依照Kabat编号系统，将第4位M突变为L，其他以此类推。
mAb89人源化抗体轻链可变区/重链可变区序列如下：

注：上述序列中，下划线部分为依照Kabat编号系统确定的CDR序列，非下划线部分为FR序列。
另外，对mAb89分子进行的改序列优化设计，以去除翻译后修饰高风险位点，在Hu89VH2的重链可变区CDR上99和/或101位氨基酸进行改造，FR上28和/或44位氨基酸进行改造。mAb89人源化抗体CDR改造序列如下表12：
表12.mAb89人源化抗体CDR改造
mAb89人源化抗体重链可变区序列如下：

注：序列中斜体为FR序列，下划线为依照Kabat编号系统确定的CDR序列。
4.构建和表达抗N3pGlu Aβ人源化抗体IgG1形式
设计引物PCR搭建各人源化抗体VH/VL基因片段，再与表达载体(带信号肽及恒定区基因(CH1-FC/CL)片段，实验室构建)进行同源重组，构建抗体全长表达载体VH-CH1-FC/VL-CL。抗体的重链恒定区可选自人IgG1、IgG2、IgG3、IgG4或其变体的重链恒定区，轻链恒定区可选自人κ、λ链或其变体的轻链恒定区。示例性的，以下实施例中，抗体重链恒定区为人IgG1重链恒定区，轻链恒定区为人κ轻链恒定区。
将前面设计的mAb81、mAb84、mAb89的人源化抗体重链可变区C端与人IgG1重链恒定区N端连接形成抗体全长重链，将人源化抗体轻链可变区C端与人κ轻链恒定区N端连接形成抗体全长轻链，可得到如下表13至表15所示的人源化抗体：
表13.mAb81的人源化抗体

注：“Hu81001”表示重链可变区为Hu81VH1(SEQ ID NO：42)，轻链可变区为Hu81VL1(SEQ ID NO：37)，且重链恒定区如SEQ ID NO：23所示，轻链恒定区如SEQ ID NO：24所示的人源化抗体，其它以此类推。
表14.mAb84的人源化抗体

注：“Hu84001”表示重链可变区为Hu84VH1(SEQ ID NO：99)，轻链可变区为Hu84VL1(SEQ ID NO：97)，且重链恒定区如SEQ ID NO：23所示，轻链恒定区如SEQ ID NO：24所示的人源化抗体，其它以此类推。
表15.mAb89的人源化抗体
注：“Hu89001”表示重链可变区为Hu89VH1(SEQ ID NO：132)，轻链可变区为Hu89VL1(SEQ ID NO：129)，且重链恒定区如SEQ ID NO：23所示，轻链恒定区如SEQ ID NO：24所示的人源化抗体，其它以此类推。
示例性的人源化抗体轻链/重链全长序列如下：
>Hu81001、Hu81033、Hu81065、Hu81097、Hu81129重链序列
>Hu81002、Hu81034、Hu81066、Hu81098、Hu81130重链序列

>Hu81003、Hu81035、Hu81067、Hu81099、Hu81131重链序列
>Hu81004、Hu81036、Hu81068、Hu81100、Hu81132、Hu81164、Hu81196、Hu81228、Hu81260重链序列
>Hu81005、Hu81037、Hu81069、Hu81101、Hu81133、Hu81165、Hu81197、Hu81229、Hu81261重链序列

>Hu81070重链序列
>Hu81071重链序列
>Hu81072、Hu81168、Hu81200、Hu81232、Hu81264重链序列

>Hu81073重链序列
>Hu81074重链序列
>Hu81075重链序列

>Hu81076重链序列
>Hu81077重链序列
>Hu81078重链序列
>Hu81079重链序列
>Hu81080重链序列
>Hu81273重链序列
>Hu81274重链序列

>Hu81275重链序列
>Hu81276重链序列
>Hu81277重链序列

>Hu81278重链序列
>Hu81279重链序列
>Hu81280重链序列
>Hu81281重链序列
>Hu81282重链序列
>Hu81283重链序列
>Hu81284重链序列

>Hu81285重链序列
>Hu81286重链序列
>Hu81287重链序列

>Hu81288重链序列
>Hu81001、Hu81002、Hu81003、Hu81004、Hu81005轻链序列
>Hu81033、Hu81034、Hu81035、Hu81036、Hu81037轻链序列
>Hu81065、Hu81066、Hu81067、Hu81068、Hu81069、Hu81070、Hu81071、Hu81072、Hu81073、Hu81074、Hu81075、Hu81076、Hu81077、Hu81078、Hu81079、Hu81080轻链序列

>Hu81097、Hu81098、Hu81099、Hu81100、Hu81101轻链序列
>Hu81129、Hu81130、Hu81131、Hu81132、Hu81133轻链序列
>Hu81164、Hu81165、Hu81168轻链序列
>Hu81196、Hu81197、Hu81200轻链序列
>Hu81228、Hu81229、Hu81232轻链序列

>Hu81260、Hu81261、Hu81264、Hu81273、Hu81274、Hu81275、Hu81276、Hu81277、Hu81278、Hu81279、Hu81280、Hu81281、Hu81282、Hu81283、Hu81284、Hu81285、Hu81286、Hu81287、Hu81288轻链序列
>Hu84001、Hu84019重链序列
>Hu84002、Hu84020重链序列
>Hu84003、Hu84021重链序列

>Hu84004、Hu84022重链序列
>Hu84005、Hu84023重链序列
>Hu84006、Hu84024重链序列

>Hu84007、Hu84025重链序列
>Hu84008、Hu84026重链序列
>Hu84009、Hu84027重链序列

>Hu84010、Hu84028重链序列
>Hu84011、Hu84029重链序列
>Hu84012、Hu84030重链序列
>Hu84013、Hu84031重链序列
>Hu84014、Hu84032重链序列
>Hu84015、Hu84033重链序列
>Hu84016、Hu84034重链序列

>Hu84017、Hu84035重链序列
>Hu84018、Hu84036重链序列
>Hu84001、Hu84002、Hu84003、Hu84004、Hu84005、Hu84006、Hu84007、Hu84008、Hu84009、Hu84010、Hu84011、Hu84012、Hu84013、Hu84014、Hu84015、Hu84016、Hu84017、Hu84018轻链序列

>Hu84019、Hu84020、Hu84021、Hu84022、Hu84023、Hu84024、Hu84025、Hu84026、Hu84027、Hu84028、Hu84029、Hu84030、Hu84031、Hu84032、Hu84033、Hu84034、Hu84035、Hu84036轻链序列
>Hu89001、Hu89009、Hu89017重链序列
>Hu89002、Hu89010、Hu89018重链序列
>Hu89003、Hu89011、Hu89019重链序列

>Hu89004、Hu89012、Hu89020重链序列
>Hu89005、Hu89013、Hu89021重链序列
>Hu89006、Hu89014、Hu89022重链序列

>Hu89007、Hu89015、Hu89023重链序列
>Hu89008、Hu89016、Hu89024重链序列
>Hu89001、Hu89002、Hu89003、Hu89004、Hu89005、Hu89006、Hu89007、Hu89008轻链序列
>Hu89009、Hu89010、Hu89011、Hu89012、Hu89013、Hu89014、Hu89015、Hu89016轻链序列
>Hu89017、Hu89018、Hu89019、Hu89020、Hu89021、Hu89022、Hu89023、Hu89024轻链序列
注：上述抗体全长序列中，下划线部分为抗体可变区序列，无下划线部分为抗体恒定区序列。
另外，本公开实施例中的阳性对照抗体Donanemab(参见WO2012021469)的轻重链序列如下：
>Donanemab重链序列：
>Donanemab轻链序列：

本公开实施例中使用的阳性对照抗体：Remternetug(参见WO2018194951)的轻重链序列如下：
>Remternetug重链序列：
>Remternetug轻链序列：
示例性的，本披露中使用鼠mIgG2a重链恒定区和鼠mκ轻链恒定区与人源化可变区融合，得到mIgG2a形式的嵌合抗体。mIgG2a形式的嵌合抗体相关序列如下：
>Hu81283-mIgG2a抗体重链序列：
>Hu81283-mIgG2a抗体轻链序列：

>Hu84009-mIgG2a抗体重链序列：
>Hu84009-mIgG2a抗体轻链序列：
>Hu89008-mIgG2a抗体重链序列：
>Hu89008-mIgG2a抗体轻链序列：
>鼠mIgG2a重链恒定区序列

>鼠mκ轻链恒定区序列
>Donanemab-mIgG2a抗体重链序列：
>Donanemab-mIgG2a抗体轻链序列：
注：下划线代表可变区，非下划线代表恒定区。
示例性地，本披露中使用了hIgG1抗体作为同型抗体对照(其VH/VL来源于专利US6114143A的C25抗体)，相关序列如下：
>hIgG1抗体重链序列

>hIgG1抗体轻链序列
示例性地，本披露中使用了人N3pGlu-40 Aβ作为检测用抗原，相关序列如下：
>人N3pGlu-40 Aβ多肽序列
注：X为焦谷氨酸(pyroglutamic acid)。
测试例
测试例1：ELISA检测抗N3pGlu Aβ抗体亲和力实验
用ELISA实验测试本公开嵌合抗体及人源化抗体对人N3pGlu Aβ抗原的亲和力，方法如下：
N3pGlu Aβ单体制备：将合成的N3pGlu-40 Aβ(吉尔生化)，N3pGlu-42 Aβ(中肽)多肽粉末分别溶解于100％ DMSO中，浓度为1mg/mL分装备用。
N3pGlu Aβ纤维制备：将合成的N3pGlu-42 Aβ(中肽)多肽粉末溶解在DMSO中(0.5mg肽用10μL DMSO)，然后加入去离子水制成溶液(0.5mg肽需要434μL去离子水)，将该溶液37℃孵育11天获得N3pGlu-42 Aβ纤维，并分装备用。
将制备好的N3pGlu-40 Aβ单体、N3pGlu-42 Aβ单体、N3pGlu-42 Aβ纤维各2μg/mL，50μL/孔包被在ELISA板中(corning，3590)，4℃孵育过夜。弃去液体，然后用1％BSA，200μL/孔室温封闭板子1小时，弃去封闭液，再用PBST(含0.1％吐温20的PBS溶液)清洗板子3次，再加入50μL/孔用1％ BSA稀释的不同浓度待测抗体，室温孵育30分钟，再用PBST清洗板子3次，加入50μL/孔用1％BSA稀释的羊抗人二抗(Jackson Immuno Research，109-035-003)，室温孵育30分钟，再用PBST清洗板子3次，加入50μL/孔TMB显色底物(KPL，5120-0077)，于室温孵育2-5分钟，加入50μL/孔1M H2SO4终止反应，用VersaMax酶标仪在450nm处读取吸收值，分析处理数据并计算抗体对N3pGlu Aβ抗原的结合EC50值。实验结果见表16。
表16.抗N3pGlu Aβ人源化抗体对人N3pGlu Aβ抗原的亲和力检测结果

实验结果显示，上述抗N3pGlu Aβ抗体与人N3pGlu Aβ抗原均具有高亲和力，且Hu81283、Hu84009、Hu89008优于Remternetug阳性抗体；同时，Hu81283-mIgG2a、Hu84009-mIgG2a、Hu89008-mIgG2a、Donanemab-mIgG2a对人N3pGlu Aβ抗原的亲和力分别与Hu81283、Hu84009、Hu89008、Donanemab相当。
测试例2：Biacore检测抗N3pGlu Aβ抗体亲和力实验
用Biacore仪器测试本公开人源化抗体对人N3pGlu Aβ抗原的亲和力。方法如下：
用Protein A生物传感芯片(GE，29127556)亲和捕获抗体，然后于芯片表面流经抗原人N3pGlu-42 Aβ单体，用Biacore T200(GE)仪器实时检测反应信号获得结合和解离曲线。在每个实验循环解离完成后，用10mM Glycine-HCl(pH1.5)(GE，BR-1003-54)将生物传感芯片洗净再生。数据拟合模型采用1:1Model。实验结果如下表17所示。
表17.抗N3pGlu Aβ人源化抗体对人N3pGlu-42 Aβ单体抗原的SPR亲和力
用氨基偶联的方式将N3pGlu-42 Aβ纤维偶联到CM5生物传感芯片，然后于芯片表面流经待测抗体分子，用Biacore 8K仪器实时检测反应信号获得结合和解离曲线。在每个实验循环解离完成后，用NaOH 50及Glycine1.5将生物传感芯片洗净再生。数据拟合模型采用动力学1:1binding或Steady State模型。实验结果如下表18所示。
表18.抗N3pGlu Aβ人源化抗体对人N3pGlu-42 Aβ纤维抗原的SPR亲和力
实验结果显示，本公开的抗N3pGlu Aβ抗体与人N3pGlu-42 Aβ单体及人N3pGlu-42Aβ纤维均具有高亲和力，且优于Remternetug阳性抗体。
测试例3：抗N3pGlu Aβ抗体阻断N3pGlu-42 Aβ单体形成纤维实验
本实验用硫代黄素T(ThT)(sigma，T3516)来检测反应系统中N3pGlu-42 Aβ纤维的含量，以此来判断受试抗体阻断N3pGlu-42 Aβ单体聚集形成N3pGlu-42 Aβ纤维的能力。硫代黄素T能快速、特异性地与反向平行β-折叠的N3pGlu-42 Aβ纤维结合，但是它不与N3pGlu-42 Aβ单体或者寡聚体结合。硫代黄素T与N3pGlu-42 Aβ纤维结合后，会产生特征性120nm红色激发光谱转移，可用于N3pGlu-42 Aβ纤维的定量检测。将N3pGlu-42 Aβ多肽经氢氧化钠(sigma,G19852D)单体化处理后，与ThT溶于缓冲体系，并加入3.4μM的抗体，在37℃下于384孔板(corning，4514)中共孵育24小时，在FlexStation3(Molecular Devices)上读取荧光吸收值，激发波长为440nm，发射波长为485nm。通过荧光强度，分析不同浓度抗体对N3pGlu-42 Aβ单体聚集形成N3pGlu-42 Aβ纤维的影响。用检测所得的荧光信号，计算抗体对N3pGlu-42 Aβ单体聚集形成N3pGlu-42Aβ纤维的抑制率，计算公式如下：
抑制率％＝(荧光信号阴性对照孔-荧光信号待测抗体孔)/荧光信号阴性对照孔×100％
不同浓度抗体抑制N3pGlu-42 Aβ单体聚集成N3pGlu-42 Aβ纤维的效果见表19。
表19.待测抗体对N3pGlu-42 Aβ单体聚集成N3pGlu-42 Aβ纤维的抑制率
实验结果显示，本公开的抗N3pGlu Aβ抗体均能阻断N3pGlu-42 Aβ单体形成纤维，并且抑制N3pGlu-42 Aβ单体进一步聚集形成纤维的能力均优于阳性抗体Remternetug。
测试例4：N3pGlu Aβ抗体促进BV2对N3pGlu-42 Aβ纤维的吞噬
运用流式细胞术检测各N3pGlu Aβ抗体介导的小鼠小胶质细胞BV2对N3pGlu Aβ纤维的吞噬能力。实验方法如下：
取对数生长期BV2细胞(中国典型培养物保藏中心细胞库，3142C0001000000337)，用F12-K(Gibco，21127022)完全培养基传代铺板96孔平底板(Corning，3599)，每孔3×104细胞。用F12-K完全培养基梯度稀释各N3pGlu Aβ抗体。在铺板过夜的BV2细胞100μL培养物中，吸出80μL培养基，每孔加入20μL抗体，混匀室温孵育5分钟。然后，每孔加入20μL带有Alexa Fluor 488(Thermo，A30006)标记的N3pGlu-42 Aβ纤维(中肽生化)，混匀后在37℃培养箱中孵育80分钟。用枪头吹吸细胞5-10次，用显微镜(OLYNPUS，CKX53)观察到贴壁细胞被吹落，转移细胞至96孔U底板(Corning，3795)，1000g离心1分钟，弃上清。用200μL FACS缓冲液重悬细胞，1000g离心1分钟，弃上清，重复洗三次。最后，加200μL FACS缓冲液，流式细胞仪(Thermo，Attune NxT)上样，吸60μL，读取细胞FITC荧光强度。将各浓度抗体对应的荧光强度与对应浓度的hIgG1(同型抗体对照，isotype control)进行归一化处理。
表20.抗体促进BV2对N3pGlu Aβ纤维的吞噬实验

注：归一化计算公式＝(测试抗体MFI值-无抗体MFI背景值)/(hIgG1抗体MFI值-无抗体MFI背景值)，其中无抗体MFI背景值为3253。
实验结果如表20所示，本公开的N3pGlu Aβ抗体均可介导BV2细胞对N3pGlu-42 Aβ纤维的吞噬，且优于阳性抗体Donanemab。
虽然为了清楚的理解，已经借助于附图和实例详细描述了上述发明，但是描述和实例不应当解释为限制本披露的范围。本文中引用的所有专利和科学文献的公开内容通过引用完整地清楚结合。

Claims (11)

  1. 一种抗N3pGlu Aβ抗体，其包含重链可变区和轻链可变区，其中，所述重链可变区包含HCDR1、HCDR2和HCDR3，和所述轻链可变区包含LCDR1、LCDR2和LCDR3，其中：
    (1)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：234的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
    (2)所述重链可变区的HCDR1包含SEQ ID NO：229的氨基酸序列，HCDR2包含SEQ ID NO：230的氨基酸序列，和HCDR3包含SEQ ID NO：231的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：232的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    (3)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：233的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；
    优选地，
    (1)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136、13或135的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
    (2)所述重链可变区的HCDR1包含SEQ ID NO：49、1、35、47或48的氨基酸序列，HCDR2包含SEQ ID NO：52、2、36、53、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：54、3、58、55、56、57、59、60、61或62的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32、4、31、33或34的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    (3)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107、8、94、96、110、95、105、106、108、109、111、112、113、114、115或116的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；
    更优选地，
    (1)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：13的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：135的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
    (2)所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：4的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：58的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：35的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：4的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：4的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：35的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：31的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：36、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：35的氨基酸序列，HCDR2包含SEQ ID NO：2或36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：47的氨基酸序列，HCDR2包含SEQ ID NO：36、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：48的氨基酸序列，HCDR2包含SEQ ID NO：36、50或51的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：55、56、57、58、59、60或61的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：50或51的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：58或62的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：53的氨基酸序列，和HCDR3包含SEQ ID NO：54或62的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：33的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：33的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：2的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：34的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1或35的氨基酸序列，HCDR2包含SEQ ID NO：36的氨基酸序列，和HCDR3包含SEQ ID NO：3的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：34的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    (3)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：8的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：94的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：96的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：110的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；或
    所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：95、105、106、108、109、111、112、113、114、115或116的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列；
    最优选地，
    (1)所述重链可变区的HCDR1包含SEQ ID NO：11的氨基酸序列，HCDR2包含SEQ ID NO：12的氨基酸序列，和HCDR3包含SEQ ID NO：136的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：14的氨基酸序列，LCDR2包含SEQ ID NO：15的氨基酸序列，和LCDR3包含SEQ ID NO：16的氨基酸序列；或
    (2)所述重链可变区的HCDR1包含SEQ ID NO：49的氨基酸序列，HCDR2包含SEQ ID NO：52的氨基酸序列，和HCDR3包含SEQ ID NO：54的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：32的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：6的氨基酸序列；或
    (3)所述重链可变区的HCDR1包含SEQ ID NO：1的氨基酸序列，HCDR2包含SEQ ID NO：7的氨基酸序列，和HCDR3包含SEQ ID NO：107的氨基酸序列，和所述轻链可变区的LCDR1包含SEQ ID NO：9的氨基酸序列，LCDR2包含SEQ ID NO：5的氨基酸序列，和LCDR3包含SEQ ID NO：10的氨基酸序列。
  2. 根据权利要求1所述的抗N3pGlu Aβ抗体，其中所述的抗N3pGlu Aβ抗体为鼠源抗体、嵌合抗体、人源化抗体或全人源抗体；
    优选地，所述抗N3pGlu Aβ抗体为鼠源抗体、嵌合抗体或人源化抗体；
    更优选地，所述抗N3pGlu Aβ抗体为人源化抗体。
  3. 根据权利要求1或2所述的抗N3pGlu Aβ抗体，其中：
    (1)所述重链可变区包含与SEQ ID NO：141、132、133、137、134、138、139或140具有至少75％序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：129、131或130具有至少75％序列同一性的氨基酸序列；或
    所述重链可变区包含与SEQ ID NO：21具有至少75％序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：22具有至少75％序列同一性的氨基酸序列；或
    (2)所述重链可变区包含与SEQ ID NO：88、42、45、69、78、79、80、91、43、44、46、67、68、70、71、72、73、74、75、76、77、81、82、83、84、85、86、87、89、90、92或93具有至少75％序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：66、37、38、39、65、40、41、63或64具有至少75％序列同一性的氨基酸序列；或
    所述重链可变区包含与SEQ ID NO：17具有至少75％序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：18具有至少75％序列同一性的氨基酸序列；或
    (3)所述重链可变区包含与SEQ ID NO：119、100、102、104、122、99、101、103、117、118、120、121、123、124、125、126、127或128具有至少75％序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：97或98具有至少75％序列同一性的氨基酸序列；或
    所述重链可变区包含与SEQ ID NO：19具有至少75％序列同一性的氨基酸序列，和所述轻链可变区包含与SEQ ID NO：20具有至少75％序列同一性的氨基酸序列；
    优选地，
    (1)所述重链可变区包含SEQ ID NO：141、132、133、137、134、138、139或140的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129、131或130的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：21的氨基酸序列，和所述轻链可变区包含SEQ ID NO：22的氨基酸序列；或
    (2)所述重链可变区包含SEQ ID NO：88、42、45、69、78、79、80、91、43、44、46、67、68、70、71、72、73、74、75、76、77、81、82、83、84、85、86、87、89、90、92或93的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66、37、38、39、65、40、41、63或64的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：17的氨基酸序列，和所述轻链可变区包含SEQ ID NO：18的氨基酸序列；或
    (3)所述重链可变区包含SEQ ID NO：119、100、102、104、122、99、101、103、117、118、120、121、123、124、125、126、127或128的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97或98的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：19的氨基酸序列，和所述轻链可变区包含SEQ ID NO：20的氨基酸序列；
    更优选地，
    (1)所述重链可变区包含SEQ ID NO：141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：21的氨基酸序列，和所述轻链可变区包含SEQ ID NO：22的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：132的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：133的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：137的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：133的氨基酸序列，和所述轻链可变区包含SEQ ID NO：131的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：134、138、139或140的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：132、133、134、137、138、139、140或141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：130的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：132、134、137、138、139、140或141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：131的氨基酸序列；或
    (2)所述重链可变区包含SEQ ID NO：88的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：17的氨基酸序列，和所述轻链可变区包含SEQ ID NO：18的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：42的氨基酸序列，和所述轻链可变区包含SEQ ID NO：37的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：45的氨基酸序列，和所述轻链可变区包含SEQ ID NO：38的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：42的氨基酸序列，和所述轻链可变区包含SEQ IDNO：39的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：39的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：65的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：78的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：79的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：80的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：91的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：43、44、45或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：37的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：42、43、44或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：38的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：43、44、45、46、67、68、70、71、72、73、74、75、76或77的氨基酸序列，和所述轻链可变区包含SEQ ID NO：39的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：42、43、44、45或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：40的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：42、43、44、45或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：41的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：45、46或69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：63的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：45、46或69的氨基酸序列，和所述轻链可变区包含SEQ ID NO：64的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：45或46的氨基酸序列，和所述轻链可变区包含SEQ ID NO：65的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：45、46、81、82、83、84、85、86、87、89、90、92或93的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
    (3)所述重链可变区包含SEQ ID NO：119的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：19的氨基酸序列，和所述轻链可变区包含SEQ ID NO：20的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：100的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：102的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：104的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：122的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：99、101、103、117、118、120、121、123、124、125、126、127或128的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列；或
    所述重链可变区包含SEQ ID NO：99、100、101、102、103、104、117、118、119、120、121、122、123、124、125、126、127或128的氨基酸序列，和所述轻链可变区包含SEQ ID NO：98的氨基酸序列；
    最优选地，
    (1)所述重链可变区包含SEQ ID NO：141的氨基酸序列，和所述轻链可变区包含SEQ ID NO：129的氨基酸序列；或
    (2)所述重链可变区包含SEQ ID NO：88的氨基酸序列，和所述轻链可变区包含SEQ ID NO：66的氨基酸序列；或
    (3)所述重链可变区包含SEQ ID NO：119的氨基酸序列，和所述轻链可变区包含SEQ ID NO：97的氨基酸序列。
  4. 根据权利要求1至3中任一项所述的抗N3pGlu Aβ抗体，其中所述抗体包含重链恒定区和轻链恒定区；
    优选地，所述重链恒定区为人IgG1、IgG2、IgG3、IgG4或其变体、或鼠mIgG2a或其变体的重链恒定区，和所述轻链恒定区为人κ链、λ链或其变体、或鼠κ链、λ链或其变体的轻链恒定区；
    更优选地，所述重链恒定区为人IgG1或鼠mIgG2a的重链恒定区，和所述轻链恒定区为人κ链或鼠κ链的轻链恒定区；
    进一步优选地，所述重链恒定区包含SEQ ID NO：23或225的氨基酸序列，和所述轻链恒定区包含SEQ ID NO：24或226的氨基酸序列；
    最优选地，所述重链恒定区包含SEQ ID NO：23的氨基酸序列，和所述轻链恒定区包含SEQ ID NO：24的氨基酸序列。
  5. 根据权利要求1至4中任一项所述的抗N3pGlu Aβ抗体，其中所述的抗N3pGlu Aβ抗体包含重链和轻链，其中：
    (1)所述重链包含与SEQ ID NO：211、204、205、207、206、208、209或210具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：212、214或213具有至少75％序列同一性的氨基酸序列；或
    所述重链包含与SEQ ID NO：29具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：30具有至少75％序列同一性的氨基酸序列；或
    所述重链包含与SEQ ID NO：223具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：224具有至少75％序列同一性的氨基酸序列；或
    (2)所述重链包含与SEQ ID NO：169、143、146、150、159、160、161、172、144、145、147、148、149、151、152、153、154、155、156、157、158、162、163、164、165、166、167、168、170、171、173或174具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：183、175、176、177、182、178、179、180或181具有至少75％序列同一性的氨基酸序列；或
    所述重链包含与SEQ ID NO：25具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：26具有至少75％序列同一性的氨基酸序列；或
    所述重链包含与SEQ ID NO：219具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：220具有至少75％序列同一性的氨基酸序列；或
    (3)所述重链包含与SEQ ID NO：192、185、187、189、195、184、186、188、190、191、193、194、196、197、198、199、200或201具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：202或203具有至少75％序列同一性的氨基酸序列；或
    所述重链包含与SEQ ID NO：27具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：28具有至少75％序列同一性的氨基酸序列；或
    所述重链包含与SEQ ID NO：221具有至少75％序列同一性的氨基酸序列，和所述轻链包含与SEQ ID NO：222具有至少75％序列同一性的氨基酸序列；
    优选地，
    (1)所述重链包含SEQ ID NO：211、204、205、207、206、208、209或210的氨基酸序列，和所述轻链包含SEQ ID NO：212、214或213的氨基酸序列；或
    所述重链包含SEQ ID NO：29的氨基酸序列，和所述轻链包含SEQ ID NO：30的氨基酸序列；或
    所述重链包含SEQ ID NO：223的氨基酸序列，和所述轻链包含SEQ ID NO：224的氨基酸序列；或
    (2)所述重链包含SEQ ID NO：169、143、146、150、159、160、161、172、144、145、147、148、149、151、152、153、154、155、156、157、158、162、163、164、165、166、167、168、170、171、173或174的氨基酸序列，和所述轻链包含SEQ ID NO：183、175、176、177、182、178、179、180或181的氨基酸序列；或
    所述重链包含SEQ ID NO：25的氨基酸序列，和所述轻链包含SEQ ID NO：26的氨基酸序列；或
    所述重链包含SEQ ID NO：219的氨基酸序列，和所述轻链包含SEQ ID NO：220的氨基酸序列；或
    (3)所述重链包含SEQ ID NO：192、185、187、189、195、184、186、188、190、191、193、194、196、197、198、199、200或201的氨基酸序列，和所述轻链包含SEQ ID NO：202或203的氨基酸序列；或
    所述重链包含SEQ ID NO：27的氨基酸序列，和所述轻链包含SEQ ID NO：28的氨基酸序列；或
    所述重链包含SEQ ID NO：221的氨基酸序列，和所述轻链包含SEQ ID NO：222的氨基酸序列；
    更优选地，
    (1)所述重链包含SEQ ID NO：211的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
    所述重链包含SEQ ID NO：29的氨基酸序列，和所述轻链包含SEQ ID NO：30的氨基酸序列；或
    所述重链包含SEQ ID NO：204的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
    所述重链包含SEQ ID NO：205的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
    所述重链包含SEQ ID NO：207的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
    所述重链包含SEQ ID NO：205的氨基酸序列，和所述轻链包含SEQ ID NO：214的氨基酸序列；或
    所述重链包含SEQ ID NO：223的氨基酸序列，和所述轻链包含SEQ ID NO：224的氨基酸序列；或
    所述重链包含SEQ ID NO：206、208、209或210的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
    所述重链包含SEQ ID NO：204、205、206、207、208、209、210或211的氨基酸序列，和所述轻链包含SEQ ID NO：213的氨基酸序列；或
    所述重链包含SEQ ID NO：204、206、207、208、209、210或211的氨基酸序列，和所述轻链包含SEQ ID NO：214的氨基酸序列；或
    (2)所述重链包含SEQ ID NO：169的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
    所述重链包含SEQ ID NO：25的氨基酸序列，和所述轻链包含SEQ ID NO：26的氨基酸序列；或
    所述重链包含SEQ ID NO：143的氨基酸序列，和所述轻链包含SEQ ID NO：175的氨基酸序列；或
    所述重链包含SEQ ID NO：146的氨基酸序列，和所述轻链包含SEQ ID NO：176的氨基酸序列；或
    所述重链包含SEQ ID NO：143的氨基酸序列，和所述轻链包含SEQ ID NO：177的氨基酸序列；或
    所述重链包含SEQ ID NO：150的氨基酸序列，和所述轻链包含SEQ ID NO：177的氨基酸序列；或
    所述重链包含SEQ ID NO：150的氨基酸序列，和所述轻链包含SEQ ID NO：182的氨基酸序列；或
    所述重链包含SEQ ID NO：150的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
    所述重链包含SEQ ID NO：159的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
    所述重链包含SEQ ID NO：160的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
    所述重链包含SEQ ID NO：161的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
    所述重链包含SEQ ID NO：172的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
    所述重链包含SEQ ID NO：219的氨基酸序列，和所述轻链包含SEQ ID NO：220的氨基酸序列；或
    所述重链包含SEQ ID NO：144、145、146或147的氨基酸序列，和所述轻链包含SEQ ID NO：175的氨基酸序列；或
    所述重链包含SEQ ID NO：143、144、145或147的氨基酸序列，和所述轻链包含SEQ ID NO：176的氨基酸序列；或
    所述重链包含SEQ ID NO：144、145、146、147、148、149、151、152、153、154、155、156、157或158的氨基酸序列，和所述轻链包含SEQ ID NO：177的氨基酸序列；或
    所述重链包含SEQ ID NO：143、144、145、146或147的氨基酸序列，和所述轻链包含SEQ ID NO：178的氨基酸序列；或
    所述重链包含SEQ ID NO：143、144、145、146或147的氨基酸序列，和所述轻链包含SEQ ID NO：179的氨基酸序列；或
    所述重链包含SEQ ID NO：146、147或150的氨基酸序列，和所述轻链包含SEQ ID NO：180的氨基酸序列；或
    所述重链包含SEQ ID NO：146、147或150的氨基酸序列，和所述轻链包含SEQ ID NO：181的氨基酸序列；或
    所述重链包含SEQ ID NO：146或147的氨基酸序列，和所述轻链包含SEQ ID NO：182的氨基酸序列；或
    所述重链包含SEQ ID NO：146、147、162、163、164、165、166、167、168、170、171、173或174的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
    (3)所述重链包含SEQ ID NO：192的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
    所述重链包含SEQ ID NO：27的氨基酸序列，和所述轻链包含SEQ ID NO：28的氨基酸序列；或
    所述重链包含SEQ ID NO：185的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
    所述重链包含SEQ ID NO：187的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
    所述重链包含SEQ ID NO：189的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
    所述重链包含SEQ ID NO：195的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
    所述重链包含SEQ ID NO：221的氨基酸序列，和所述轻链包含SEQ ID NO：222的氨基酸序列；或
    所述重链包含SEQ ID NO：184、186、188、190、191、193、194、196、197、198、199、200或201的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列；或
    所述重链包含SEQ ID NO：184、185、186、187、188、189、190、191、192、193、194、195、196、197、198、199、200或201的氨基酸序列，和所述轻链包含SEQ ID NO：203的氨基酸序列；
    最优选地，
    (1)所述重链包含SEQ ID NO：211的氨基酸序列，和所述轻链包含SEQ ID NO：212的氨基酸序列；或
    (2)所述重链包含SEQ ID NO：169的氨基酸序列，和所述轻链包含SEQ ID NO：183的氨基酸序列；或
    (3)所述重链包含SEQ ID NO：192的氨基酸序列，和所述轻链包含SEQ ID NO：202的氨基酸序列。
  6. 根据权利要求1至3中任一项所述的抗N3pGlu Aβ抗体，其中所述抗N3pGlu Aβ抗体是抗原结合片段；
    优选地，所述的抗原结合片段选自Fab、Fab′、F(ab′)2、Fd、Fv、scFv和dsFv。
  7. 一种药物组合物，其包含权利要求1至6中任一项所述的抗N3pGlu Aβ抗体，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  8. 一种分离的核酸，其编码权利要求1至6中任一项所述的抗N3pGlu Aβ抗体。
  9. 一种宿主细胞，其包含权利要求8中所述的分离的核酸。
  10. 一种用于生产权利要求1至6中任一项所述的抗N3pGlu Aβ抗体的方法，所述方法包括将权利要求9中所述的宿主细胞在培养基中进行培养以形成并积累权利要求1至6中任一项所述的抗N3pGlu Aβ抗体，以及从培养物回收所述抗体的步骤。
  11. 一种治疗或预防与N3pGlu Aβ相关的疾病或病症的方法，所述方法包括向受试者施用治疗或预防有效量的权利要求1至6中任一项所述的抗N3pGlu Aβ抗体，或权利要求7中所述的药物组合物；
    优选地，所述与N3pGlu Aβ相关的疾病或病症为神经系统疾病、退行性疾病或脑血管病；
    更优选地，所述与N3pGlu Aβ相关的疾病或病症为阿尔茨海默病、认知障碍或脑淀粉样蛋白血管病；
    最优选地，所述与N3pGlu Aβ相关的疾病或病症为阿尔茨海默病。
PCT/CN2025/095336 2024-05-16 2025-05-16 抗N3pGlu Aβ抗体及其医药用途 Pending WO2025237397A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410608148 2024-05-16
CN202410608148.7 2024-05-16

Publications (1)

Publication Number Publication Date
WO2025237397A1 true WO2025237397A1 (zh) 2025-11-20

Family

ID=97719386

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/095336 Pending WO2025237397A1 (zh) 2024-05-16 2025-05-16 抗N3pGlu Aβ抗体及其医药用途

Country Status (1)

Country Link
WO (1) WO2025237397A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068848A (zh) * 2010-08-12 2013-04-24 伊莱利利公司 抗N3pGlu淀粉样蛋白BETA肽抗体及其用途
AU2014233615A1 (en) * 2010-08-12 2014-10-16 Eli Lilly And Company Anti-N3pGlu Amyloid Beta Peptide Antibodies And Uses Thereof
CN108473566A (zh) * 2016-01-15 2018-08-31 伊莱利利公司 抗N3pGlu淀粉样蛋白β肽抗体及其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068848A (zh) * 2010-08-12 2013-04-24 伊莱利利公司 抗N3pGlu淀粉样蛋白BETA肽抗体及其用途
US20130142806A1 (en) * 2010-08-12 2013-06-06 Eli Lilly And Company ANTI-N3pGlu AMYLOID BETA PEPTIDE ANTIBODIES AND USES THEREOF
AU2014233615A1 (en) * 2010-08-12 2014-10-16 Eli Lilly And Company Anti-N3pGlu Amyloid Beta Peptide Antibodies And Uses Thereof
CN108473566A (zh) * 2016-01-15 2018-08-31 伊莱利利公司 抗N3pGlu淀粉样蛋白β肽抗体及其用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE PROTEIN 17 January 2024 (2024-01-17), XP093374682, Database accession no. 5MY4_B *
DATABASE PROTEIN 8 May 2024 (2024-05-08), XP093374683, Database accession no. 8YX9_C *
DATABASE PROTEIN 8 November 2023 (2023-11-08), XP093374686, Database accession no. 4LKX_B *

Similar Documents

Publication Publication Date Title
CN108503708B (zh) 抗人cd47抗体及其用途
WO2019238012A1 (zh) 可以阻断CD47和SIRPa相互作用的抗体及其应用
WO2019062832A1 (zh) Tigit抗体、其抗原结合片段及医药用途
KR102942600B1 (ko) 항-pd-1 항체, 이의 항원-결합 단편 및 이의 약학적 용도
US20220185875A1 (en) Bispecific antibody specifically bound to vegf and ang2
WO2019091449A1 (zh) Cd96抗体、其抗原结合片段及医药用途
WO2023208182A1 (zh) 抗ccr8抗体及其用途
US20250376519A1 (en) Antigen-binding molecule specifically binding to dll3 and cd3, and pharmaceutical use thereof
EP4696711A1 (en) Antigen binding molecule specifically binding to egfr and muc1, drug conjugate thereof, and medical use thereof
US20250215083A1 (en) Antigen-binding molecule specifically binding to gprc5d and cd3 and medical use thereof
TW202246333A (zh) 特異性結合ｂｃｍａ和ｃｄ３的抗原結合分子及其醫藥用途
US20260028421A1 (en) Antigen-binding molecule specifically binding to gucy2c and cd3 and pharmaceutical use thereof
US20250043022A1 (en) Antigen-binding molecule specifically binding to psma and cd3, and pharmaceutical use thereof
CN115850499A (zh) 特异性结合angptl3和pcsk9的抗原结合分子及其医药用途
WO2023051798A1 (zh) 抗il23抗体融合蛋白及用途
WO2025237397A1 (zh) 抗N3pGlu Aβ抗体及其医药用途
TW202613161A (zh) 抗Ｎ３ｐＧｌｕ Ａβ抗體及其醫藥用途
EP4585618A1 (en) Anti-ilt4 antibody and pharmaceutical use thereof
WO2026008055A1 (zh) 抗kit抗体及其医药用途
WO2026077408A1 (zh) 特异性结合ox40和/或il-13的抗原结合分子及其医药用途
WO2026057014A1 (zh) 抗b7-h3抗体及其医药用途
TW202504927A (zh) 抗ｎｐｒ１抗體及其醫藥用途
WO2026008041A1 (zh) 特异性结合潜伏肌生长抑制素的抗原结合分子及其医药用途
WO2023165514A1 (zh) 特异性结合flt3和cd3的抗原结合分子及其医药用途
WO2025113639A1 (zh) 抗gdf15的抗体及其方法和用途

Legal Events

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

Ref document number: 25803071

Country of ref document: EP

Kind code of ref document: A1